Not available / text

Not available / text

Not available / text

The development of new technologies and the advancement of existing technical expertise can allow for dramatic improvements to be realized in analytical instrumentation. The development of an integrating solid-state ion detector, designed to have a high sensitivity as well as maintaining a high-level of stability, is described and evaluated. Several versions of the charge-transimpedance amplifier (CTIA) technology were constructed with different operating features. The CTIA-1 is a 32-pixel array detector designed for mass spectrometry. It has the capability to simultaneously detect multiple ion channels with a detection limit less than 100 ions. The CTIA-2 detector features an independent selectable gain for each detection channel. The CTIA-2 is a 4-channel device designed for ion mobility. Further design features were built into the CTIA-5 such as differential noise reduction capabilities.The CTIA-1 technology was evaluated for use in isotope ratio mass spectrometry on a custom-built Mattauch-Herzog mass spectrometer. An evaluation was conducted in terms of the detector sensitivity, stability, accuracy, precision, resolution, and mass bias. The CTIA-2 was tested on a sector mass spectrometer for its response to low ion currents of both positive and negative ions. The detector stability, its accuracy, and its precision were studied.The technique of ion mobility spectrometry is rapidly growing, as it is the main technology used for the detection of explosives at security checkpoints. The need to improve the sensitivity of existing ion mobility instruments has led to the exploration of using the CTIA detector in ion mobility instruments. Improvements in sensitivity of two to three orders of magnitude have been demonstrated using the described CTIA detectors. Additional applications that use ion mobility instruments for the detection of analytes have been presented, the chemical mapping of a halogen-contaminated sand bed, the detection of pesticides, as well as the detection of TNT in drinking water.Results indicate that the CTIA detector technology is well suited for use in both mass spectrometry and ion mobility. The sensitive and stable multi-array CTIA detectors perform well in isotope ratio mass spectrometry. Ion mobility instruments of all types can benefit from the added sensitivity supplied by this technology.

DNA copy number alterations (CNAs) are genetic changes that can produce adverse effects in numerous human diseases, including cancer. CNAs are segments of DNA that have been deleted or amplified and can range in size from one kilobases to whole chromosome arms. Development of array comparative genomic hybridization (aCGH) technology enables CNAs to be measured at sub-megabase resolution using tens of thousands of probes. However, aCGH data are noisy and result in continuous valued measurements of the discrete CNAs. Consequently, the data must be processed through algorithmic and statistical techniques in order to derive meaningful biological insights. We introduce model-based approaches to analysis of aCGH data and develop state-of-the-art solutions to three distinct analytical problems. In the simplest scenario, the task is to infer CNAs from a single aCGH experiment. We apply a hidden Markov model (HMM) to accurately identify CNAs from aCGH data. We show that borrowing statistical strength across chromosomes and explicitly modeling outliers in the data, improves on baseline models. In the second scenario, we wish to identify recurrent CNAs in a set of aCGH data derived from a patient cohort. These are locations in the genome altered in many patients, providing evidence for CNAs that may be playing important molecular roles in the disease. We develop a novel hierarchical HMM profiling method that explicitly models both statistical and biological noise in the data and is capable of producing a representative profile for a set of aCGH experiments. We demonstrate that our method is more accurate than simpler baselines on synthetic data, and show our model produces output that is more interpretable than other methods. Finally, we develop a model based clustering framework to stratify a patient cohort, expected to be composed of a fixed set of molecular subtypes. We introduce a model that jointly infers CNAs, assigns patients to subgroups and infers the profiles that represent each subgroup. We show our model to be more accurate on synthetic data, and show in two patient cohorts how the model discovers putative novel subtypes and clinically relevant subgroups.

