Draft Genome Sequences of Antibiotic-Resistant Commensal Escherichia coli

Antimicrobial resistance is a significant public health issue. We report here the draft genome sequences of three drug-resistant strains of commensal Escherichia coli isolated from a single healthy college student. Each strain has a distinct genome, but two of the three contain an identical large plasmid with multiple resistance genes

The Impact of Separate Taxation on the Intra-Household Allocation of Assets: Evidence from the UK

The income tax system in the United Kingdom moved from joint to independent taxation of husbands' and wives' income in 1990. One interesting aspect of independent taxation is the ability for households to choose the division of household assets between the two spouses. This tax reform therefore creates an opportunity for households to engage in a form of tax avoidance by shifting their investment income to the spouse with the lower marginal tax rate. We use Family Expenditure Survey data to examine the impact of this tax reform on the magnitude of investment income shifting between spouses with different marginal tax rates. We find a sizeable shift in the share and incidence of asset income claimed by wives, who typically have lower marginal tax rates, as well as in the incidence of the wife claiming all the household asset income, indicating that households responded to this policy change by reallocating asset ownership.

Multiple gene aberrations and breast cancer: lessons from super-responders.

BackgroundThe presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.Case presentationsWe performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.ConclusionsPatients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted

User’s Guide to For2R: A Module of Fortran 95 Output Routines Compatible with the R Statistics Language

For2R is a collection of Fortran routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 For2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the For2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer For2R to others in the hope that they will find it useful. (PDF contains 31 pages

User’s Guide to C2R: A Set of C Language Output Routines Compatible with the R Statistics Language

C2R is a collection of C routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 C2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the C2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer C2R to others in the hope that they will find it useful. (PDF contains 27 pages

Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance.

BackgroundPatients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.MethodsTumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X.ResultsThree of the ten patients (median number of prior therapies = 2) attained prolonged CR (duration = 23.6+ to 28.7+ months); seven patients achieved either a PR or a short-lived CR. One patient who achieved CR ongoing at 28.7+ months and had tissue available close to the time of initiating BRAF inhibitor therapy had only a BRAF mutation. Abnormalities in addition to BRAF mutation found in other patients included: mutations in NRAS, APC and NF1; amplifications in BRAF, aurora kinase A, MYC, MITF and MET; deletions in CDKN2A/B and PAX5; and, alterations in RB1 and ATM. Heterogeneity between patients and molecular evolution within patients was noted.ConclusionNGS identified potentially actionable DNA alterations that could account for resistance in patients with BRAF mutation-positive advanced melanoma who achieved a PR or CR but whose tumors later progressed. A subset of patients with advanced melanoma may harbor only a BRAF mutation and achieve a durable CR on BRAF pathway inhibitors

Human Engineering of Space Vehicle Displays and Controls

Proper attention to the integration of the human needs in the vehicle displays and controls design process creates a safe and productive environment for crew. Although this integration is critical for all phases of flight, for crew interfaces that are used during dynamic phases (e.g., ascent and entry), the integration is particularly important because of demanding environmental conditions. This panel addresses the process of how human engineering involvement ensures that human-system integration occurs early in the design and development process and continues throughout the lifecycle of a vehicle. This process includes the development of requirements and quantitative metrics to measure design success, research on fundamental design questions, human-in-the-loop evaluations, and iterative design. Processes and results from research on displays and controls; the creation and validation of usability, workload, and consistency metrics; and the design and evaluation of crew interfaces for NASA's Crew Exploration Vehicle are used as case studies

Effect of Acute Antioxidant Consumption on Cardiac Baroreflex Sensitivity in Young Healthy Adults

There is an emerging body of evidence in animals indicating that elevated oxidative stress impairs baroreflex sensitivity (BRS) function, however studies in healthy humans have yielded equivocal results. One potential reason for this discrepancy is that previous studies have used individual antioxidant treatments (e.g., Vitamin C only) to investigate the effect of oxidative stress on BRS. Recent studies in healthy humans have demonstrated significant reductions in reactive oxygen species using an antioxidant cocktail (AOC; Vitamin C, Vitamin E, and Co-enzyme Q10) suggesting the effectiveness of this treatment. Whether this AOC induced reduction in oxidative species affects BRS in young, healthy adults remains unknown. PURPOSE: We tested the hypothesis that AOC will improve cardiac BRS in young healthy adults. METHODS: Five young men were studied on two separate days: placebo (sugar pills) and AOC (2000 mg Vitamin C, 150 IU Vitamin E and 100 mg Co-enzyme Q10) performed in random order. Resting heart rate (ECG) and arterial blood pressure (automated sphygmomanometer and finger photoplethysmography) were measured 90 minutes after AOC or placebo (a time period this AOC has been shown to have peak effects on oxidative stress). Spontaneous cardiac BRS was determined for all sequences combined (overall BRS), and also separately for up (increase systolic blood pressure: increase R-R interval) and down (decrease systolic blood pressure: decrease R-R interval) sequences. RESULTS: Systolic blood pressure on AOC day tended to be lower relative to the placebo day (127 ± 4 vs. 131 ± 5; p=0.098). However, no differences in overall cardiac BRS were found between placebo and AOC (18.0 ± 2.7 vs.17.3 ± 2.6 ms/mmHg; p=0.59). Likewise, up sequences (17.02 ± 2.9 vs 14.04 ± 4.0 ms/mmHg; p=0.51) and down sequences (18.0 ± 2.7 placebo vs. 18.0 ± 2.6 ms/mmHg AOC; p=0.98) were not different between conditions. Equal number of sequences were found between the placebo and AOC days. CONCLUSION: These preliminary data suggest that antioxidant treatment does not affect resting cardiac BRS in young, healthy men

<i>desynaptic5 </i>carries a spontaneous semi-dominant mutation affecting <i>Disrupted Meiotic cDNA 1</i> in barley

Despite conservation of the process of meiosis, recombination landscapes vary between species, with large genome grasses such as barley (Hordeum vulgare L.) exhibiting a pattern of recombination that is very heavily skewed to the ends of chromosomes. We have been using a collection of semi-sterile desynaptic meiotic mutant lines to help elucidate how recombination is controlled in barley and the role of the corresponding wild-type (WT) meiotic genes within this process. Here we applied a combination of genetic segregation analysis, cytogenetics, and immunocytology to genetically map and characterize the meiotic mutant desynaptic5 (des5). We identified an exonic insertion in the positional candidate ortholog of Disrupted Meiotic cDNA 1 (HvDMC1) on chromosome 5H of des5. des5 exhibits a severe meiotic phenotype with disturbed synapsis, reduced crossovers, and chromosome mis-segregation. The meiotic phenotype and reduced fertility of des5 is similarly observed in Hvdmc1RNAi transgenic plants and HvDMC1p:GusPlus reporter lines show DMC1 expression specifically in the developing inflorescence. The des5 mutation maintains the reading frame of the gene and exhibits semi-dominance with respect to recombination in the heterozygote indicating the value of non-knockout mutations for dissection of the control of recombination in the early stages of meiosis.</p

Overexpression and Down-Regulation of Barley Lipoxygenase<i> LOX2.2 </i>Affects Jasmonate-Regulated Genes and Aphid Fecundity

Aphids are pests on many crops and depend on plant phloem sap as their food source. In an attempt to find factors improving plant resistance against aphids, we studied the effects of overexpression and down-regulation of the lipoxygenase gene LOX2.2 in barley (Hordeum vulgare L.) on the performance of two aphid species. A specialist, bird cherry-oat aphid (Rhopalosiphum padi L.) and a generalist, green peach aphid (Myzus persicae Sulzer) were studied. LOX2.2 overexpressing lines showed up-regulation of some other jasmonic acid (JA)-regulated genes, and antisense lines showed down-regulation of such genes. Overexpression or suppression of LOX2.2 did not affect aphid settling or the life span on the plants, but in short term fecundity tests, overexpressing plants supported lower aphid numbers and antisense plants higher aphid numbers. The amounts and composition of released volatile organic compounds did not differ between control and LOX2.2 overexpressing lines. Up-regulation of genes was similar for both aphid species. The results suggest that LOX2.2 plays a role in the activation of JA-mediated responses and indicates the involvement of LOX2.2 in basic defense responses