The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony

A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for ≥6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria

Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies

PURPOSE: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2'-position of paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of DHA-paclitaxel. EXPERIMENTAL DESIGN: The blood distribution of DHA-paclitaxel was studied in vitro using equilibrium dialysis and in 23 cancer patients receiving the drug as a 2-h i.v. infusion (dose, 200-1100 mg/m(2)). RESULTS: In vitro, DHA-paclitaxel was found to bind extensively to human plasma (99.6 +/- 0.057%). The binding was concentration independent (P = 0.63), indicating a nonspecific, nonsaturable process. The fraction of unbound paclitaxel increased from 0.052 +/- 0.0018 to 0.055 +/- 0.0036 (relative increase, 6.25%; P = 0.011) with an increase in DHA-paclitaxel concentration (0-1000 microg/ml), suggesting weakly competitive drug displacement from protein-binding sites. The mean (+/- SD) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 +/- 0.029 microg.h/ml (at 660 mg/m(2)) to 0.624 +/- 0.216 microg.h/ml (at 1100 mg/m(2)), and was associated with the dose-limiting neutropenia in a maximum-effect model (R(2) = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m(2)) is similar to that achieved with paclitaxel on clinically relevant dose schedules. CONCLUSIONS: Extensive binding to plasma proteins may explain, in part, the unique pharmacokinetic profile of DHA-paclitaxel described previously with a small volume of distribution ( approximately 4 liters) and slow systemic clearance ( approximately 0.11 liters/h)

A global map to aid the identification and screening of critical habitat for marine industries

Marine industries face a number of risks that necessitate careful analysis prior to making decisions on the siting of operations and facilities. An important emerging regulatory framework on environmental sustainability for business operations is the International Finance Corporation’s Performance Standard 6 (IFC PS6). Within PS6, identification of biodiversity significance is articulated through the concept of “Critical Habitat”, a definition developed by the IFC and detailed through criteria aligned with those that support internationally accepted biodiversity designations. No publicly available tools have been developed in either the marine or terrestrial realm to assess the likelihood of sites or operations being located within PS6-defined Critical Habitat. This paper presents a starting point towards filling this gap in the form of a preliminary global map that classifies more than 13 million km2 of marine and coastal areas of importance for biodiversity (protected areas, Key Biodiversity Areas [KBA], sea turtle nesting sites, cold- and warm-water corals, seamounts, seagrass beds, mangroves, saltmarshes, hydrothermal vents and cold seeps) based on their overlap with Critical Habitat criteria, as defined by IFC. In total, 5798×103 km2 (1.6%) of the analysis area (global ocean plus coastal land strip) were classed as Likely Critical Habitat, and 7526×103 km2 (2.1%) as Potential Critical Habitat; the remainder (96.3%) were Unclassified. The latter was primarily due to the paucity of biodiversity data in marine areas beyond national jurisdiction and/or in deep waters, and the comparatively fewer protected areas and KBAs in these regions. Globally, protected areas constituted 65.9% of the combined Likely and Potential Critical Habitat extent, and KBAs 29.3%, not accounting for the overlap between these two features. Relative Critical Habitat extent in Exclusive Economic Zones varied dramatically between countries. This work is likely to be of particular use for industries operating in the marine and coastal realms as an early screening aid prior to in situ Critical Habitat assessment; to financial institutions making investment decisions; and to those wishing to implement good practice policies relevant to biodiversity management. Supplementary material (available online) includes other global datasets considered, documentation and justification of biodiversity feature classification, detail of IFC PS6 criteria/scenarios, and coverage calculations

Slavnov-Taylor identities in Coulomb gauge Yang-Mills theory

The Slavnov-Taylor identities of Coulomb gauge Yang-Mills theory are derived from the (standard, second order) functional formalism. It is shown how these identities form closed sets from which one can in principle fully determine the Green's functions involving the temporal component of the gauge field without approximation, given appropriate input.Comment: 20 pages, no figure

Genomic evidence for distinct carbon substrate preferences and ecological niches of Bathyarchaeota in estuarine sediments

Investigations of the biogeochemical roles of benthic Archaea in marine sediments are hampered by the scarcity of cultured representatives. In order to determine their metabolic capacity, we reconstructed the genomic content of four widespread uncultured benthic Archaea recovered from estuary sediments at 48% to 95% completeness. Four genomic bins were found to belong to different subgroups of the former Miscellaneous Crenarcheota Group (MCG) now called Bathyarchaeota: MCG-6, MCG-1, MCG-7/17 and MCG-15. Metabolic predictions based on gene content of the different genome bins indicate that subgroup 6 has the ability to hydrolyse extracellular plant-derived carbohydrates, and that all four subgroups can degrade detrital proteins. Genes encoding enzymes involved in acetate production as well as in the reductive acetyl-CoA pathway were detected in all four genomes inferring that these Archaea are organo-heterotrophic and autotrophic acetogens. Genes involved in nitrite reduction were detected in all Bathyarchaeota subgroups and indicate a potential for dissimilatory nitrite reduction to ammonium. Comparing the genome content of the different Bathyarchaeota subgroups indicated preferences for distinct types of carbohydrate substrates and implicitly, for different niches within the sedimentary environment

The orbit rigidity matrix of a symmetric framework

A number of recent papers have studied when symmetry causes frameworks on a graph to become infinitesimally flexible, or stressed, and when it has no impact. A number of other recent papers have studied special classes of frameworks on generically rigid graphs which are finite mechanisms. Here we introduce a new tool, the orbit matrix, which connects these two areas and provides a matrix representation for fully symmetric infinitesimal flexes, and fully symmetric stresses of symmetric frameworks. The orbit matrix is a true analog of the standard rigidity matrix for general frameworks, and its analysis gives important insights into questions about the flexibility and rigidity of classes of symmetric frameworks, in all dimensions. With this narrower focus on fully symmetric infinitesimal motions, comes the power to predict symmetry-preserving finite mechanisms - giving a simplified analysis which covers a wide range of the known mechanisms, and generalizes the classes of known mechanisms. This initial exploration of the properties of the orbit matrix also opens up a number of new questions and possible extensions of the previous results, including transfer of symmetry based results from Euclidean space to spherical, hyperbolic, and some other metrics with shared symmetry groups and underlying projective geometry.Comment: 41 pages, 12 figure

Possible background reductions in double beta decay experiments

The background induced by radioactive impurities of $^{208}\rm Tl$ and $^{214}\rm Bi$ in the source of the double beta experiment NEMO-3 has been investigated. New methods of data analysis which decrease the background from the above mentioned contamination are identified. The techniques can also be applied to other double beta decay experiments capable of measuring independently the energies of the two electrons.Comment: 15 pages, 13 figures, accepted in the Nuclear Instruments and Methods

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

Merger of binary neutron stars of unequal mass in full general relativity

We present results of three dimensional numerical simulations of the merger of unequal-mass binary neutron stars in full general relativity. A $\Gamma$-law equation of state $P=(\Gamma-1)\rho\epsilon$ is adopted, where $P$, $\rho$, \varep, and $\Gamma$ are the pressure, rest mass density, specific internal energy, and the adiabatic constant, respectively. We take $\Gamma=2$ and the baryon rest-mass ratio $Q_M$ to be in the range 0.85--1. The typical grid size is $(633,633,317)$ for $(x,y,z)$ . We improve several implementations since the latest work. In the present code, the radiation reaction of gravitational waves is taken into account with a good accuracy. This fact enables us to follow the coalescence all the way from the late inspiral phase through the merger phase for which the transition is triggered by the radiation reaction. It is found that if the total rest-mass of the system is more than $\sim 1.7$ times of the maximum allowed rest-mass of spherical neutron stars, a black hole is formed after the merger irrespective of the mass ratios. The gravitational waveforms and outcomes in the merger of unequal-mass binaries are compared with those in equal-mass binaries. It is found that the disk mass around the so formed black holes increases with decreasing rest-mass ratios and decreases with increasing compactness of neutron stars. The merger process and the gravitational waveforms also depend strongly on the rest-mass ratios even for the range $Q_M= 0.85$--1.Comment: 32 pages, PRD68 to be publishe