Small Cell Lung Cancer (SCLC) is a very aggressive neuroendocrine tumour of the lung, which demonstrates a 5 year survival of only 10% for extensive stage disease (20-30% for limited stage), with only modest improvement over the last few decades. Identification of new molecular diagnostic and therapeutic targets is thus imperative. Previous efforts in identifying molecular changes in SCLC by gene expression profiling using microarrays have facilitated disease classification but yielded very limited information on SCLC biology. Previous DNA studies have been successful in identifying several loci important to SCLC. However the low resolution of conventional chromosomal Comparative Genomic Hybridization (CGH) has limited the findings to large chromosomal regions with only a few specific candidate genes discovered to date. Thus, to further understand the biological behaviour of SCLC, better methods for studying the genomic alterations in SCLC are necessary. This thesis highlights the development of array CGH technology for the high resolution dissection of aneuploidy in cancer genomes and the application of this new technology to the study of SCLC. I present the development of the first whole genome CGH array which offered unprecedented resolution in the profiling of cancer genomes allowing fine mapping of genes in a single experiment. Through application of DNA based analysis in conjunction with integrated expression analysis and comparison of SCLC to less aggressive non-small cell lung tumours I have identified novel patterns of pathway disruption specific to SCLC. This included alteration to Wnt pathway members and striking patterns of cell cycle activation through predominantly downstream disruption of signalling pathways including direct activation of the E2F transcription factors, which are normally repressed by the Rb gene. Analysis of targets of the E2F/Rb pathway identified EZH2 as being specifically hyper-activated in SCLC, compared to NSCLC. EZH2 is a polycomb group gene involved in the control of many cellular functions including targeted DNA methylation and escape from senescence in hematopoietic stem cells. Taken together these results suggest that in SCLC, downstream disruption may replace multiple upstream alterations leading to activation independent of a specific mitogenic pathway, and that EZH2 represents a potentially important therapeutic target.

Electroretinoraphic signals (ERGs) are affected when recorded under isoflurane anesthesia in the operating room. We explored the effect of isoflurane and propofol in ex vivo guinea pig retinal preparations using a multielectrode array to record simultaneously ERGs and retinal ganglion cell (RGC) activity. The viability and light-response characteristics of the model were documented. In the presence of isoflurane, the ERG and RGC activity was reduced in a dose-dependent manner, even at sub-clinical doses; the OFF responses were consistently more affected. Propofol had minimal effects: at subclinical doses, a small excitation was measured while a concentration a hundred times stronger than the clinical concentration was required to measure a significant decline in EGR and RGC signals. This study confirms the usefulness of the guinea pig model to study clinically relevant retinal issues and shows that propofol is a better anesthetic to use in the operating room when retinal investigations are required.

The Houston Lightning Mapping Array (LMA) is a lightning detection network providing total lightning mapping for the Houston metropolitan area and southeast Texas. The network is comprised of twelve Very High Frequency (VHF) time-of-arrival total lightning mapping sensors built by New Mexico Institute of Mining and Technology and purchased by Texas A&M University. The sensors, installed in April 2012, are of the latest, modular design and built to be independent stations that utilize a solar panel for electricity and cellular data modems for communication. Each sensor detects the time of arrival of a VHF impulse emitted as part of the electrical breakdown and lightning propagation process. Data from each sensor are processed on a central LMA server to provide three-dimensional mapping of these impulses, also called LMA sources. This processing facilitates the analysis of variations in thunderstorm structure and the associated changes in both space and time. The primary objectives for the installation of the Houston LMA network are twofold: first, to provide a dataset enabling research into thunderstorm electrification in the context of a coastal, urban, polluted environment; and second, to enable improvements in operational forecasting and public safety by providing total lightning data to partners including the National Weather Service (NWS). A workflow was established to create and share real-time data to these partners, while simultaneously maintaining a full, research-quality dataset. Data are retrieved from the field sensors and backed up to a central LMA server for processing and storage. Archived network data are available from July 2012 through the present. The network measures 150 km from north to south, with stations in College Station and Galveston complementing the ten sites surrounding downtown Houston. This extends the region constrained by the network beyond the immediate metropolitan Houston area, resulting in increased accuracy in locating sources further from the network center. Based on initial analyses, the effective range of the Houston LMA is 75 km for three-dimensional mapping and approximately 250 km for two-dimension mapping.

No description available.

No description available.