An efficient approach for high-fidelity modeling incorporating contour-based sampling and uncertainty

During the design process for an aerospace vehicle, decision-makers must have an accurate understanding of how each choice will affect the vehicle and its performance. This understanding is based on experiments and, increasingly often, computer models. In general, as a computer model captures a greater number of phenomena, its results become more accurate for a broader range of problems. This improved accuracy typically comes at the cost of significantly increased computational expense per analysis. Although rapid analysis tools have been developed that are sufficient for many design efforts, those tools may not be accurate enough for revolutionary concepts subject to grueling flight conditions such as transonic or supersonic flight and extreme angles of attack. At such conditions, the simplifying assumptions of the rapid tools no longer hold. Accurate analysis of such concepts would require models that do not make those simplifying assumptions, with the corresponding increases in computational effort per analysis. As computational costs rise, exploration of the design space can become exceedingly expensive. If this expense cannot be reduced, decision-makers would be forced to choose between a thorough exploration of the design space using inaccurate models, or the analysis of a sparse set of options using accurate models. This problem is exacerbated as the number of free parameters increases, limiting the number of trades that can be investigated in a given time. In the face of limited resources, it can become critically important that only the most useful experiments be performed, which raises multiple questions: how can the most useful experiments be identified, and how can experimental results be used in the most effective manner? This research effort focuses on identifying and applying techniques which could address these questions. The demonstration problem for this effort was the modeling of a reusable booster vehicle, which would be subject to a wide range of flight conditions while returning to its launch site after staging. Contour-based sampling, an adaptive sampling technique, seeks cases that will improve the prediction accuracy of surrogate models for particular ranges of the responses of interest. In the case of the reusable booster, contour-based sampling was used to emphasize configurations with small pitching moments; the broad design space included many configurations which produced uncontrollable aerodynamic moments for at least one flight condition. By emphasizing designs that were likely to trim over the entire trajectory, contour-based sampling improves the predictive accuracy of surrogate models for such designs while minimizing the number of analyses required. The simplified models mentioned above, although less accurate for extreme flight conditions, can still be useful for analyzing performance at more common flight conditions. The simplified models may also offer insight into trends in the response behavior. Data from these simplified models can be combined with more accurate results to produce useful surrogate models with better accuracy than the simplified models but at less cost than if only expensive analyses were used. Of the data fusion techniques evaluated, Ghoreyshi cokriging was found to be the most effective for the problem at hand. Lastly, uncertainty present in the data was found to negatively affect predictive accuracy of surrogate models. Most surrogate modeling techniques neglect uncertainty in the data and treat all cases as deterministic. This is plausible, especially for data produced by computer analyses which are assumed to be perfectly repeatable and thus truly deterministic. However, a number of sources of uncertainty, such as solver iteration or surrogate model prediction accuracy, can introduce noise to the data. If these sources of uncertainty could be captured and incorporated when surrogate models are trained, the resulting surrogate models would be less susceptible to that noise and correspondingly have better predictive accuracy. This was accomplished in the present effort by capturing the uncertainty information via nuggets added to the Kriging model. By combining these techniques, surrogate models could be created which exhibited better predictive accuracy while selecting the most informative experiments possible. This significantly reduced the computational effort expended compared to a more standard approach using space-filling samples and data from a single source. The relative contributions of each technique were identified, and observations were made pertaining to the most effective way to apply the separate and combined methods.Ph.D

Deconvoluting heme biosynthesis to target blood-stage malaria parasites

Heme metabolism is central to blood-stage infection by the malaria parasite Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations. DOI: http://dx.doi.org/10.7554/eLife.09143.00

Copper mediated, heterogeneous, enantioselective intramolecular Buchner reactions of a-diazoketones using continuous flow processing

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper−bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process

Leptin receptor signaling via Janus kinase 2/Signal transducer and activator of transcription 3 impacts on ovarian cancer cell phenotypes

Ovarian cancer is a leading cause of cancer mortality in women world-wide. Considerable progress has been made to characterize the different subtypes of ovarian cancer, but specific therapies remain limited and prognosis poor. Cytokine signaling via the interleukin-6 receptor (IL-6R) family and related receptors has been implicated in a number of cancers, including those with an ovarian origin. The leptin receptor (LEPR) is structurally related to these receptors and utilizes similar downstream pathways. LEPR has diverse roles in metabolism, appetite and bone formation with obesity linked to both elevated levels of leptin and increased cancer incidence. This study investigated a potential role for LEPR signaling in ovarian cancer. Leptin stimulation led to increased proliferation, survival and migration of LEPR-expressing ovarian cancer cell lines, with the effects shown to be mediated by the downstream Janus kinase 2/Signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. A significant correlation was identified between high co-expression of leptin and LEPR and decreased patient survival. This study collectively suggests that leptin/LEPR signaling via JAK2/STAT3 has the potential to significantly impact on pathogenesis in a subset of ovarian cancer patients who may benefit from strategies that dampen this pathway

Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era

Taming tosyl azide: the development of a scalable continuous diazo transfer process

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including beta-ketoesters, beta-ketoamides, malonate esters and beta-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an alpha-diazocarbonyl in > 98% purity without any column chromatography

Preventing species extinctions: A global conservation consortium for Erica

Societal Impact Statement Human-caused habitat destruction and transformation is resulting in a cascade of impacts to biological diversity, of which arguably the most fundamental is species extinctions. The Global Conservation Consortia (GCC) are a means to pool efforts and expertise across national boundaries and between disciplines in the attempt to prevent such losses in focal plant groups. GCC Erica coordinates an international response to extinction threats in one such group, the heaths, or heathers, of which hundreds of species are found only in South Africa's spectacularly diverse Cape Floristic Region. Summary Effectively combating the biodiversity crisis requires coordinated conservation efforts. Botanic Gardens Conservation International (BGCI) and numerous partners have established Global Conservation Consortia (GCC) to collaboratively develop and implement comprehensive conservation strategies for priority threatened plant groups. Through these networks, institutions with specialised collections and staff can leverage ongoing work to optimise impact for threatened plant species. The genus Erica poses a challenge similar in scale to that of the largest other GCC group, Rhododendron, but almost 700 of the around 800 known species of Erica are concentrated in a single biodiversity hotspot, the Cape Floristic Region (CFR) of South Africa. Many species are known to be threatened, suffering the immediate impacts of habitat destruction, invasive species, changes in natural fire regimes and climate change. Efforts to counter these threats face general challenges: disproportionate burden of in situ conservation falling on a minority of the community, limited knowledge of species-rich groups, shortfalls in assessing and monitoring threat, lack of resources for in situ and limitations of knowledge for ex situ conservation efforts and in communicating the value of biological diversity to a public who may never encounter it in the wild. GCC Erica brings together the world's Erica experts, conservationists and the botanical community, including botanic gardens, seed banks and organisations in Africa, Madagascar, Europe, the United States, Australia and beyond. We are collaboratively pooling our unique sets of skills and resources to address these challenges in working groups for conservation prioritisation, conservation in situ, horticulture, seed banking, systematic research and outreach.publishedVersio

Exploiting continuous processing for challenging diazo transfer and telescoped copper-catalyzed asymmetric transformations

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C–H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity

Dirhodium carboxylate catalysts from 2-fenchyloxy or 2-menthyloxy arylacetic acids: enantioselective C-H insertion, aromatic addition and oxonium ylide formation/rearrangement

A new class of dirhodium carboxylate catalysts have been designed and synthesized from 2-fenchyloxy or 2-menthyloxy arylacetic acids which display excellent enantioselectivity across a range of transformations of alpha-diazocarbonyl compounds. The catalysts were successfully applied to enantioselective C-H insertion reactions of aryldiazoacetates and alpha-diazo-beta-oxosulfones affording the respective products in up to 93 % ee with excellent trans diastereoselectivity in most cases. Furthermore, efficient desymmetrization in an intramolecular C-H insertion was achieved. In addition, these catalysts prove highly enantioselective for intramolecular aromatic addition with up to 88% ee, and oxonium ylide formation and rearrangement with up to 74% ee

Small RNA combination therapy for lung cancer

MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051)National Institutes of Health (U.S.) (Grant 2-PO1-CA42063)National Institutes of Health (U.S.) (Grant RO1-EB000244)National Institutes of Health (U.S.) (Grant RO1-CA115527)National Institutes of Health (U.S.) (Grant RO1-CA132091)National Cancer Institute (U.S.) (1K99CA169512)American Association for Cancer Research (Fellowship)Leukemia & Lymphoma Society of America (Fellowship)National Science Foundation (U.S.). Graduate Research Fellowship ProgramMassachusetts Institute of Technology. Presidential FellowshipUnited States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship