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Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.

Droplet impingement of metallic surfaces at high impact velocities results, after some time, in erosion of the surface due to fatigue. By extending our previously published analytical model to enable the use of experimental fatigue data (S-N curves), here, for the first time, a wide range of experimental liquid droplet erosion incubation period test states for both ferrous (stainless steel AISI 316) and non-ferrous (aluminium 6061-T6) engineering metals have been investigated. To achieve this, the developed model includes additional surface hardening and a residual compressive stress state at the surface due to a water drop peening effect. As such, the interrelation of the physical and mechanical properties that follows from the model has been used to identify how changes in selected metal properties might enhance droplet impingement erosion incubation life. Model predictions for both metals, using fatigue data from S-N curves from different literature sources, showed for the droplet impact velocity range of 140 to 400 m/s an excellent agreement with results from a multi-regression equation as determined from an ASTM interlaboratory test program.

MotivationWith high-throughput genotyping systems now available, it has become feasible to fully integration genotyping information into breeding programs [22]. To make use of this information effectively requires DNA extraction facilities and marker production facilities that can efficiently deploy the desired set of markers across samples with a rapid turnaround time that allows for selection before crosses needed to be made. In reality, breeders often have a short window of time to make decisions by the time they are able collect all their phenotyping data and receive corresponding genotyping data. This presents a challenge to organize information and utilize them in downstream analyses to support decisions made by breeders. In order to implement genomic selection routinely as part of breeding programs one would need an efficient genotype data storage system. We selected and benchmarked six popular open-source data storage systems, including relational database management and columnar storage systems.ResultsWe found that data extract times are greatly influenced by the orientation in which genotype data is stored in a system. HDF5 consistently performed best, in part because it can more efficiently work with both orientations of the allele matrix.Availabilityhttp://gobiinx1.bti.cornell.edu:6083/projects/GBM/repos/benchmarking/browseContactyn259@cornell.edu

The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.

Numerous papers discuss the mechanism of alkaline oxidation of pyrite but there is limited information available describing the actual kinetics of the pyrite sulphide to thiosulphate reaction. A previous investigation in this series determined the rate of sulphide sulphur oxidation and thiosulphate yield in the reaction of pyrite with sodium hydroxide under various testing conditions. The goal of the current study is to validate these rates using two different gold-containing pyrite concentrates. A further objective of the current work is to investigate the simultaneous dissolution of gold with in situ formed thiosulphate during pyrite oxidation. It was found that at 20 psi oxygen overpressure and a temperature of 80 °C, the initial rate of sulphide oxidation and thiosulphate yield were close to 0.08 mol/h and 0.0155 mol/h, respectively. These rates are in agreement with previously published data. However, a shift from linearity occurred when the pH decreased below 12. A rapid decay of thiosulphate was evidenced at pH 8.3–9.2 while E H was in the range of 22–141 mV. Based on relevant thermodynamic analysis of metastable thiosalts system, such rapid decomposition is not expected at these pH and E H values. It is believed that the presence of unreacted pyrite acting as a catalyst caused this behaviour. It appears that under mildly alkaline conditions, the rate of oxidation of sulphide to thiosulphate becomes slower than the rate of thiosulphate degradation, which causes a net loss of thiosulphate in the system. The maximum extraction of gold and silver (96% and 75% respectively) was achieved under conditions of pH

Motivation Modern genomic breeding methods rely heavily on very large amounts of phenotyping and genotyping data, presenting new challenges in effective data management and integration. Recently, the size and complexity of datasets have increased significantly, with the result that data are often stored on multiple systems. As analyses of interest increasingly require aggregation of datasets from diverse sources, data exchange between disparate systems becomes a challenge. Results To facilitate interoperability among breeding applications, we present the public plant Breeding Application Programming Interface (BrAPI). BrAPI is a standardized web service API specification. The development of BrAPI is a collaborative, community-based initiative involving a growing global community of over a hundred participants representing several dozen institutions and companies. Development of such a standard is recognized as critical to a number of important large breeding system initiatives as a foundational technology. The focus of the first version of the API is on providing services for connecting systems and retrieving basic breeding data including germplasm, study, observation, and marker data. A number of BrAPI-enabled applications, termed BrAPPs, have been written, that take advantage of the emerging support of BrAPI by many databases. Availability and implementation More information on BrAPI, including links to the specification, test suites, BrAPPs, and sample implementations is available at https://brapi.org/. The BrAPI specification and the developer tools are provided as free and open source.

A pyrite concentrate with a grind size P 80 of 14 μm was oxidized in an alkaline medium at an oxygen overpressure between 10 and 40 psig, at a temperature of 80 °C. Sodium hydroxide was used to neutralize the acid produced as a result of pyrite oxidation. When the pH was maintained above 12.5, there were three dominant sulphur oxyanions detected in the solution, thiosulphate, sulphite and sulphate. The focus of this study was the calculation of thiosulphate yield as a function of sulphide sulphur concentration of the pyrite in the feed. This calculation included the effect of other sulphur oxyanions on the thiosulphate yield since it is well known that thiosulphate oxidizes fairly rapidly to tetrathionate and trithionate and higher sulphur oxyanions under high alkalinity conditions. The transient formation of tetrathionate and trithionate can only be estimated when the mechanism of formation of these oxyanions is known. Various schemes involving branching of the reaction pathways can be found in the literature but unfortunately, no widely accepted mechanism has emerged from these studies. In the present study, the transformation mechanism is based on the least electron transfer principle and assumes that the transformation reactions occur in series. Based on this approach, linear equations were derived and used to set up a kinetic model of the system with respect to thiosulphate yield. In determining the kinetic constants, the presence of unseen and unmeasured intermediates was assumed and calculated based on the corresponding reaction stoichiometry. A single rate expression combining kinetic constants of all the metastable oxyanions was derived to predict the thiosulphate yield as a function of the known pyrite sulphide sulphur concentration under the experimental conditions that were adopted. dC S 2 O 3 dt = 2 - 1 k 1 k 2 [ C o s - 2 ] [ P O 2 ] ∝ 1 [ OH ] β 2 { 1 - k 4 [ P O 2 ] ∝ 4 + 2 - 3 k 4 k 5 [ P O 2 ] ∝ 4 [ OH ] β 5 ( 5 + k 6 [ OH ] β 6 ) }

Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.

Understanding the contribution of nitrification and denitrification to production of nitrous oxide (N2O), a potent greenhouse gas, is important in devising effective mitigation strategies to reduce emissions. In this study the 15N gas flux method was used to investigate N2O and N2 emissions following an application of 15N labelled ammonium nitrate (0.71 mol N m−2) to intensive grassland swards (grazed at 2.74 or 2.05 livestock units ha−1 year−1) at a site in Southern Ireland. The 15N labelled fertiliser (NO3 moiety 15N labelled at 60 at. %) was applied to designated soil areas in the field, enclosed by static chambers, in June 2009, September 2009 and March 2010. Fluxes of N2O and N2 were determined over 12 days on each occasion. N2O and N2 emissions were significantly (P

This section discusses the process of developing and constructing Earth System Models (ESMs). The construction of an ESM is fundamentally an action of configuration management (CM), the process of handling change in software systems which may be large and complex. Essentially, configuration management involves identifying, at a level suitable for management, the components of a software system, controlling changes to components over time (i.e. version control), providing traceability of changes made and supporting the maintenance of auditable versions of the software system. Configuration management typically uses the language of trunks, branches, commits, merging and releases and we assume the reader has some familiarity with these terms.

