Using seasonal climate forecasting in agriculture: a participatory decision-making approach

Farm Management,

From membrane to nucleus: New roles and functions of SUMOylated IGF-1R and EGFR

Cell surface receptor tyrosine kinases (RTKs) role in cell signaling have been studied for decades and their role in cancer progression are undisputable. The insulin-like growth factor 1 receptor, IGF-1R, has been demonstrated to play a critical part in tumorigenesis; downregulation of the IGF-1R in tumor xenografts results in complete tumor regression. Previously, RTK research has focused on the canonical signaling pathways activated by ligand binding at the plasma membrane. However, strong evidence keeps emerging that several RTKs have a second functionally mechanism, inside the cell nucleus, where the receptors reside after ligand stimulation. The aim of this thesis was to elucidate the function of recently discovered nuclear IGF-1R as well as to investigate its nuclear translocation pathway. Since it was previously shown that SUMOylation of the IGF-1R is essential for its nuclear translocation we also set out to investigate SUMO modification of the epidermal growth factor receptor (EGFR). In paper I, we present a functional role for nuclear IGF-1R in gene transcription. Inside the nucleus, IGF-1R functions as a co-activator to LEF-1/TCF transcription factor. Nuclear IGF-1R enhances transcription of cyclin D1 and axin2, and we show that it is enriched in the cyclin D1 promoter region. In the following study, paper II, we propose a pathway by which IGF-1R is transported into the nucleus. IGF-1R is transported along microtubules via the dynactin transportation complex, to the nuclear pore where it is transferred to importin-β which guides the receptor to the nuclear pore complex protein RanBP2, which further assists the receptor into the cell nucleus in a RanGTPase dependent manner. Inhibition or obstruction of any of these components results in a reduction in nuclear IGF-1R. Further, we suggest that RanBP2 is the SUMO E3 ligase in IGF-1R SUMOylation and we show that SUMO-1 modification of the receptor is also important for its stability. In paper III, we demonstrate that the EGFR is SUMOylated and propose five lysine residues as SUMO-1 targets which were identified by two different mass spectrometry strategies. One of these residues, lysine 37, came up as a suggested target in both mass spectrometry methods. EGFR mutated in this site – EGFR-K37R – causes a decrease in protein levels as well as transcriptional activity of cyclin D1 and c-myc, two target genes of nuclear EGFR. To summarize, our data shows (I) a pathway by which nuclear IGF-1R is being transported and the functional importance of nuclear IGF-1R as a co-activator in transcription and (II) that the EGFR is also SUMOylated and might play a role in its transcriptional activity. Together these results may unravel new mechanisms for IGF-1R and EGFR that have implications in carcinogenesis

Credit gap risk in a first passage time model with jumps

The payoff of many credit derivatives depends on the level of credit spreads. In particular, credit derivatives with a leverage component are subject to gap risk, a risk associated with the occurrence of jumps in the underlying credit default swaps. In the framework of first passage time models, we consider a model that addresses these issues. The principal idea is to model a credit quality process as an Itô integral with respect to a Brownian motion with a stochastic volatility. Using a representation of the credit quality process as a time-changed Brownian motion, one can derive formulas for conditional default probabilities and credit spreads. An example for a volatility process is the square root of a Lévy-driven Ornstein-Uhlenbeck process. The model can be implemented efficiently using a technique called Panjer recursion. Calibration to a wide range of dynamics is supported. We illustrate the effectiveness of the model by valuing a leveraged credit-linked note. --gap risk,credit spreads,credit dynamics,first passage time models,stochastic volatility,general Ornstein-Uhlenbeck processes

Latin hypercube sampling with dependence and applications in finance

In Monte Carlo simulation, Latin hypercube sampling (LHS) [McKay et al. (1979)] is a well-known variance reduction technique for vectors of independent random variables. The method presented here, Latin hypercube sampling with dependence (LHSD), extends LHS to vectors of dependent random variables. The resulting estimator is shown to be consistent and asymptotically unbiased. For the bivariate case and under some conditions on the joint distribution, a central limit theorem together with a closed formula for the limit variance are derived. It is shown that for a class of estimators satisfying some monotonicity condition, the LHSD limit variance is never greater than the corresponding Monte Carlo limit variance. In some valuation examples of financial payoffs, when compared to standard Monte Carlo simulation, a variance reduction of factors up to 200 is achieved. LHSD is suited for problems with rare events and for high-dimensional problems, and it may be combined with Quasi-Monte Carlo methods. --Monte Carlo simulation,variance reduction,Latin hypercube sampling,stratified sampling

Financial interests of patient organisations contributing to technology appraisal at England's National Institute for Health and Care Excellence (NICE): a policy review

Objectives: To investigate the prevalence of financial interests among patient organisations contributing to health technology assessment at the National Institute for Health and Care Excellence (NICE) in England, and the extent to which current disclosure policy ensures decision-making committees are aware of these interests. Design: Policy review using annual accounts, reports and websites of patient organisations, a database of payments declared by pharmaceutical manufacturers (Disclosure UK), other manufacturer declarations, responses from patient organisations, and declarations of interests by nominated representatives of patient organisations. Setting: Appraisals of medicines and treatments for use in the English and Welsh National Health Service. Participants: 53 patient organisations contributing to 41 NICE technology appraisals published in 2015 and 2016, with 117 separate occasions that a patient organisation contributed to the appraisal of a technology. Main outcome measures: (i) Prevalence of specific interests, i.e. funding from manufacturer(s) of a technology under appraisal or competitor products; (ii) Proportion of specific interests of which NICE decision-making committees were aware; (iii) Proportion of specific interests for which disclosure was not required by current NICE policy. Results: 38/53 (71.7%) patient organisations had accepted funding from the manufacturer(s) of a technology or a competitor product in the same or previous year that they had contributed to the appraisal of that technology. Specific interests were 46 present on 92 out of 117 (78.6%) occasions that patient organisations contributed to appraisals in 2015 and 2016. NICE decision-making committees were aware of less than a third of specific interests (36/115, 31.3%). For over half of the specific interests of which committees were unaware (42/79, 53.2%), disclosure by patient organisations was not required by current NICE policy. Conclusions: Specific interests are highly prevalent among patient organisations contributing to health technology assessment. NICE is reviewing its disclosure policy to ensure that decision-making committees are aware of all relevant interests

Academic Freedom and 21st Century European Universities

It is argued that university education has a moral and social function in society. Its purpose is to provide a liberal education (developing the intellect by challenging it to grapple freely with difficult ideas), the development of new knowledge and the provision of trustworthy, disinterested research. To serve society in this way safeguards are necessary: a separation from the state, giving institutional autonomy and academic freedom in teaching and research. With the rise of extreme free market capitalism and the "knowledge society", these safeguards are being eroded: national governments, partly through the ramifications of the Bologna convergence process, are in the process of moulding universities to the needs of the market, and now see the accommodation of students to the workplace as the principal, or indeed only, objective for a university education. Example of the consequences of these changes are discussed, including the corruption of research integrity and erosion of individual liberties

The Vector-APP: a Broadband Apodizing Phase Plate that yields Complementary PSFs

The apodizing phase plate (APP) is a solid-state pupil optic that clears out a D-shaped area next to the core of the ensuing PSF. To make the APP more efficient for high-contrast imaging, its bandwidth should be as large as possible, and the location of the D-shaped area should be easily swapped to the other side of the PSF. We present the design of a broadband APP that yields two PSFs that have the opposite sides cleared out. Both properties are enabled by a half-wave liquid crystal layer, for which the local fast axis orientation over the pupil is forced to follow the required phase structure. For each of the two circular polarization states, the required phase apodization is thus obtained, and, moreover, the PSFs after a quarter-wave plate and a polarizing beam-splitter are complementary due to the antisymmetric nature of the phase apodization. The device can be achromatized in the same way as half-wave plates of the Pancharatnam type or by layering self-aligning twisted liquid crystals to form a monolithic film called a multi-twist retarder. As the VAPP introduces a known phase diversity between the two PSFs, they may be used directly for wavefront sensing. By applying an additional quarter-wave plate in front, the device also acts as a regular polarizing beam-splitter, which therefore furnishes high-contrast polarimetric imaging. If the PSF core is not saturated, the polarimetric dual-beam correction can also be applied to polarized circumstellar structure. The prototype results show the viability of the vector-APP concept.Comment: Proc. SPIE 8450-2

HST and Spitzer point source detection and optical extinction in powerful narrow-line radio galaxies

We present the analysis of infrared HST and Spitzer data for a sample of 13 FRII radio galaxies at 0.03<z<0.11 that are classified as narrow-line radio galaxies (NLRG). In the context of the unified schemes for active galactic nuclei (AGN), our direct view of the AGN in NLRG is impeded by a parsec-scale dusty torus structure. Our high resolution infrared observations provide new information about the degree of extinction induced by the torus, and the incidence of obscured AGN in NLRG. We find that the point-like nucleus detection rate increases from 25 per cent at 1.025$\mu$m, to 80 per cent at 2.05$\mu$m, and to 100 per cent at 8.0$\mu$m. This supports the idea that most NLRG host an obscured AGN in their centre. We estimate the extinction from the obscuring structures using X-ray, near-IR and mid-IR data. We find that the optical extinction derived from the 9.7$\mu$m silicate absorption feature is consistently lower than the extinction derived using other techniques. This discrepancy challenges the assumption that all the mid-infrared emission of NLRG is extinguished by a simple screen of dust at larger radii. This disagreement can be explained in terms of either weakening of the silicate absorption feature by (i) thermal mid-IR emission from the narrow-line region, (ii) non-thermal emission from the base of the radio jets, or (iii) by direct warm dust emission that leaks through a clumpy torus without suffering major attenuation.Comment: 18 pages, 7 figures, 8 tables, accepted for publication in MNRA