Enabling rapid iterative model design within the laboratory environment

This thesis presents a proof of concept study for the better integration of the electrophysiological and modelling aspects of neuroscience. Members of these two sub-disciplines collaborate regularly, but due to differing resource requirements, and largely incompatible spheres of knowledge, cooperation is often impeded by miscommunication and delays. To reduce the model design time, and provide a platform for more efficient experimental analysis, a rapid iterative model design method is proposed. The main achievement of this work is the development of a rapid model evaluation method based on parameter estimation, utilising a combination of evolutionary algorithms (EAs) and graphics processing unit (GPU) hardware acceleration. This method is the primary force behind the better integration of modelling and laboratorybased electrophysiology, as it provides a generic model evaluation method that does not require prior knowledge of model structure, or expertise in modelling, mathematics, or computer science. If combined with a suitable intuitive and user targeted graphical user interface, the ideas presented in this thesis could be developed into a suite of tools that would enable new forms of experimentation to be performed. The latter part of this thesis investigates the use of excitability-based models as the basis of an iterative design method. They were found to be computationally and structurally simple, easily extensible, and able to reproduce a wide range of neural behaviours whilst still faithfully representing underlying cellular mechanisms. A case study was performed to assess the iterative design process, through the implementation of an excitability-based model. The model was extended iteratively, using the rapid model evaluation method, to represent a vasopressin releasing neuron. Not only was the model implemented successfully, but it was able to suggest the existence of other more subtle cell mechanisms, in addition to highlighting potential failings in previous implementations of the class of neuron

A Soft Budget Constraint Explanation for the Venture Capital Cycle

We explore why venture capital funds limit the amount of capital they raise and do not reinvest the proceeds. This structure is puzzling because it leads to a succession of several funds financing each new venture which multiplies the well known agency problems. We argue that an inside investor cannot provide a hard budget constraint while a less well informed outsider can. Therefore, the venture capitalist delegates the continuation decision to the outsider by ex ante restricting the amount of capital he has under management. The soft budget constraint problem becomes the more important the higher the entrepreneur’s private benefits are and the higher the probability of failure of a project is

Spitzer Space Telescope Infrared Imaging and Spectroscopy of the Crab Nebula

We present 3.6, 4.5, 5.8, 8.0, 24, and 70 micron images of the Crab Nebula obtained with the Spitzer Space Telescope IRAC and MIPS cameras, Low- and High-resolution Spitzer IRS spectra of selected positions within the nebula, and a near-infrared ground-based image made in the light of [Fe II]1.644 micron. The 8.0 micron image, made with a bandpass that includes [Ar II]7.0 micron, resembles the general morphology of visible H-alpha and near-IR [Fe II] line emission, while the 3.6 and 4.5 micron images are dominated by continuum synchrotron emission. The 24 micron and 70 micron images show enhanced emission that may be due to line emission or the presence of a small amount of warm dust in the nebula on the order of less than 1% of a solar mass. The ratio of the 3.6 and 4.5 micron images reveals a spatial variation in the synchrotron power law index ranging from approximately 0.3 to 0.8 across the nebula. Combining this information with optical and X-ray synchrotron images, we derive a broadband spectrum that reflects the superposition of the flatter spectrum jet and torus with the steeper diffuse nebula, and suggestions of the expected pileup of relativistic electrons just before the exponential cutoff in the X-ray. The pulsar, and the associated equatorial toroid and polar jet structures seen in Chandra and HST images (Hester et al. 2002) can be identified in all of the IRAC images. We present the IR photometry of the pulsar. The forbidden lines identified in the high resolution IR spectra are all double due to Doppler shifts from the front and back of the expanding nebula and give an expansion velocity of approximately 1264 km/s.Comment: 21 pages, 4 tables, 16 figure

Melting and differentiation of early-formed asteroids: The perspective from high precision oxygen isotope studies