The Orion spacecraft is designed to return astronauts to a landing within 10 km of the intended landing target from low Earth orbit, lunar direct-entry, and lunar skip-entry trajectories. Al pile the landing is nominally controlled autonomously, the crew can fly precision entries manually in the event of an anomaly. The onboard entry displays will be used by the crew to monitor and manually fly the entry, descent, and landing, while the Entry Monitor System (EMS) will be used to monitor the health and status of the onboard guidance and the trajectory. The entry displays are driven by the entry display feeder, part of the Entry Monitor System (EMS). The entry re-targeting module, also part of the EMS, provides all the data required to generate the capability footprint of the vehicle at any point in the trajectory, which is shown on the Primary Flight Display (PFD). It also provides caution and warning data and recommends the safest possible re-designated landing site when the nominal landing site is no longer within the capability of the vehicle. The PFD and the EMS allow the crew to manually fly an entry trajectory profile from entry interface until parachute deploy having the flexibility to manually steer the vehicle to a selected landing site that best satisfies the priorities of the crew. The entry display feeder provides data from the ENIS and other components of the GNC flight software to the displays at the proper rate and in the proper units. It also performs calculations that are specific to the entry displays and which are not made in any other component of the flight software. In some instances, it performs calculations identical to those performed by the onboard primary guidance algorithm to protect against a guidance system failure. These functions and the interactions between the entry display feeder and the other components of the EMS are described.

This paper presents a new system, called BGPmon, for monitoring the Border Gateway Protocol (BGP). BGP is the routing protocol for the global Internet. Monitoring BGP is important for both operations and research; a number of public and private BGP monitors are deployed and widely used. These existing monitors typically collect data using a full implementation of a BGP router. In contrast, BGPmon eliminates the unnecessary functions of route selection and data forwarding to focus solely on the monitoring function. BGPmon uses a publish/subscribe overlay network to provide real-time access to vast numbers of peers and clients. All routing events are consolidated into a single XML stream. XML allows us to add additional features such as labeling updates to allow easy identification of useful data by clients. Clients subscribe to BGPmon and receive the XML stream, performing tasks such as archiving, filtering, or real-time data analysis. BGPmon enables scalable real-time monitoring data distribution by allowing monitors to peer with each other and form an overlay network to provide new services and features without modifying the monitors. We illustrate the effectiveness of the BGPmon data using the Cyclops route monitoring system.

WaterNet is a new international network of researchers, stakeholders, and end-users of remote sensing tools that will benefit the water resources management community. This paper provides an overview and it discusses the concept of solutions networks focusing on the WaterNet. It invites Danubian research and applications teams to join our WaterNet network. The NASA Water cycle Solutions Network's goal is to improve and optimize the sustained ability of water cycle researchers, stakeholders, organizations and networks to interact, identify, harness, and extend NASA research results to augment decision support tools and meet national needs. Our team will develop WaterNet by engaging relevant NASA water cycle research resources and community-of-practice organizations, to develop what we term an "actionable database" that can be used to communicate and connect NASA Water cycle research Results (NWRs) towards the improvement of water-related Decision Support Tools (DSTs). Recognizing that the European Commission and European Space Agency have also developed many related Water Research products (EWRs), we seek to learn about these and network with the EU teams to include their information in the WaterNet actionable data base and Community of Practice. WaterNet will then develop strategies to connect researchers and decision-makers via innovative communication strategies, improved user access to NASA and EU – Danubian resources, improved water cycle research community appreciation for user requirements, improved policymaker, management and stakeholder knowledge of research and application products, and improved identification of pathways for progress. Finally, WaterNet will develop relevant benchmarking and metrics, to understand the network's characteristics, to optimize its performance, and to establish sustainability. This paper provides examples of several NASA products based on remote sensing and land data assimilation systems that integrate remotely sensed and in situ observed forcing data that drive a Land Surface Model to simulate surface hydrologic variables of value to water and emergency managers. It clearly shows the limitations of coarse resolution observations and models especially during flash flood events. Snow water equivalent and soil moisture estimates for water and drought management purposes appear to have some value at the coarser resolutions of ¼ degree; however, higher resolution information at the 1 to 5 km scale is desirable. In conclusion, this paper invites interested water-cycle researchers and decision-makers to join our WaterNet Community of Practice to exchange information and share the latest emerging technologies of value to decision-makers.