Ultrafast infrared studies of complex ligand rearrangements in solution

The complete description of a chemical reaction in solution depends upon an understanding of the reactive molecule as well as its interactions with the surrounding solvent molecules. Using ultrafast infrared spectroscopy it is possible to observe both the solute-solvent interactions and the rearrangement steps which determine the overall course of a chemical reaction. The topics addressed in these studies focus on reaction mechanisms which require the rearrangement of complex ligands and the spectroscopic techniques necessary for the determination of these mechanisms. Ligand rearrangement is studied by considering two different reaction mechanisms for which the rearrangement of a complex ligand constitutes the most important step of the reaction. The first system concerns the rearrangement of a cyclopentadienyl ring as the response of an organometallic complex to a loss of electron density. This mechanism, commonly referred to as ''ring slip'', is frequently cited to explain reaction mechanisms. However, the ring slipped intermediate is too short-lived to be observed using conventional methods. Using a combination of ultrafast infrared spectroscopy and electronic structure calculations it has been shown that the intermediate exists, but does not form an eighteen-electron intermediate as suggested by traditional molecular orbital models. The second example examines the initial steps of alkyne polymerization. Group 6 (Cr, Mo, W) pentacarbonyl species are generated photolytically and used to catalyze the polymerization of unsaturated hydrocarbons through a series of coordination and rearrangement steps. Observing this reaction on the femto- to millisecond timescale indicates that the initial coordination of an alkyne solvent molecule to the metal center results in a stable intermediate that does not rearrange to form the polymer precursor. This suggests that polymerization requires the dissociation of additional carbonyl ligands before rearrangement can occur. Overall, this research demonstrates the importance of examining reaction dynamics on the ultrafast timescale. In the case of both ring slip and alkyne polymerization, early time dynamics have been invaluable in understanding the exact reaction mechanisms which show important differences from previously accepted models

The Impact of Urinary Urgency and Frequency on Health-Related Quality of Life in Overactive Bladder: Results from a National Community Survey

AbstractObjectivesOveractive bladder (OAB) is described as urinary urgency, with and without urge incontinence and usually with frequency and nocturia. Most attention to OAB's impact on health-related quality of life (HRQL), however, has focused on urge incontinence. The objective of this study was to evaluate the burden of OAB, specifically urinary urgency and frequency on HRQL.MethodsIn the National Overactive Bladder Evaluation Program (NOBLE), a computer-assisted telephone interview survey was conducted to assess the prevalence of OAB in the United States. Based on interview responses, respondents were classified into three groups: continent OAB, incontinent OAB, and controls. To evaluate the HRQL impact of OAB, HRQL questionnaires were mailed to all respondents with OAB and age- and sex-matched controls as a performed nested case–control study. Continuous data were compared using Student's t tests and analysis of variance with post hoc pairwise comparisons; results were adjusted for age, sex, and comorbid conditions. Multivariable regressions were performed to assess the impact of each urinary variable on symptom bother and HRQL.ResultsA total of 919 participants responded to the questionnaires (52% response rate) with a mean age of 54.2 years (SD 16.4 years); 70.4% were female and 85% were white. Continent OAB participants comprised 24.8% of the sample, incontinent OAB 18.3%, and controls 56.9%. In each regression analysis, urinary urge intensity accounted for the greatest variance for increases in symptom bother and decreases in HRQL.ConclusionsThe experience of urinary urgency has a significant negative effect on HRQL and increases symptom bother, an effect that, in this community sample, is greater than that of incontinence, frequency, or nocturia

High Intensity Interval Training in High Risk Individuals: A Systematic Review of the Literature

Purpose: This systematic review of the literature (SRL) aims to demonstrate that high intensity interval training is an effective, safe, and more efficient training protocol as compared to continuous moderate intensity exercise in patients with COPD or HFhttps://jdc.jefferson.edu/dptcapstones/1005/thumbnail.jp

Peripheral blood mononuclear cells of breast cancer patients can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells [poster abstract]

Barriers limiting the efficacy of adoptive cellular therapy (ACT) for breast cancer patients include immune suppression mediated by myeloid-derived suppressor cells (MDSC) and a low frequency of tumor-reactive memory T cells (Tm). Recently, we developed an ex vivo protocol to reprogram tumor-reactive murine splenocytes; these cells were found to be resistant to MDSC suppression and protected FVBN202 mice from tumor challenge. Here, we evaluated the clinical applicability of reprogramming tumor-sensitized PBMCs isolated from patients with early stage breast cancer by treatment with bryostatin 1 and ionomycin (B/I) combined with IL-2, IL-7 and IL-15. Our data demonstrate that reprogrammed cells are enriched with Tm cells (n=5; p=0.006), as well as activated CD56+(n=6; p=0.003) and CD161+ (n=4; p=0.02) NKT cells, and demonstrate expansion in total cell numbers (n=16; p=0.003) compared to baseline cells. Reprogrammed PBMCs displayed enhanced HER-2/neu-specific IFN-γ producing immune responses (n=6; p=0.04); non-reprogrammed control PBMC IFN-γ production was not significant (n=6; p=0.4). Furthermore, high-throughput sequencing analysis of the T cell receptor (TcR) Vβ in one patient demonstrated clonal expansion of specific TcR VJ recombination events resulting from cellular reprogramming, suggestive of an enriched frequency of specific tumor antigen-primed T cell clones. Interestingly, reprogrammed T cells were resistant to autologous CD33+ CD11b+ HLA-DRlo/- MDSCs, as determined by further enhanced HER-2/neu-specific IFN-γ secretion in the presence of MDSCs (n=6; p=0.03). Activated CD161+ NKT cells comprising 3% or greater of total reprogrammed cells rendered T cells resistant to MDSCs (n=3; p=0.02). Upregulation of NKG2D expression on CD161+(n=5; p=0.0006) and CD56+ (n=5; p=0.04) NKT cells resulted from cellular reprogramming. Therefore, NKG2D signaling was blocked using anti-NKG2D blocking antibody in our co-culture system, resulting in the abrogation of resistance to MDSCs as determined by blunted IFN-γ secretion (n=3; p=0.04). Finally, the phenotype of MDSCs after co-culture with reprogrammed PBMC was examined; we observed downregulation of CD11b expression (n=3; p=0.02) concomitant with HLA-DR upregulation on MDSCs (n=3; p=0.001); suggestive of induced maturation of MDSCs into Dendritic Cells (DC). The results of our study offer the following strategies to improve ACT of breast cancer: i) inclusion of activated NKT cells in ACT to overcome MDSC suppression by inducing MDSC maturation into DCs, and ii) PBMC reprogramming to enrich the frequency of tumor-reactive Tm cells

QTL mapping in autotetraploids using SNP dosage information

Dense linkage maps derived by analysing SNP dosage in autotetraploids provide detailed information about the location of, and genetic model at, quantitative trait loci. Recent developments in sequencing and genotyping technologies enable researchers to generate high-density single nucleotide polymorphism (SNP) genotype data for mapping studies. For polyploid species, the SNP genotypes are informative about allele dosage, and Hackett et al. (PLoS ONE 8:e63939, 2013) presented theory about how dosage information can be used in linkage map construction and quantitative trait locus (QTL) mapping for an F1 population in an autotetraploid species. Here, QTL mapping using dosage information is explored for simulated phenotypic traits of moderate heritability and possibly non-additive effects. Different mapping strategies are compared, looking at additive and more complicated models, and model fitting as a single step or by iteratively re-weighted modelling. We recommend fitting an additive model without iterative re-weighting, and then exploring non-additive models for the genotype means estimated at the most likely position. We apply this strategy to re-analyse traits of high heritability from a potato population of 190 F1 individuals: flower colour, maturity, height and resistance to late blight (Phytophthora infestans (Mont.) de Bary) and potato cyst nematode (Globodera pallida), using a map of 3839 SNPs. The approximate confidence intervals for QTL locations have been improved by the detailed linkage map, and more information about the genetic model at each QTL has been revealed. For several of the reported QTLs, candidate SNPs can be identified, and used to propose candidate trait genes. We conclude that the high marker density is informative about the genetic model at loci of large effects, but that larger populations are needed to detect smaller QTLs

An investigation of causes of false positive single nucleotide polymorphisms using simulated reads from a small eukaryote genome

Background: Single Nucleotide Polymorphisms (SNPs) are widely used molecular markers, and their use has increased massively since the inception of Next Generation Sequencing (NGS) technologies, which allow detection of large numbers of SNPs at low cost. However, both NGS data and their analysis are error-prone, which can lead to the generation of false positive (FP) SNPs. We explored the relationship between FP SNPs and seven factors involved in mapping-based variant calling - quality of the reference sequence, read length, choice of mapper and variant caller, mapping stringency and filtering of SNPs by read mapping quality and read depth. This resulted in 576 possible factor level combinations. We used error- and variant-free simulated reads to ensure that every SNP found was indeed a false positive. Results: The variation in the number of FP SNPs generated ranged from 0 to 36,621 for the 120 million base pairs (Mbp) genome. All of the experimental factors tested had statistically significant effects on the number of FP SNPs generated and there was a considerable amount of interaction between the different factors. Using a fragmented reference sequence led to a dramatic increase in the number of FP SNPs generated, as did relaxed read mapping and a lack of SNP filtering. The choice of reference assembler, mapper and variant caller also significantly affected the outcome. The effect of read length was more complex and suggests a possible interaction between mapping specificity and the potential for contributing more false positives as read length increases. Conclusions: The choice of tools and parameters involved in variant calling can have a dramatic effect on the number of FP SNPs produced, with particularly poor combinations of software and/or parameter settings yielding tens of thousands in this experiment. Between-factor interactions make simple recommendations difficult for a SNP discovery pipeline but the quality of the reference sequence is clearly of paramount importance. Our findings are also a stark reminder that it can be unwise to use the relaxed mismatch settings provided as defaults by some read mappers when reads are being mapped to a relatively unfinished reference sequence from e.g. a non-model organism in its early stages of genomic exploration

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Role of Innate Immunity in the Pathogenesis of Chronic Rhinosinusitis: Progress and New Avenues

Chronic rhinosinusitis is a heterogeneous and multifactorial disease with unknown etiology. Aberrant responses to microorganisms have been suggested to play a role in the pathophysiology of the disease. Research has focused on the presence, detection, response to, and eradication of these potential threats. Main topics seem to center on the contribution of structural cells such as epithelium and fibroblasts, on the consequences of activation of pattern-recognition receptors, and on the role of antimicrobial agents. This research should be viewed not only in the light of a comparison between healthy and diseased individuals, but also in a comparison between patients who do or do not respond to treatment. New players that could play a role in the pathophysiology seem to surface at regular intervals, adding to our understanding (and the complexity) of the disease and opening new avenues that may help fight this incapacitating disease

Crop Updates 2010 - Crop Specific

This session covers twenty four papers from different authors: PLENARY 1. Challenges facing western Canadian cropping over the next 10 years, Hugh J Beckie, Research Centre, Agriculture and Agri-Food Canada, Saskatoon, Saskatchewan CROP SPECIFIC Breeding 2. The challenge of breeding canola hybrids – new opportunities for WA growers, Wallace Cowling, Research Director, Canola Breeders Western Australia Pty Ltd 3. Chickpea 2009 crop variety testing of germplasm developed by DAFWA/CLIMA/ICRISAT/COGGO alliance. Khan, TN1,3, Adhikari, K1,3, Siddique, K2, Garlinge, J1, Smith, L1, Morgan, S1 and Boyd, C1 1Department of Agriculture and Food, Western Australia (DAFWA), 2Insititute of Agriculture, The University of Western Australia (UWA), 3Centre for Legumes in Mediterranean Agriculture (CLIMA), The University of Western Australia 4. PBA Pulse Breeding Australia – 2009 Field Pea Results, Ian Pritchard1, Chris Veitch1, Colin Boyd1, Stuart Morgan1, Alan Harris1 and Tony Leonforte2, 1Department of Agriculture and Food, Western Australia, 2Department of Primary Industries, Victoria 5. PBA Pulse Breeding Australia – 2009 Chickpea Results, Ian Pritchard1, Chris Veitch1, Colin Boyd1, Murray Blyth1, Shari Dougal1 and Kristy Hobson2 1Department of Agriculture and Food, Western Australia, 2Department of Primary Industries, Victoria Decision Support 6. A tool for identifying problems in wheat paddocks, Ben Curtis and Doug Sawkins, Department of Agriculture and Food 7. DAFWA Seasonal Forecast for 2010, Stephens, D, Department of Agriculture and Food, Western Australian, Climate and Modelling Group Disease 8. Enhancement of black spot resistance in field pea, Kedar Adhikari, T Khan, S Morgan and C Boyd, Department of Agriculture and Food, 9. fungicide management of yellow spot in wheat, Ciara Beard, Kith Jayasena, Kazue Tanaka and Anne Smith, Department of Agriculture and Food 10. Resistance to infection by Beet western yellows virus in four Australian canola varieties, Brenda Coutts and Roger Jones, Department of Agriculture and Food 11. Yellow spot carryover risk from stubble in wheat-on-wheat rotations, Jean Galloway, Pip Payne and Tess Humphreys, Department of Agriculture and Food 12. Fungicides for the future: Management of Barley Powdery Mildew and Leaf Rust, Kith Jayasena, Kazue Tanaka and William MacLeod, Department of Agriculture and Food 13. 2009 canola disease survey and management options for blackleg and Sclerotinia in 2010, Ravjit Khangura, WJ MacLeod, M Aberra and H Mian, Department of Agriculture and Food 14. Impact of variety and fungicide on carryover of stubble borne inoculum and yellow spot severity in continuous wheat cropping, Geoff Thomas, Pip Payne, Tess Humphreys and Anne Smith, Department of Agriculture and Food 15. Limitations to the spread of Wheat streak mosaic virus by the Wheat curl mite in WA during 2009, Dusty Severtson, Peter Mangano, Brenda Coutts, Monica Kehoe and Roger Jones, Department of Agriculture and Food 16. Viable solutions for barley powdery mildew, Madeline A. Tucker, Australian Centre for Necrotrophic Fungal Pathogens, Murdoch University Marketing 17. The importance of varietal accreditation in a post-deregulation barley marketing environment, Neil Barker, Barley Australia 18. Can Australia wheat meet requirements for a new middle east market? Robert Loughman, Larisa Cato, Department of Agriculture and Food, and Ken Quail, BRI Australia VARIETY PERFORMANCE 19. Sowing rate and time for hybrid vs open-pollinated canola, Mohammad Amjad and Mark Seymour, Department of Agriculture and Food 20. HYOLA® National Hybrid vs OP Canola Hybrid F1 vs Retained Seed Generation Trial Results and recommendations for growers, Justin Kudnig, Mark Thompson, Anton Mannes, Michael Uttley, Chris Fletcher, Andrew Etherton, Nick Joyce and Kate Light, Pacific Seeds Australia 21. HYOLA® National Hybrid vs OP Canola Sowing Rate Trial Results and plant population recommendations for Australian growers, Justin Kudnig, Mark Thompson, Anton Mannes, Michael Uttley, Andrew Etherton, Chris Fletcher, Nick Joyce and Kate Light, Pacific Seeds Australia; Peter Hamblin, Agritech Research Young, NSW, Michael Lamond, Agrisearch, York, Western Australia 22. Desi chickpea agronomy for 2010, Alan Meldrum, Pulse Australia and Wayne Parker, Department of Agriculture and Food 23. New wheat varieties – exploit the benefits and avoid the pitfalls, Steve Penny, Sarah Ellis, Brenda Shackley, Christine Zaicou, Shahajahan Miyan, Darshan Sharma and Ben Curtis, Department of Agriculture and Food 24. The influence of genetics and environment on the level of seed alkaloid in narrow-leafed lupins, Greg Shea1, Bevan Buirchell1, David Harris2 and Bob French1, 1Department of Agriculture and Food, 2ChemCentr