A number of distinct methodologies are available for determining the oxygen isotope composition of minerals and rocks, these include laser-assisted fluorination, secondary ion mass spectrometry (SIMS)and UV laser ablation. In this review we focus on laser-assisted fluorination, which currently achieves the highest levels of precision available for oxygen isotope analysis. In particular, we examine how results using this method have furthered our understanding of early-formed differentiated meteorites. Due to its rapid reaction times and low blank levels, laser-assisted fluorination has now largely superseded the conventional externally-heated Ni “bomb” technique for bulk analysis. Unlike UV laser ablation and SIMS analysis, laser-assisted fluorination is not capable of focused spot analysis. While laser fluorination is now a mature technology, further analytical improvements are possible via refinements to the construction of sample chambers, clean-up lines and the use of ultra-high resolution mass spectrometers. High-precision oxygen isotope analysis has proved to be a particularly powerful technique for investigating the formation and evolution of early-formed differentiated asteroids and has provided unique insights into the interrelationships between various groups of achondrites. A clear example of this is seenin samples that lie close to the terrestrial fractionation line (TFL). Based on the data from conventional oxygen isotope analysis, it was suggested that the main-group pallasites, the howardite eucrite diogenite suite (HEDs) and mesosiderites could all be derived from a single common parent body. However,high precision analysis demonstrates that main-group pallasites have a Δ17O composition that is fully resolvable from that of the HEDs and mesosiderites, indicating the involvement of at least two parent bodies. The range of Δ17O values exhibited by an achondrite group provides a useful means of assessing the extent to which their parent body underwent melting and isotopic homogenization. Oxygen isotope analysis can also highlight relationships between ungrouped achondrites and the more well-populated groups. A clear example of this is the proposed link between the evolved GRA 06128/9 meteorites and the brachinites. The evidence from oxygen isotopes, in conjunction with that from other techniques, indicates that we have samples from approximately 110 asteroidal parent bodies (∼60 irons, ∼35 achondrites and stony-iron, and ∼15 chondrites) in our global meteorite collection. However, compared to the likely size of the original protoplanetary asteroid population, this is an extremely low value. In addition, almost all of the differentiated samples (achondrites, stony-iron and irons) are derived from parent bodies that were highly disrupted early in their evolution. High-precision oxygen isotope analysis of achondrites provides some important insights into the origin of mass-independent variation in the early Solar System. In particular, the evidence from various primitive achondrite groups indicates that both the slope 1 (Y&R) and CCAM lines are of primordial significance. Δ17O differences between water ice and silicate-rich solids were probably the initial source of the slope 1 anomaly. These phases most likely acquired their isotopic composition as a result of UV photo-dissociation of CO that took place either in the early solar nebula or precursor giant molecular cloud. Such small-scale isotopic heterogeneities were propagated into larger-sized bodies, such as asteroids and planets, as a result of early Solar System processes, including dehydration, aqueous alteration,melting and collisional interactions

Origin of volatiles in the Main Belt

We propose a scenario for the formation of the Main Belt in which asteroids incorporated icy particles formed in the outer Solar Nebula. We calculate the composition of icy planetesimals formed beyond a heliocentric distance of 5 AU in the nebula by assuming that the abundances of all elements, in particular that of oxygen, are solar. As a result, we show that ices formed in the outer Solar Nebula are composed of a mix of clathrate hydrates, hydrates formed above 50 K and pure condensates produced at lower temperatures. We then consider the inward migration of solids initially produced in the outer Solar Nebula and show that a significant fraction may have drifted to the current position of the Main Belt without encountering temperature and pressure conditions high enough to vaporize the ices they contain. We propose that, through the detection and identification of initially buried ices revealed by recent impacts on the surfaces of asteroids, it could be possible to infer the thermodynamic conditions that were present within the Solar Nebula during the accretion of these bodies, and during the inward migration of icy planetesimals. We also investigate the potential influence that the incorporation of ices in asteroids may have on their porosities and densities. In particular, we show how the presence of ices reduces the value of the bulk density of a given body, and consequently modifies its macro-porosity from that which would be expected from a given taxonomic type.Comment: Accepted for publication in MNRA

Macrosomia and Hyperinsulinaemic Hypoglycaemia in Patients with Heterozygous Mutations in the HNF4A Gene

BACKGROUND: Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS: We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS: HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life

Mitochondrial phylogeography and demographic history of the Vicuña: implications for conservation

The vicuña (Vicugna vicugna; Miller, 1924) is a conservation success story, having recovered from near extinction in the 1960s to current population levels estimated at 275 000. However, lack of information about its demographic history and genetic diversity has limited both our understanding of its recovery and the development of science-based conservation measures. To examine the evolution and recent demographic history of the vicuña across its current range and to assess its genetic variation and population structure, we sequenced mitochondrial DNA from the control region (CR) for 261 individuals from 29 populations across Peru, Chile and Argentina. Our results suggest that populations currently designated as Vicugna vicugna vicugna and Vicugna vicugna mensalis comprise separate mitochondrial lineages. The current population distribution appears to be the result of a recent demographic expansion associated with the last major glacial event of the Pleistocene in the northern (18 to 22°S) dry Andes 14–12 000 years ago and the establishment of an extremely arid belt known as the 'Dry Diagonal' to 29°S. Within the Dry Diagonal, small populations of V. v. vicugna appear to have survived showing the genetic signature of demographic isolation, whereas to the north V. v. mensalis populations underwent a rapid demographic expansion before recent anthropogenic impacts

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies