Flow heterogeneity in the fractured Chalk aquifer of southern England

The aim of the current work is to investigate the heterogeneity of flow in the Chalk aquifer of southern England. The rock mass properties and hydraulic characteristics of the aquifer have been characterised using a suite of geological and geophysical surveys and hydraulic tests. Fracture logs have been produced based on core logging and using optical images of boreholes. Flow has been characterised using borehole flow logs and dilution tests and hydraulic conductivity measured using packer tests. Fractures have been recorded with apertures in the range <1mm to about 30cm (sub-karstic enlargement) in diameter, however, hydrogeologically significant flow is not restricted to the enlarged fractures and is affected by the local groundwater head distribution. The work is being undertaken as part of the LOCAR Programme. LOCAR is a multi-project programme with the aim of measuring and modelling processes controlling water and material fluxes within lowland permeable catchments in the UK

Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library

The diverse physiological roles of the neurotrophin family have long prompted exploration of their potential as therapeutic agents for nerve injury and neurodegenerative diseases. To date, clinical trials of one family member, brain-derived neurotrophic factor (BDNF), have disappointingly failed to meet desired endpoints. Contributing to these failures is the fact that BDNF is pharmaceutically a nonideal biologic drug candidate. It is a highly charged, yet is a net hydrophobic molecule with a low molecular weight that confers a short t1/2 in man. To circumvent these shortcomings of BDNF as a drug candidate, we have employed a function-based cellular screening assay to select activating antibodies of the BDNF receptor TrkB from a combinatorial human short-chain variable fragment antibody library. We report here the successful selection of several potent TrkB agonist antibodies and detailed biochemical and physiological characterization of one such antibody, ZEB85. By using a human TrkB reporter cell line and BDNF-responsive GABAergic neurons derived from human ES cells, we demonstrate that ZEB85 is a full agonist of TrkB, comparable in potency to BDNF toward human neurons in activation of TrkB phosphorylation, canonical signal transduction, and mRNA transcriptional regulation

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

The retinal explant as a model to investigate neuronal pathology and neuroprotective strategies

Despite the association of neuronal cell loss with a wide range of neurodegenerative disorders, the mechanisms leading to this cell death remain poorly understood. In this thesis I have investigated these mechanisms and tested whether they represent viable targets for therapeutic intervention. The adult mouse retinal explant is a popular model of axotomy-induced neuronal degeneration but has been limited by the lack of morphometric data. Since dendritic pruning is well-evidenced to precede cell loss in neurodegenerative diseases, including glaucoma and Alzheimer’s disease, I investigated whether the quantification of dendritic morphology of retinal ganglion cells in the retinal explant could be used as a more sensitive measure of neuronal health after axotomy. I report here that retinal ganglion cell dendrite loss precedes cell loss by at least 7 days and that this retraction is substantially retarded following treatment with brain-derived neurotrophic factor applied at the time of explantation. Perhaps most importantly, I demonstrate for the first time in this model that delayed application of brain-derived neurotrophic factor significantly protects against dendritic retraction of retinal ganglion cells. The work outlined in this thesis thus supports the targeting of dendritic outgrowth and/or synaptic connectivity for the treatment of neurodegenerative disorders

Integrated time-lapse geoelectrical imaging of wetland hydrological processes

Wetlands provide crucial habitats, are critical in the global carbon cycle, and act as key biogeochemical and hydrological buffers. The effectiveness of these services is mainly controlled by hydrological processes, which can be highly variable both spatially and temporally due to structural complexity and seasonality. Spatial analysis of 2D geoelectrical monitoring data integrated into the interpretation of conventional hydrological data has been implemented to provide a detailed understanding of hydrological processes in a riparian wetland. This study shows that a combination of processes can define the resistivity signature of the shallow subsurface, highlighting the seasonality of these processes and its corresponding effect on biogeochemical processesthe wetland hydrology. Groundwater exchange between peat and the underlying river terrace deposits, spatially and temporally defined by geoelectrical imaging and verified by point sensor data, highlighted the groundwater dependent nature of the wetland. A 30 % increase in peat resistivity was shown to be caused by a nearly entire exchange of the saturating groundwater. For the first time, we showed that automated interpretation of geoelectrical data can be used to quantify shrink-swell of expandable soils, affecting hydrological parameters, such as, porosity, water storage capacity, and permeability. This study shows that an integrated interpretation of hydrological and geophysical data can significantly improve the understanding of wetland hydrological processes. Potentially, this approach can provide the basis for the evaluation of ecosystem services and may aid in the optimization of wetland management strategies

