The mechanism of maturation of insulin-like growth factor-1

This study, to elucidate the role of des(1-3)IGF-I in the maturation of IGF-I,used two strategies. The first was to detect the presence of enzymes in tissues, which would act on IGF-I to produce des(1-3)IGF-I, and the second was to detect the potential products of such enzymic activity, namely Gly-Pro-Glu(GPE), Gly-Pro(GP) and des(l- 3)IGF-I. No neutral tripeptidyl peptidase (TPP II), which would release the tripeptide GPE from IGF-I, was detected in brain, urine nor in red or white blood cells. The TPPlike activity which was detected, was attributed to a combined action of a dipeptidyl peptidase (DPP N) and an aminopeptidase (AP A). A true TPP II was, however, detected in platelets. Two purified TPP II enzymes were investigated but they did not release GPE from IGF-I under a variety of conditions. Consequently, TPP II seemed unlikely to participate in the formation of des(1-3)IGF-I. In contrast, an acidic tripeptidyl peptidase activity (TPP I) was detected in brain and colostrum, the former with a pH optimum of 4.5 and the latter 3.8. It seems likely that such an enzyme would participate in the formation of des( 1-3 )IGF-I in these tissues in vitro, ie. that des(1-3)IGF-I may have been produced as an artifact in the isolation of IGF-I from brain and colostrum in acidic conditions. This contrasts with suggestions of an in vivo role for des(1-3)IGF-I, as reported by others. The activity of a dipeptidyl peptidase N (DPP N) from urine, which should release the dipeptide GP from IGF-I, was assessed under a variety of conditions and with a variety of additives and potential enzyme stimulants, but there was no release of GP. The DPP N also exhibited a transferase activity with synthetic substrates in the presence of dipeptides, at lower concentrations than previously reported for other acceptors or other proteolytic enzymes. In addition, a low concentration of a product,possibly the tetrapeptide Gly-Pro-Gly-Leu, was detected with the action of the enzyme on IGF-I in the presence of the dipeptide Gly-Leu. As part of attempts to detect tissue production of des(1-3)IGF-I, a monoclonal antibody (MAb ), directed towards the GPE- end ofiGF-I was produced by immunisation with a 10-mer covalently attached to a carrier protein. By the use of indirect ELISA and inhibitor studies, the MAb was shown to selectively recognise peptides with anNterminal GPE- sequence, and applied to the indirect detection of des(1-3)IGF-I. The concentration of GPE in brain, measured by mass spectrometry ( MS), was low, and the concentration of total IGF-I (measured by ELISA with a commercial polyclonal antibody [P Ab]) was 40 times higher at 50 nmol/kg. This also, was not consistent with the action of a tripeptidyl peptidase in brain that converted all IGF-I to des(1-3)IGF-I plus GPE. Contrasting ELISA results, using the MAb prepared in this study, suggest an even higher concentration of intact IGF-I of 150 nmollkg. This would argue against the presence of any des( 1-3 )IGF-I in brain, but in turn, this indicates either the presence of other substances containing a GPE amino-terminus or other cross reacting epitope. Although the results of the specificity studies reported in Chapter 5 would make this latter possibility seem unlikely, it cannot be completely excluded. No GP was detected in brain by MS. No GPE was detected in colostrum by capillary electrophoresis (CE) but the interference from extraneous substances reduced the detectability of GPE by CE and this approach would require further, prior, purification and concentration steps. A molecule, with a migration time equal to that of the peptide GP, was detected in colostrum by CE, but the concentration (~ 10 11mo/L) was much higher than the IGF-I concentration measured by radio-immunoassay using a PAb (80 nmol/L) or using a Mab (300-400 nmolL). A DPP IV enzyme was detected in colostrum and this could account for the GP, derived from substrates other than IGF-1. Based on the differential results of the two antibody assays, there was no indication of the presence of des(1-3)IGF-I in brain or colostrum. In the absence of any enzyme activity directed towards the amino terminus of IGF-I and the absence any potential products, IGF-I, therefore, does not appear to "mature" via des(1-3)IGF-I in the brain, nor in the neutral colostrum. In spite of these results which indicate the absence of an enzymic attack on IGF-I and the absence of the expected products in tissues, the possibility that the conversion of IGF-I may occur in neutral conditions in limited amounts, cannot be ruled out. It remains possible that in the extracellular environment of the membrane, a complex interaction of IGF-I, binding protein, aminopeptidase(s) and receptor, produces des(1- 3)IGF-I as a transient product which is bound to the receptor and internalised.

Real-time performance modelling of a sustained attention to response task

Vigilance declines when exposed to highly predictable and uneventful tasks. Monotonous tasks provide little cognitive and motor stimulation and contribute to human errors. This paper aims to model and detect vigilance decline in real time through participant’s reaction times during a monotonous task. A lab-based experiment adapting the Sustained Attention to Response Task (SART) is conducted to quantify the effect of monotony on overall performance. Then relevant parameters are used to build a model detecting hypovigilance throughout the experiment. The accuracy of different mathematical models are compared to detect in real-time – minute by minute - the lapses in vigilance during the task. We show that monotonous tasks can lead to an average decline in performance of 45%. Furthermore, vigilance modelling enables to detect vigilance decline through reaction times with an accuracy of 72% and a 29% false alarm rate. Bayesian models are identified as a better model to detect lapses in vigilance as compared to Neural Networks and Generalised Linear Mixed Models. This modelling could be used as a framework to detect vigilance decline of any human performing monotonous tasks.

Experiments in visual localisation around underwater structures

Localisation of an AUV is challenging and a range of inspection applications require relatively accurate positioning information with respect to submerged structures. We have developed a vision based localisation method that uses a 3D model of the structure to be inspected. The system comprises a monocular vision system, a spotlight and a low-cost IMU. Previous methods that attempt to solve the problem in a similar way try and factor out the effects of lighting. Effects, such as shading on curved surfaces or specular reflections, are heavily dependent on the light direction and are difficult to deal with when using existing techniques. The novelty of our method is that we explicitly model the light source. Results are shown of an implementation on a small AUV in clear water at night.

Discrete choice modelling of combined mode and departure time

Typical daily decision-making process of individuals regarding use of transport system involves mainly three types of decisions: mode choice, departure time choice and route choice. This paper focuses on the mode and departure time choice processes and studies different model specifications for a combined mode and departure time choice model. The paper compares different sets of explanatory variables as well as different model structures to capture the correlation among alternatives and taste variations among the commuters. The main hypothesis tested in this paper is that departure time alternatives are also correlated by the amount of delay. Correlation among different alternatives is confirmed by analyzing different nesting structures as well as error component formulations. Random coefficient logit models confirm the presence of the random taste heterogeneity across commuters. Mixed nested logit models are estimated to jointly account for the random taste heterogeneity and the correlation among different alternatives. Results indicate that accounting for the random taste heterogeneity as well as inter-alternative correlation improves the model performance.

Performance evaluation of an adaptive travel time prediction model

This paper presents a travel time prediction model and evaluates its performance and transferability. Advanced Travelers Information Systems (ATIS) are gaining more and more importance, increasing the need for accurate, timely and useful information to the travelers. Travel time information quantifies the traffic condition in an easy to understand way for the users. The proposed travel time prediction model is based on an efficient use of nearest neighbor search. The model is calibrated for optimal performance using Genetic Algorithms. Results indicate better performance by using the proposed model than the presently used naïve model.

Estimation of travel time on urban networks with midlink sources and sinks

This paper presents a methodology for estimation of average travel time on signalized urban networks by integrating cumulative plots and probe data. This integration aims to reduce the relative deviations in the cumulative plots due to midlink sources and sinks. During undersaturated traffic conditions, the concept of a virtual probe is introduced, and therefore, accurate travel time can be obtained when a real probe is unavailable. For oversaturated traffic conditions, only one probe per travel time estimation interval—360 s or 3% of vehicles traversing the link as a probe—has the potential to provide accurate travel time.

Cluster-based network model for time-course gene expression data

We propose a model-based approach to unify clustering and network modeling using time-course gene expression data. Specifically, our approach uses a mixture model to cluster genes. Genes within the same cluster share a similar expression profile. The network is built over cluster-specific expression profiles using state-space models. We discuss the application of our model to simulated data as well as to time-course gene expression data arising from animal models on prostate cancer progression. The latter application shows that with a combined statistical/bioinformatics analyses, we are able to extract gene-to-gene relationships supported by the literature as well as new plausible relationships.