Interspecies Differences in the Metabolism of a Multiester Prodrug by Carboxylesterases

The penta-ethyl ester prodrug of the chelating agent diethylene triamine pentaacetic acid (DTPA) referred to as C2E5, is being developed as an orally bioavailable radionuclide decorporation agent. The predicted human efficacy obtained in these experimental animals is confounded by interspecies variations of metabolism. Therefore, in the present study, carboxylesterase-mediated metabolism of [14C]-C2E5 was compared in the S9 intestinal and hepatic fractions of human, dog and rat and their respective plasma. Intestinal hydrolysis of C2E5, resulting in the formation of the tetraethyl ester of DTPA (C2E4), was only detected in human and rat. The primary metabolite in human and dog hepatic fractions was C2E4 whereas the predominant species identified in rat hepatic fractions was the triethyl ester (C2E3). Hepatic hydrolysis of C2E5 causes the formation of C2E4 in human, dog and rat and C2E3 in rat only. Minimal C2E5 hydrolysis was observed in human and dog plasma whereas in rat plasma C2E5 converted to C2E3 rapidly, followed by slower further metabolism. Both recombinant CES1 and CES2 play roles in C2E5 metabolism. Together, these data suggest that dogs may be the most appropriate species for predicting human C2E5 metabolism whereas rats might be useful for clarifying the potential toxicity of C2E5 metabolites

The citric acid cough threshold and the ventilatory response to carbon dioxide on ascent to high altitude

SummaryVentilatory control undergoes profound changes on ascent to high altitude. We hypothesized that the fall in citric acid cough threshold seen on ascent to altitude is mediated by changes in the central control of cough and would parallel changes in central ventilatory control assessed by the hypercapnic ventilatory response (HCVR). Twenty-five healthy volunteers underwent measurements of HCVR and citric acid sensitivity at sea level and during a 9 day sojourn at 5200m. None of the subjects had any evidence of respiratory infection. Citric acid cough threshold fell significantly on ascent to 5200m. The slope, S, of the HCVR increased significantly on ascent to 5200m and during the stay at altitude. There was no correlation between citric acid sensitivity and HCVR. We conclude that the change in citric acid cough threshold seen on exposure to hypobaric hypoxia is unlikely to be mediated by changes in the central control of cough. Sensitivity to citric acid may be due to early subclinical pulmonary edema stimulating airway sensory nerve endings

Orally Administered DTPA Penta-Ethyl Ester for the Decorporation of Inhaled 241Am

Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [14C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared to a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of 241Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of 241Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized

Suppressed basal melting in the eastern Thwaites Glacier grounding zone

This work is from the MELT project, a component of the International Thwaites Glacier Collaboration (ITGC). Support from the National Science Foundation (NSF, grant no. 1739003) and the Natural Environment Research Council (NERC, grant no. NE/S006656/1). Logistics provided by NSF U.S. Antarctic Program and NERC British Antarctic Survey. The ship-based CTD data were supported by the ITGC TARSAN project (NERC grant nos. NE/S006419/1 and NE/S006591/1; NSF grant no. 1929991). ITGC contribution no. ITGC 047.Thwaites Glacier is one of the fastest-changing ice–ocean systems in Antarctica1,2,3. Much of the ice sheet within the catchment of Thwaites Glacier is grounded below sea level on bedrock that deepens inland4, making it susceptible to rapid and irreversible ice loss that could raise the global sea level by more than half a metre2,3,5. The rate and extent of ice loss, and whether it proceeds irreversibly, are set by the ocean conditions and basal melting within the grounding-zone region where Thwaites Glacier first goes afloat3,6, both of which are largely unknown. Here we show—using observations from a hot-water-drilled access hole—that the grounding zone of Thwaites Eastern Ice Shelf (TEIS) is characterized by a warm and highly stable water column with temperatures substantially higher than the in situ freezing point. Despite these warm conditions, low current speeds and strong density stratification in the ice–ocean boundary layer actively restrict the vertical mixing of heat towards the ice base7,8, resulting in strongly suppressed basal melting. Our results demonstrate that the canonical model of ice-shelf basal melting used to generate sea-level projections cannot reproduce observed melt rates beneath this critically important glacier, and that rapid and possibly unstable grounding-line retreat may be associated with relatively modest basal melt rates.Publisher PDFPeer reviewe

History and Applications of Dust Devil Studies

Studies of dust devils, and their impact on society, are reviewed. Dust devils have been noted since antiquity, and have been documented in many countries, as well as on the planet Mars. As time-variable vortex entities, they have become a cultural motif. Three major stimuli of dust devil research are identified, nuclear testing, terrestrial climate studies, and perhaps most significantly, Mars research. Dust devils present an occasional safety hazard to light structures and have caused several deaths

The New Look pMSSM with Neutralino and Gravitino LSPs

The pMSSM provides a broad perspective on SUSY phenomenology. In this paper we generate two new, very large, sets of pMSSM models with sparticle masses extending up to 4 TeV, where the lightest supersymmetric particle (LSP) is either a neutralino or gravitino. The existence of a gravitino LSP necessitates a detailed study of its cosmological effects and we find that Big Bang Nucleosynthesis places strong constraints on this scenario. Both sets are subjected to a global set of theoretical, observational and experimental constraints resulting in a sample of \sim 225k viable models for each LSP type. The characteristics of these two model sets are briefly compared. We confront the neutralino LSP model set with searches for SUSY at the 7 TeV LHC using both the missing (MET) and non-missing ET ATLAS analyses. In the MET case, we employ Monte Carlo estimates of the ratios of the SM backgrounds at 7 and 8 TeV to rescale the 7 TeV data-driven ATLAS backgrounds to 8 TeV. This allows us to determine the pMSSM parameter space coverage for this collision energy. We find that an integrated luminosity of \sim 5-20 fb^{-1} at 8 TeV would yield a substantial increase in this coverage compared to that at 7 TeV and can probe roughly half of the model set. If the pMSSM is not discovered during the 8 TeV run, then our model set will be essentially void of gluinos and lightest first and second generation squarks that are \lesssim 700-800 GeV, which is much less than the analogous mSUGRA bound. Finally, we demonstrate that non-MET SUSY searches continue to play an important role in exploring the pMSSM parameter space. These two pMSSM model sets can be used as the basis for investigations for years to come.Comment: 54 pages, 22 figures; typos fixed, references adde

Suppressed basal melting in the eastern Thwaites Glacier grounding zone

Thwaites Glacier is one of the fastest-changing ice–ocean systems in Antarctica1,2,3. Much of the ice sheet within the catchment of Thwaites Glacier is grounded below sea level on bedrock that deepens inland4, making it susceptible to rapid and irreversible ice loss that could raise the global sea level by more than half a metre2,3,5. The rate and extent of ice loss, and whether it proceeds irreversibly, are set by the ocean conditions and basal melting within the grounding-zone region where Thwaites Glacier first goes afloat3,6, both of which are largely unknown. Here we show—using observations from a hot-water-drilled access hole—that the grounding zone of Thwaites Eastern Ice Shelf (TEIS) is characterized by a warm and highly stable water column with temperatures substantially higher than the in situ freezing point. Despite these warm conditions, low current speeds and strong density stratification in the ice–ocean boundary layer actively restrict the vertical mixing of heat towards the ice base7,8, resulting in strongly suppressed basal melting. Our results demonstrate that the canonical model of ice-shelf basal melting used to generate sea-level projections cannot reproduce observed melt rates beneath this critically important glacier, and that rapid and possibly unstable grounding-line retreat may be associated with relatively modest basal melt rates

Continent-wide genomic analysis of the African buffalo (<i>Syncerus caffer</i>)

AbstractThe African buffalo (Syncerus caffer) is a wild bovid with a historical distribution across much of sub-Saharan Africa. Genomic analysis can provide insights into the evolutionary history of the species, and the key selective pressures shaping populations, including assessment of population level differentiation, population fragmentation, and population genetic structure. In this study we generated the highest qualityde novogenome assembly (2.65 Gb, scaffold N50 69.17 Mb) of African buffalo to date, and sequenced a further 195 genomes from across the species distribution. Principal component and admixture analyses provided surprisingly little support for the currently described four subspecies, but indicated three main lineages, in Western/Central, Eastern and Southern Africa, respectively. Estimating Effective Migration Surfaces analysis suggested that geographical barriers have played a significant role in shaping gene flow and the population structure. Estimated effective population sizes indicated a substantial drop occurring in all populations 5-10,000 years ago, coinciding with the increase in human populations. Finally, signatures of selection were enriched for key genes associated with the immune response, suggesting infectious disease exert a substantial selective pressure upon the African buffalo. These findings have important implications for understanding bovid evolution, buffalo conservation and population management

Politics ahead of patients: The battle between medical and chiropractic professional associations over the inclusion of chiropractic in the American Medicare System

Health care professions struggling for legitimacy, recognition, and market share can become disoriented to their priorities. Health care practitioners are expected to put the interests of patients first. Professional associations represent the interests of their members. So when a professional association is composed of health care practitioners, its interests may differ from those of patients, creating a conflict for members. In addition, sometimes practitioners’ perspectives may be altered by indoctrination in a belief system, or misinformation, so that a practitioner could be confused about the reality of patient needs. Politicians, in attempting to find an expedient compromise, can value a “win” in the legislative arena over the effects of that legislation. These forces all figure into the events that led to the acceptance of chiropractic into the American Medicare system. Two health care systems in a political fight lost sight of their main purpose: to provide care to patients without doing harm. Dans leur recherche de légitimité, de reconnaissance et d’une juste part sur le marché de la santé, les professionnels de la santé peuvent perdre de vue leurs priorités. Ces praticiens doivent donner préséance aux intérêts des patients tandis que les associations professionnelles représentent ceux de leurs membres. Lorsqu’une association professionnelle regroupe des praticiens de la santé cependant, ses intérêts s’opposent parfois à ceux des patients, créant ainsi un conflit pour les membres. De plus, les praticiens peuvent être endoctrinés par un système de valeurs ou mal informés, au point de se tromper dans l’évaluation des besoins réels des patients. De leur côté, les politiciens peuvent préférer une « victoire » dans l’arène législative à une juste appréciation des impacts d’une loi. Ces forces ont toutes participé aux évènements qui ont mené à l’acceptation de la chiropraxie par le système américain Medicare. Dans cette bataille politique, deux systèmes de santé ont négligé leur principal objectif : soigner des patients sans leur nuire

The past and future(s) of environmental peacebuilding

Environmental peacebuilding is a rapidly growing field of research and practice at the intersection of environment, conflict, peace and security. Focusing on these linkages is crucial in a time when the environment is a core issue of international politics and the number of armed conflicts remains high. This article introduces a special issue with a particular emphasis on environmental opportunities for building and sustaining peace. We first detail the definitions, theoretical assumptions and intellectual background of environmental peacebuilding. The article then provides context for the special issue by briefly reviewing core findings and debates of the first two generations of environmental peacebuilding research. Finally, we identify knowledge gaps that should be addressed in the next generation of research, and to which the articles in this special issue contribute: bottom-up approaches, gender, conflict-sensitive programming, use of big data and frontier technology, and monitoring and evaluation