Phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes

Background \ud Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin– like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four \ud Caenorhabditis species. \ud \ud Methodology/Principal Findings \ud We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged \ud significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions \ud The gonochoristic species display a significantly longer lifespan (p < 0.0001)and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

Phenotypic covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes

Background: Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. \ud \ud Methodology/Principal Findings: We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions: The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

PocketWATCH: design and operation of a multi-use test bed for water Cherenkov detector components in pure and gadolinium loaded water

The PocketWATCH facility is a unique multi-purpose test bed designed to replicate the conditions of large water Cherenkov detectors. Housed at the University of Sheffield, the facility consists of a light-tight 2000 L ultrapure water tank with purification and temperature control systems. Water temperature, resistivity, and UV attenuation in the tank are monitored and shown to be stable over time. The system is also shown to be compatible with a solution of 0.2% gadolinium sulfate, allowing further utility in testing equipment bound for the next generation neutrino and nucleon decay water Cherenkov particle detectors. The relevant water quality parameters are shown to be stable whilst running in Gd-mode, thereby providing a suitable test bed for hardware development in a realistic, ex situ environment

Implications of transient methane flux on associated biological communities in high-arctic seep habitats, Storbanken, Norwegian Barents sea

The continental margins of the Arctic Ocean basin contain methane seeps, where transient fluxes of seafloor methane are released due to the thermal dissociation of gas hydrates. An increase in shallow methane seeps identified over the past decade, potentially due to enhanced warming of the Arctic Ocean bottom water and associated destabilization of hydrate structure. Biological communities associated with methane release east of Svalbard in the Barents Sea (Storbanken Crater site, 76° 46.7′N, 35° 43.5′E, depths between 120 m–300 m depths) were investigated using towed camera imagery and ship-based platforms during a 2017 CAGE17-2 cruise on the RV Helmer Hanssen. We analyzed relationships among methane flux data, seafloor habitat characteristics, and biological community structure (i.e., presence and distribution of megafauna and expression of microbial mats) from a total of 14 surveys (6827 images and 40 multicore sediment cores) within the Storbanken Crater area and compared it to 2015 data. Unlike seep expressions at deeper sites (∼1200 m) in the Norwegian margin region, no seep-endemic, chemosynthetic-associated megafaunal species were observed at the shallow surveyed sites and all sites hosted similarly diverse communities of non-seep species, including commercially important fish and crustaceans. Methane concentrations did not markedly differ between the crater and non-crater sites. Rates of methane gas advection through sediments (in the form of flares) were relatively low and concentration of methane was even lower in porewater samples at the crater site. We present the first evidence of methane flare flux and intermittent microbial mat distribution with associated folliculinid ciliates, which suggests a long history of methane emissions and a transient seep environment in spatial and temporal flux. Together, this study presents a critical baseline on the temporal release of arctic methane and benthic biological communities to initiate temporal studies that identify future changes and predict the impact of climate chang

PocketWATCH: Design and operation of a multi-use test bed for water Cherenkov detector components in pure and gadolinium loaded water

The PocketWATCH facility is a unique multi-purpose test bed designed to replicate the conditions of large water Cherenkov detectors. Housed at the University of Sheffield, the facility consists of a light-tight 2000L ultrapure water tank with purification and temperature control systems. Water temperature, resistivity, and UV attenuation in the tank are monitored and shown to be stable over time. The system is also shown to be compatible with a solution of 0.2% gadolinium sulfate, allowing further utility in testing equipment bound for the next generation neutrino and nucleon decay water Cherenkov particle detectors. The relevant water quality parameters are shown to be stable whilst running in Gd-mode, thereby providing a suitable test bed for hardware development in a realistic, ex situ environment

The use of a centrifugal contactor for component concentration by solvent extraction

Theoretical and experimental work was undertaken to explore the use of the Argonne design centrifugal contactor as a concentrating device for metal ions in solutions such as transuranic-containing waste streams and contaminated groundwater. First, the theoretical basis for operating the contactor as a concentrator was developed. Then, the ability of the contactor to act as a concentrating device was experimentally demonstrated with neodymium over a wide range of organic-to-aqueous (O/A) flow ratios (0.01 to 33). These data were also used to derive a correlation for the effect of O/A flow ratio on extraction efficiency

Evolutionary conservation of regulated longevity assurance mechanisms

Short abstract: A multi-level cross-species comparative analysis of gene-expression changes accompanying increased longevity in mutant nematodes, fruit flies and mice with reduced insulin/IGF-1 signaling revealed candidate conserved mechanisms

REDD+ on the rocks? Conflict over forest and politics of justice in Vietnam

In Vietnam, villagers involved in a REDD+ (reduced emissions from deforestation and forest degradation) pilot protect areas with rocks which have barely a tree on them. The apparent paradox indicates how actual practices differ from general ideas about REDD+ due to ongoing conflict over forest, and how contestations over the meaning of justice are a core element in negotiations over REDD+. We explore these politics of justice by examining how the actors involved in the REDD+ pilot negotiate the particular subjects, dimensions, and authority of justice considered relevant, and show how politics of justice are implicit to practical decisions in project implementation. Contestations over the meaning of justice are an important element in the practices and processes constituting REDD+ at global, national and local levels, challenging uniform definitions of forest justice and how forests ought to be managed

Fibroblast cell-based therapy prevents induction of alopecia areata in an experimental model

YesAlopecia areata (AA) is an autoimmune hair loss disease with infiltration of proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory mainly because of the potential for side effects and/or limited efficacy. Here we report that cultured, transduced fibroblasts, which express the immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal fibroblasts was given to C3H/HeJ mice at the time of AA induction. While 60–70% of mice that received either control fibroblasts or vehicle injections developed extensive AA, none of the IDO-expressing fibroblast-treated mice showed new hair loss up to 20 weeks post injection. IDO cell therapy significantly reduced infiltration of CD4+ and CD8+ T cells into hair follicles and resulted in decreased expression of TNF-α, IFN-γ and IL-17 in the skin. Skin draining lymph nodes of IDO fibroblast-treated mice were significantly smaller, with more CD4+ CD25+ FoxP3+ regulatory T cells and fewer Th17 cells than those of control fibroblast and vehicle-injected mice. These findings indicate that IP injected IDO-expressing dermal fibroblasts can control inflammation and thereby prevent AA hair loss.Canadian Institutes of Health Researches (Funding Reference Number: 134214 and 136945)

UGT2B17 Genetic Polymorphisms Dramatically Affect the Pharmacokinetics of MK-7246 in Healthy Subjects in a First-in-Human Study

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration–time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246