Lack of Protection following Passive Transfer of Polyclonal Highly Functional Low-Dose Non-Neutralizing Antibodies

Recent immune correlates analysis from the RV144 vaccine trial has renewed interest in the role of non-neutralizing antibodies in mediating protection from infection. While neutralizing antibodies have proven difficult to induce through vaccination, extra-neutralizing antibodies, such as those that mediate antibody-dependent cellular cytotoxicity (ADCC), are associated with long-term control of infection. However, while several non-neutralizing monoclonal antibodies have been tested for their protective efficacy in vivo, no studies to date have tested the protective activity of naturally produced polyclonal antibodies from individuals harboring potent ADCC activity. Because ADCC-inducing antibodies are highly enriched in elite controllers (EC), we passively transferred highly functional non-neutralizing polyclonal antibodies, purified from an EC, to assess the potential impact of polyclonal non-neutralizing antibodies on a stringent SHIV-SF162P3 challenge in rhesus monkeys. Passive transfer of a low-dose of ADCC inducing antibodies did not protect from infection following SHIV-SF162P3 challenge. Passively administered antibody titers and gp120-specific, but not gp41-specific, ADCC and antibody induced phagocytosis (ADCP) were detected in the majority of the monkeys, but did not correlate with post infection viral control. Thus these data raise the possibility that gp120-specific ADCC activity alone may not be sufficient to control viremia post infection but that other specificities or Fc-effector profiles, alone or in combination, may have an impact on viral control and should be tested in future passive transfer experiments

Derivation of lowland riparian wetland deposit architecture using geophysical image analysis and interface detection

For groundwater-surface water interactions to be understood in complex wetland settings, the architecture of the underlying deposits requires investigation at a spatial resolution sufficient to characterize significant hydraulic pathways. Discrete intrusive sampling using conventional approaches provides insufficient sample density and can be difficult to deploy on soft ground. Here a noninvasive geophysical imaging approach combining three-dimensional electrical resistivity tomography (ERT) and the novel application of gradient and isosurface-based edge detectors is considered as a means of illuminating wetland deposit architecture. The performance of three edge detectors were compared and evaluated against ground truth data, using a lowland riparian wetland demonstration site. Isosurface-based methods correlated well with intrusive data and were useful for defining the geometries of key geological interfaces (i.e., peat/gravels and gravels/Chalk). The use of gradient detectors approach was unsuccessful, indicating that the assumption that the steepest resistivity gradient coincides with the associated geological interface can be incorrect. These findings are relevant to the application of this approach in settings with a broadly layered geology with strata of contrasting resistivities. In addition, ERT revealed substantial structures in the gravels related to the depositional environment (i.e., braided fluvial system) and a complex distribution of low-permeability putty Chalk at the bedrock surface—with implications for preferential flow and variable exchange between river and groundwater systems. These results demonstrate that a combined approach using ERT and edge detectors can provide valuable information to support targeted monitoring and inform hydrological modeling of wetlands

Complex conductivity of soils

The complex conductivity of soils remains poorly known despite the growing importance of this method in hydrogeophysics. In order to fill this gap of knowledge, we investigate the complex conductivity of 71 soils samples (including four peat samples) and one clean sand in the frequency range 0.1 Hz to 45 kHz. The soil samples are saturated with six different NaCl brines with conductivities (0.031, 0.53, 1.15, 5.7, 14.7, and 22 S m21, NaCl, 258C) in order to determine their intrinsic formation factor and surface conductivity. This data set is used to test the predictions of the dynamic Stern polarization model of porous media in terms of relationship between the quadrature conductivity and the surface conductivity. We also investigate the relationship between the normalized chargeability (the difference of in-phase conductivity between two frequencies) and the quadrature conductivity at the geometric mean frequency. This data set confirms the relationships between the surface conductivity, the quadrature conductivity, and the normalized chargeability. The normalized chargeability depends linearly on the cation exchange capacity and specific surface area while the chargeability shows no dependence on these parameters. These new data and the dynamic Stern layer polarization model are observed to be mutually consistent. Traditionally, in hydrogeophysics, surface conductivity is neglected in the analysis of resistivity data. The relationships we have developed can be used in field conditions to avoid neglecting surface conductivity in the interpretation of DC resistivity tomograms. We also investigate the effects of temperature and saturation and, here again, the dynamic Stern layer predictions and the experimental observations are mutually consistent