High-precision frequency measurements: indispensable tools at the core of the molecular-level analysis of complex systems

This perspective article provides an assessment of the state-of-the-art in the molecular-resolution analysis of complex organic materials. These materials can be divided into biomolecules in complex mixtures (which are amenable to successful separation into unambiguously defined molecular fractions) and complex nonrepetitive materials (which cannot be purified in the conventional sense because they are even more intricate). Molecular-level analyses of these complex systems critically depend on the integrated use of high-performance separation, high-resolution organic structural spectroscopy and mathematical data treatment. At present, only high-precision frequency-derived data exhibit sufficient resolution to overcome the otherwise common and detrimental effects of intrinsic averaging, which deteriorate spectral resolution to the degree of bulk-level rather than molecular-resolution analysis. High-precision frequency measurements are integral to the two most influential organic structural spectroscopic methods for the investigation of complex materials—NMR spectroscopy (which provides unsurpassed detail on close-range molecular order) and FTICR mass spectrometry (which provides unrivalled resolution)—and they can be translated into isotope-specific molecular-resolution data of unprecedented significance and richness. The quality of this standalone de novo molecular-level resolution data is of unparalleled mechanistic relevance and is sufficient to fundamentally advance our understanding of the structures and functions of complex biomolecular mixtures and nonrepetitive complex materials, such as natural organic matter (NOM), aerosols, and soil, plant and microbial extracts, all of which are currently poorly amenable to meaningful target analysis. The discrete analytical volumetric pixel space that is presently available to describe complex systems (defined by NMR, FT mass spectrometry and separation technologies) is in the range of 108–14 voxels, and is therefore capable of providing the necessary detail for a meaningful molecular-level analysis of very complex mixtures. Nonrepetitive complex materials exhibit mass spectral signatures in which the signal intensity often follows the number of chemically feasible isomers. This suggests that even the most strongly resolved FTICR mass spectra of complex materials represent simplified (e.g. isomer-filtered) projections of structural space

Cardiopulmonary Exercise Testing Provides Additional Prognostic Information in Cystic Fibrosis

RATIONALE: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. OBJECTIVES: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake (V.o2peak) following rigorous adjustment for other predictors. METHODS: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. MEASUREMENTS AND MAIN RESULTS: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that V.o2peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944–0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951–0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041–1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007–1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. CONCLUSIONS: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling

A high throughput screen for next-generation leads targeting malaria parasite transmission

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population

Debiasing the NEOWISE Cryogenic Mission Comet Populations

We use NEOWISE data from the four-band and three-band cryogenic phases of the Wide-field Infrared Survey Explorer mission to constrain size distributions of the comet populations and debias measurements of the short- and long-period comet (LPC) populations. We find that the fit to the debiased LPC population yields a cumulative size−frequency distribution (SFD) power-law slope (β) of −1.0 ± 0.1, while the debiased Jupiter-family comet (JFC) SFD has a steeper slope with β = −2.3 ± 0.2. The JFCs in our debiased sample yielded a mean nucleus size of 1.3 km in diameter, while the LPCs' mean size is roughly twice as large, 2.1 km, yielding mean size ratios (〈D_(LPC)〉/〈D_(JFC)〉) that differ by a factor of 1.6. Over the course of the 8 months of the survey, our results indicate that the number of LPCs passing within 1.5 au are a factor of several higher than previous estimates, while JFCs are within the previous range of estimates of a few thousand down to sizes near 1.3 km in diameter. Finally, we also observe evidence for structure in the orbital distribution of LPCs, with an overdensity of comets clustered near 110° inclination and perihelion near 2.9 au that is not attributable to observational bias

Tutoring Multilingual Students: Shattering the Myths

This is the author's accepted manuscript, made available 18 months after publication with the permission of the publisher.The increasing linguistic and cultural diversification of North America has resulted in large numbers of multilingual students attending college and university and seeking curricular and extracurricular support with reading and writing (Ruecker, 2011; Teranishi, C. Suárez-Orozco, & M. Suárez-Orozco, 2011). In the past, learning and writing centers hired “ESL specialists” to provide support. But this model, given the ubiquity of multilingual students in higher education today, is no longer sustainable. Instead, all tutors must learn the skills necessary to support the academic literacy development of these writers, and that means that the way tutors are trained must change. Because the lived reality of the majority of tutors (and center administrators) is monolingual (Bailey, 2012; Barron & Grimm, 2002), examining the myths generally held about multilingual students is essential to both our development as tutors and the development of our students as academic readers and writers of English. Only after raising critical awareness about these “misguided ideas” will training specific to tutoring multilingual students make sense and be put into practice (Gillespie & Lerner, 2008, p. 117). In this article, I present and challenge myths about multilingual writers and myths about how to tutor them

Biomass burning fuel consumption rates: a field measurement database

Landscape fires show large variability in the amount of biomass or fuel consumed per unit area burned. Fuel consumption (FC) depends on the biomass available to burn and the fraction of the biomass that is actually combusted, and can be combined with estimates of area burned to assess emissions. While burned area can be detected from space and estimates are becoming more reliable due to improved algorithms and sensors, FC is usually modeled or taken selectively from the literature. We compiled the peerreviewed literature on FC for various biomes and fuel categories to understand FC and its variability better, and to provide a database that can be used to constrain biogeochemical models with fire modules. We compiled in total 77 studies covering 11 biomes including savanna (15 studies, average FC of 4.6 t DM (dry matter) ha 1 with a standard deviation of 2.2),tropical forest (n = 19, FC = 126 +/- 77),temperate forest (n = 12, FC = 58 +/- 72),boreal forest (n = 16, FC = 35 +/- 24),pasture (n = 4, FC = 28 +/- 9.3),shifting cultivation (n = 2, FC = 23, with a range of 4.0-43),crop residue (n = 4, FC = 6.5 +/- 9.0),chaparral (n = 3, FC = 27 +/- 19),tropical peatland (n = 4, FC = 314 +/- 196),boreal peatland (n = 2, FC = 42 [42-43]),and tundra (n = 1, FC = 40). Within biomes the regional variability in the number of measurements was sometimes large, with e. g. only three measurement locations in boreal Russia and 35 sites in North America. Substantial regional differences in FC were found within the defined biomes: for example, FC of temperate pine forests in the USA was 37% lower than Australian forests dominated by eucalypt trees. Besides showing the differences between biomes, FC estimates were also grouped into different fuel classes. Our results highlight the large variability in FC, not only between biomes but also within biomes and fuel classes. This implies that substantial uncertainties are associated with using biome-averaged values to represent FC for whole biomes. Comparing the compiled FC values with co-located Global Fire Emissions Database version 3 (GFED3) FC indicates that modeling studies that aim to represent variability in FC also within biomes, still require improvements as they have difficulty in representing the dynamics governing FC

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

Designing the ideal model for assessment of wound contamination after gunshot injuries: a comparative experimental study

<p>Abstract</p> <p>Background</p> <p>Modern high-velocity projectiles produce temporary cavities and can thus cause extensive tissue destruction along the bullet path. It is still unclear whether gelatin blocks, which are used as a well-accepted tissue simulant, allow the effects of projectiles to be adequately investigated and how these effects are influenced by caliber size.</p> <p>Method</p> <p>Barium titanate particles were distributed throughout a test chamber for an assessment of wound contamination. We fired .22-caliber Magnum bullets first into gelatin blocks and then into porcine hind limbs placed behind the chamber. Two other types of bullets (.222-caliber bullets and 6.5 × 57 mm cartridges) were then shot into porcine hind limbs. Permanent and temporary wound cavities as well as the spatial distribution of barium titanate particles in relation to the bullet path were evaluated radiologically.</p> <p>Results</p> <p>A comparison of the gelatin blocks and hind limbs showed significant differences (<it>p </it>< 0.05) in the mean results for all parameters. There were significant differences between the bullets of different calibers in the depth to which barium titanate particles penetrated the porcine hind limbs. Almost no particles, however, were found at a penetration depth of 10 cm or more. By contrast, gas cavities were detected along the entire bullet path.</p> <p>Conclusion</p> <p>Gelatin is only of limited value for evaluating the path of high-velocity projectiles and the contamination of wounds by exogenous particles. There is a direct relationship between the presence of gas cavities in the tissue along the bullet path and caliber size. These cavities, however, are only mildly contaminated by exogenous particles.</p

MicroRNAs in Renal Cell Carcinoma: Diagnostic Implications of Serum miR-1233 Levels

BACKGROUND: MicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC). METHODOLOGY/PRINCIPAL FINDINGS: We first explored microrna expression profiles in tissue and serum using taqman low density arrays in each six malignant and benign samples: Although 109 microRNAs were circulating at higher levels in cancer patients' serum, we identified only 36 microRNAs with up-regulation in RCC tissue and serum of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients: miR-7-1*, miR-93, miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum of healthy controls (n = 30) and RCC (n = 33) patients were determined using quantitative real-time PCR (TaqMan MicroRNA Assays). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of 84 RCC patients and 93 healthy controls using quantitative real-time PCR (sensitivity 77.4%, specificity 37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters. CONCLUSIONS/SIGNIFICANCE: MicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a tumor-specific origin. We identify circulating miR-1233 as a potential biomarker for RCC patients. Larger-scaled studies are warranted to fully explore the role of circulating microRNAs in RCC

Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria.

Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies