A model of estrogen-related gene expression reveals non-linear effects in transcriptional response to tamoxifen

SynthSys is a Centre for Integrative Systems Biology (CISB) funded by BBSRC and EPSRC, reference BB/D019621/1.Background: Estrogen receptors alpha (ER) are implicated in many types of female cancers, and are the common target for anti-cancer therapy using selective estrogen receptor modulators (SERMs, such as tamoxifen). However, cell-type specific and patient-to-patient variability in response to SERMs (from suppression to stimulation of cancer growth), as well as frequent emergence of drug resistance, represents a serious problem. The molecular processes behind mixed effects of SERMs remain poorly understood, and this strongly motivates application of systems approaches. In this work, we aimed to establish a mathematical model of ER-dependent gene expression to explore potential mechanisms underlying the variable actions of SERMs. Results: We developed an equilibrium model of ER binding with 17 beta-estradiol, tamoxifen and DNA, and linked it to a simple ODE model of ER-induced gene expression. The model was parameterised on the broad range of literature available experimental data, and provided a plausible mechanistic explanation for the dual agonism/antagonism action of tamoxifen in the reference cell line used for model calibration. To extend our conclusions to other cell types we ran global sensitivity analysis and explored model behaviour in the wide range of biologically plausible parameter values, including those found in cancer cells. Our findings suggest that transcriptional response to tamoxifen is controlled in a complex non-linear way by several key parameters, including ER expression level, hormone concentration, amount of ER-responsive genes and the capacity of ER-tamoxifen complexes to stimulate transcription (e. g. by recruiting co-regulators of transcription). The model revealed non-monotonic dependence of ER-induced transcriptional response on the expression level of ER, that was confirmed experimentally in four variants of the MCF-7 breast cancer cell line. Conclusions: We established a minimal mechanistic model of ER-dependent gene expression, that predicts complex non-linear effects in transcriptional response to tamoxifen in the broad range of biologically plausible parameter values. Our findings suggest that the outcome of a SERM's action is defined by several key components of cellular micro-environment, that may contribute to cell-type-specific effects of SERMs and justify the need for the development of combinatorial biomarkers for more accurate prediction of the efficacy of SERMs in specific cell types.Publisher PDFPeer reviewe

A multi-iron system capable of rapid N\u3csub\u3e2\u3c/sub\u3e formation and N \u3csub\u3e2\u3c/sub\u3e cleavage

The six-electron oxidation of two nitrides to N2 is a key step of ammonia synthesis and decomposition reactions on surfaces. In molecular complexes, nitride coupling has been observed with terminal nitrides, but not with bridging nitride complexes that more closely resemble catalytically important surface species. Further, nitride coupling has not been reported in systems where the nitrides are derived from N2. Here, we show that a molecular diiron(II) diiron(III) bis(nitride) complex reacts with Lewis bases, leading to the rapid six-electron oxidation of two bridging nitrides to form N2. Surprisingly, these mild reagents generate high yields of iron(I) products from the iron(II/III) starting material. This is the first molecular system that both breaks and forms the triple bond of N2 at room temperature. These results highlight the ability of multi-iron species to decrease the energy barriers associated with the activation of strong bonds. © 2014 American Chemical Society

Growth and yield of 3 hybrid papayas (Carica papaya L.) under mulched and bare ground conditions

At Yarwun (151.3˚E, 23.75˚S), Australia, papaya Hybrid 29 yielded twice as much fruit as Hybrid 11 and 30% more than Hybrid 13. The plots mulched with coarse grass hay yielded 50% more fruit than the plots with bare ground. The highest yielding treatment, Hybrid 29 + mulch, averaged the equivalent of 81 t/ha.year over the 16.5-month harvest period. The yields were achieved in spite of inadequate water supply due to drought and the loss of 877 plants from 1441 plant positions (4 plants per position) due to the 3 phytoplasma diseases; dieback, yellow crinkle and mosaic. Hybrid 29 produced higher yields than the other hybrids by flowering early on shorter plants with thicker stems and setting more fruit that commenced lower down on the stem. Hybrid 13 was intermediate in size and the amount of fruit setting between Hybrid 29 and Hybrid 11 but was the slowest to flower and set fruit. Hybrid 11 had the thinnest and tallest stems, flowered at an intermediate time between the other 2 hybrids and produced fewer flowers and fruit resulting in the lowest yield. Mulching increased stem height and thickness, promoted earlier flowering and increased fruit set, yield and average fruit weigh

Post-ratoon growth and yield of three hybrid papayas (Carica papaya L.) under mulched and bare-ground conditions

At Yarwun (151.3°E, 23.75°S), a trial was conducted to compare 3 papaya hybrids (Hybrid 29, Hybrid 11 and Hybrid 13) under mulching with grass hay or in bare ground. The viability of ratooning a papaya crop was also investigated. After a 16-month cropping season plants were cut to a 750-mm stump (ratooned) about monthly over a 3.5-month period and, following a 4.5-month regrowth period, were harvested for a period of 11 months (post-ratoon). Hybrid 29 yielded (by weight) 54% more than Hybrid 11 and 92% more than Hybrid 13 during the 3.5-month ratooning period. At the commencement of ratooning, Hybrid 29 plants were 41–58 cm shorter than Hybrid 11 and 13 plants, allowing the Hybrid 29 plants to be retained for longer before being ratooned. Hybrid 29 also returned to fruiting more quickly with a greater proportion of plants (97%) with fruit at the first post-ratoon harvest compared with Hybrid 11 (87%). Following regrowth (post-ratoon) the 3 hybrids produced similar yields. All 3 hybrids were equally susceptible to the 3 phytoplasma diseases and to nematodes. The plots mulched with coarse grass hay yielded 70% more during the ratooning period and 116% more post-ratoon than the plots with bare ground. This difference was attributed in part to fewer root-knot nematodes, the roots being more heavily infected with vesicular arbuscular mycorrhiza, the use of the complete upper soil profile by the roots, reduced rainfall run off and less soil loss in the mulched treatment. The highest yielding treatment, mulched Hybrid 29, averaged the equivalent of 55 t/ha.year during ratooning, 43 t/ha.year over the 11-month post-ratoon harvest period and 65 t/ha.year over the entire plant–ratoon cycle. These yields were achieved in spite of drought conditions and quite severe outbreaks of the phytoplasma diseases, dieback, yellow crinkle and mosaic, with 60% of plant positions infected with dieback during the post-ratoon period. Theoretical yield estimations using the data from the plant and post-ratoon crops indicated that ratooning may give superior average monthly yields compared with 2 successive plant crops because of the reduced time required for the ratooned crop to return to production. The study demonstrated the benefits of mulching, the superiority of Hybrid 29 and that ratooning may be successfully used in papaya. In environments similar to Yarwun, Hybrid 29, or similar hybrids, with mulching is recommended for commercial production. If land, time or finances are limiting, consideration should be given to ratooning the plant crop based on monthly cut outs over a 3–4-month ratooning period with vacant plant positions replanted during ratooning

Incidence and risk factors of institutionalisation in Parkinson's disease and atypical parkinsonism

Open Access via the Elsevier Agreement We would like to thank the patients for their participation and the research staff who collected data and supported the study database. The PINE study was funded by Parkinson's UK (grant numbers G0502, G0914, and G1302), the Scottish Chief Scientist Office (CAF/12/05, PCL/17/10), NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation and SPRING. Yan Li is funded by a studentship from the Meikle Foundation.Peer reviewedPublisher PD

The influence of maternal glucocorticoids on offspring phenotype in high-and low-risk environments

Elevated maternal glucocorticoid levels during gestation can lead to phenotypic changes in offspring via maternal effects. Although such effects have traditionally been considered maladaptive, maternally derived glucocorticoids may adaptively prepare offspring for their future environment depending upon the correlation between maternal and offspring environments. Nevertheless, relatively few studies test the effects of prenatal glucocorticoid exposure across multiple environments. We tested the potential for ecologically relevant increases in maternal glucocorticoids in the eastern fence lizard (Sceloporus undulatus) to induce adaptive phenotypic changes in offspring exposed to high or low densities of an invasive fire ant predator. Maternal treatment had limited effects on offspring morphology and behavior at hatching, but by 10 days of age, we found maternal treatment interacted with offspring environment to alter anti-predator behaviors. We did not detect differences in early-life survival based on maternal treatment or offspring environment. Opposing selection on anti-predator behaviors from historic and novel invasive predators may confound the potential of maternal glucocorticoids to adaptively influence offspring behavior. Our test of the phenotypic outcomes of transgenerational glucocorticoid effects across risk environments provides important insight into the context-specific nature of this phenomenon and the importance of understanding both current and historic evolutionary pressures

Altered Patterns of Fungal Keratitis at a London Ophthalmic Referral Hospital: An Eight-Year Retrospective Observational Study.

PURPOSE: In previous studies of fungal keratitis (FK) from temperate countries, yeasts were the predominant isolates, with ocular surface disease (OSD) being the leading risk factor. Since the 2005-2006 outbreak of contact lens (CL)-associated Fusarium keratitis, there may have been a rise in CL-associated filamentary FK in the United Kingdom. This retrospective case series investigated the patterns of FK from 2007 to 2014. We compared these to 1994-2006 data from the same hospital. DESIGN: Retrospective observational study. METHODS: All cases of FK presenting to Moorfields Eye Hospital between 2007 and 2014 were identified. The definition of FK was either a fungal organism isolated by culture or fungal structures identified by light microscopy (LM) of scrape material, histopathology, or in vivo corneal confocal microscopy (IVCM). Main outcome measure was cases of FK per year. RESULTS: A total of 112 patients had confirmed FK. Median age was 47.2 years. Between 2007 and 2014, there was an increase in annual numbers of FK (Poisson regression, P = .0001). FK was confirmed using various modalities: 79 (70.5%) by positive culture, 16 (14.3%) by LM, and 61 (54.5%) by IVCM. Seventy-eight patients (69.6%) were diagnosed with filamentary fungus alone, 28 (25%) with yeast alone, and 6 (5.4%) with mixed filamentary and yeast infections. This represents an increase in the proportion of filamentary fungal infections from the pre-2007 data. Filamentary fungal and yeast infections were associated with CL use and OSD, respectively. CONCLUSIONS: The number of FK cases has increased. This increase is due to CL-associated filamentary FK. Clinicians should be aware of these changes, which warrant epidemiologic investigations to identify modifiable risk factors

Digital gene expression analysis of two life cycle stages of the human-infective parasite, Trypanosoma brucei gambiense reveals differentially expressed clusters of co-regulated genes

<p><b>Background</b></p> <p>The evolutionarily ancient parasite, Trypanosoma brucei, is unusual in that the majority of its genes are regulated post-transcriptionally, leading to the suggestion that transcript abundance of most genes does not vary significantly between different life cycle stages despite the fact that the parasite undergoes substantial cellular remodelling and metabolic changes throughout its complex life cycle. To investigate this in the clinically relevant sub-species, Trypanosoma brucei gambiense, which is the causative agent of the fatal human disease African sleeping sickness, we have compared the transcriptome of two different life cycle stages, the potentially human-infective bloodstream forms with the non-human-infective procyclic stage using digital gene expression (DGE) analysis.</p> <p><b>Results</b></p> <p>Over eleven million unique tags were generated, producing expression data for 7360 genes, covering 81% of the genes in the genome. Compared to microarray analysis of the related T. b. brucei parasite, approximately 10 times more genes with a 2.5-fold change in expression levels were detected. The transcriptome analysis revealed the existence of several differentially expressed gene clusters within the genome, indicating that contiguous genes, presumably from the same polycistronic unit, are co-regulated either at the level of transcription or transcript stability.</p> <p><b>Conclusions</b></p> <p>DGE analysis is extremely sensitive for detecting gene expression differences, revealing firstly that a far greater number of genes are stage-regulated than had previously been identified and secondly and more importantly, this analysis has revealed the existence of several differentially expressed clusters of genes present on what appears to be the same polycistronic units, a phenomenon which had not previously been observed in microarray studies. These differentially regulated clusters of genes are in addition to the previously identified RNA polymerase I polycistronic units of variant surface glycoproteins and procyclin expression sites, which encode the major surface proteins of the parasite. This raises a number of questions regarding the function and regulation of the gene clusters that clearly warrant further study.</p&gt