Development of electronics for microultrasound capsule endoscopy

Development of intracorporeal devices has surged in the last decade due to advancements in the semiconductor industry, energy storage and low-power sensing systems. This work aims to present a thorough systematic overview and exploration of the microultrasound (µUS) capsule endoscopy (CE) field as the development of electronic components will be key to a successful applicable µUSCE device. The research focused on investigating and designing high-voltage (HV, < 36 V) generating and driving circuits as well as a low-noise amplifier (LNA) for battery-powered and volume-limited systems. In implantable applications, HV generation with maximum efficiency is required to improve the operational lifetime whilst reducing the cost of the device. A fully integrated hybrid (H) charge pump (CP) comprising a serial-parallel (SP) stage was designed and manufactured for > 20 V and 0 - 100 µA output capabilities. The results were compared to a Dickson (DKCP) occupying the same chip area; further improvements in the SPCP topology were explored and a new switching scheme for SPCPs was introduced. A second regulated CP version was excogitated and manufactured to use with an integrated µUS pulse generator. The CP was manufactured and tested at different output currents and capacitive loads; its operation with an US pulser was evaluated and a novel self-oscillating CP mechanism to eliminate the need of an auxiliary clock generator with a minimum area overhead was devised. A single-output universal US pulser was designed, manufactured and tested with 1.5 MHz, 3 MHz, and 28 MHz arrays to achieve a means of fully-integrated, low-power transducer driving. The circuit was evaluated for power consumption and pulse generation capabilities with different loads. Pulse-echo measurements were carried out and compared with those from a commercial US research system to characterise and understand the quality of the generated pulse. A second pulser version for a 28 MHz array was derived to allow control of individual elements. The work involved its optimisation methodology and design of a novel HV feedback-based level-shifter. A low-noise amplifier (LNA) was designed for a wide bandwidth µUS array with a centre frequency of 28 MHz. The LNA was based on an energy-efficient inverter architecture. The circuit encompassed a full power-down functionality and was investigated for a self-biased operation to achieve lower chip area. The explored concepts enable realisation of low power and high performance LNAs for µUS frequencies

Theoretical and experimental studies on charge deformation densities and hydrogen bridges in borane anions and related species

Available from British Library Document Supply Centre- DSC:D85066 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Transiently Powered Computers

Demand for compact, easily deployable, energy-efficient computers has driven the development of general-purpose transiently powered computers (TPCs) that lack both batteries and wired power, operating exclusively on energy harvested from their surroundings. TPCs\u27 dependence solely on transient, harvested power offers several important design-time benefits. For example, omitting batteries saves board space and weight while obviating the need to make devices physically accessible for maintenance. However, transient power may provide an unpredictable supply of energy that makes operation difficult. A predictable energy supply is a key abstraction underlying most electronic designs. TPCs discard this abstraction in favor of opportunistic computation that takes advantage of available resources. A crucial question is how should a software-controlled computing device operate if it depends completely on external entities for power and other resources? The question poses challenges for computation, communication, storage, and other aspects of TPC design. The main idea of this work is that software techniques can make energy harvesting a practicable form of power supply for electronic devices. Its overarching goal is to facilitate the design and operation of usable TPCs. This thesis poses a set of challenges that are fundamental to TPCs, then pairs these challenges with approaches that use software techniques to address them. To address the challenge of computing steadily on harvested power, it describes Mementos, an energy-aware state-checkpointing system for TPCs. To address the dependence of opportunistic RF-harvesting TPCs on potentially untrustworthy RFID readers, it describes CCCP, a protocol and system for safely outsourcing data storage to RFID readers that may attempt to tamper with data. Additionally, it describes a simulator that facilitates experimentation with the TPC model, and a prototype computational RFID that implements the TPC model. To show that TPCs can improve existing electronic devices, this thesis describes applications of TPCs to implantable medical devices (IMDs), a challenging design space in which some battery-constrained devices completely lack protection against radio-based attacks. TPCs can provide security and privacy benefits to IMDs by, for instance, cryptographically authenticating other devices that want to communicate with the IMD before allowing the IMD to use any of its battery power. This thesis describes a simplified IMD that lacks its own radio, saving precious battery energy and therefore size. The simplified IMD instead depends on an RFID-scale TPC for all of its communication functions. TPCs are a natural area of exploration for future electronic design, given the parallel trends of energy harvesting and miniaturization. This work aims to establish and evaluate basic principles by which TPCs can operate

Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and health

Mitochondrial supercomplexes form around a conserved core of monomeric complex I and dimeric complex III; wherein a subunit of the former, NDUFA11, is conspicuously situated at the interface. We identified nduf-11 (B0491.5) as encoding the Caenorhabditis elegans homologue of NDUFA11. Animals homozygous for a CRISPR-Cas9-generated knockout allele of nduf-11 arrested at the second larval (L2) development stage. Reducing (but not eliminating) expression using RNAi allowed development to adulthood, enabling characterisation of the consequences: destabilisation of complex I and its supercomplexes and perturbation of respiratory function. The loss of NADH dehydrogenase activity was compensated by enhanced complex II activity, with the potential for detrimental reactive oxygen species (ROS) production. Cryo-electron tomography highlighted aberrant morphology of cristae and widening of both cristae junctions and the intermembrane space. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development presumably arises due to its involvement in complex I and supercomplex maintenance. This highlights the importance of respiratory complex integrity for health and the potential for its perturbation to cause mitochondrial disease. This article has an associated First Person interview with Amber Knapp-Wilson, joint first author of the paper

Das Verhalten von DASPMI in lebenden Zellen : spektral- und ortsaufgelöste Messungen der Fluoreszenz-Abklingzeit

Cellular metabolism can be envisaged by fluorescence lifetime imaging of fluorophores sensitive to specific intracellular factors such as [H+], [Ca2+], [O2], membrane potential, temperature, polarity of the probe environment, and alterations in the conformation and interactions of macromolecules. Lifetime measurements of the probes allow the quantitative determination of the intracellular factors. Fluorescence microscopy taking advantage of time-correlated single photon counting is a novel method that outperforms all other techniques with its single photon sensitivity and picoseconds time resolution. In this work, a time- and space-correlated single photon counting system was established to investigate the behavior of 2-(4-(dimethylamino)styryl)-1-methylpyridinium iodide (DASPMI) in living cells. DASPMI is known to selectively stain mitochondria in living cells. The uptake and fluorescence intensity of DASPMI in mitochondria is a dynamic measure of membrane potential. Hence, an endeavour was made to elucidate the mechanism of DASPMI fluorescence by obtaining spectrally-resolved fluorescence decays in different solvents. A bi-exponential decay model was sufficient to globally describe the wavelength dependent fluorescence in ethanol and chloroform. While in glycerol, a three-exponential decay model was necessary for global analysis. In the polar low-viscous solvent water, a mono-exponential decay model fitted the decay data. The sensitivity of DASPMI fluorescence to solvent viscosity was analysed using various proportions of glycerol/ethanol mixtures. The lifetimes were found to increase with increasing solvent viscosity. The negative amplitudes of the short lifetime component found in chloroform and glycerol at the longer wavelengths validated the formation of new excited state species from the initially excited state. Time-resolved emission spectra in chloroform and glycerol showed a biphasic increase of spectral width and emission maxima. The spectral width had an initial fast increase within 150 ps and a near constant thereafter. A two-state model based on solvation of the initially excited state and further formation of TICT state has been proposed to explain the excited state kinetics and has been substantiated by the de-composition of time-resolved spectra. The knowledge of DASPMI photophysics in a variety of solvents now provides the means of deducing complex physiological parameters of mitochondria from its behavior in living cells. Spatially-resolved fluorescence decays from single mitochondria or only very few organelles of XTH2 cells signified distinctive three-exponential decay kinetics of viscous environment. Based on DASPMI photophysics in a variety of solvents, these lifetimes have been attributed to the fluorescence from locally excited state (LE), intramolecular charge transfer state (ICT) and twisted intramolecular charge transfer (TICT) state. A considerable variation in lifetime among mitochondria of different morphology and within single cell was evident corresponding to the high physiological variations within single cells. Considerable shortening of the short lifetime component (&#964;1) under high membrane potential condition, such as in the presence of ATP and/or substrate, was similar to quenching and dramatic decrease of lifetime in polar solvents. Under these conditions &#964;2 and &#964;3 increased with decreasing contribution. Upon treatment with ionophore nigericin, hyperpolarization of mitochondria resulted in remarkable shortening of &#964;1 from 159 ps to 38 ps. Inhibiting respiration by cyanide resulted in notable increase of mean lifetime and decrease of mitochondrial fluorescence. Increase of DASPMI fluorescence on conditions elevating mitochondrial membrane potential has been attributed to uptake according Nernst distributions, to de-localisation of &#960; electrons, quenching processes of the methyl pyridinium moiety and restricted torsional dynamics at the mitochondrial inner membrane. Accordingly, determination of anisotropy in DASPMI stained mitochondria in living XTH2 cells, revealed dependence of anisotropy on membrane potential. Such changes in anisotropy attributed to restriction of the torsional dynamics about the flexible single bonds neighboring the olefinic double bond revealed the previously known sub-mitochondrial zones with higher membrane potential along its length. Membrane-potential-dependent changes in anisotropy have further been demonstrated in senescent chick embryo fibroblasts. In conclusion, spectroscopic observations of excited-state kinetics of DASPMI in solvents and its behavior in living cells had revealed for the first time its localisation, mechanism of voltage sensitive fluorescence and its membrane-potential-dependent anisotropy in living cells. The simultaneous dependence of DASPMI photophysics on mitochondrial inner membrane viscosity and transmembrane potential has been highlighted.Der Zellstoffwechsel kann durch die räumliche Messung der Fluoreszenz-Abklingzeit von Fluorophoren, die auf spezifische Änderungen intrazellulärer Bedingungen reagieren, wie z.B. [H+], [Ca2+], [O2], Membranpotential, Temperatur, lokale Polarität und Konformationsänderungen oder Interaktion von Makromolekülen ins Auge gefasst werden. Im Rahmen dieser Arbeit wurde ein Versuchsstand zur Zeit- und Orts-korrelierten Einzelphotonenregistrierung aufgebaut und spektral und ortsaufgelöste Messungen der Fluoreszenz-Abklingzeit von 2-(4-(dimethylamino)styryl)-1-methylpyridinium iodide (DASPMI) in lebenden Zellen durchgeführt. DASPMI reichert sich in lebenden Zellen in den Mitochondrien an, wobei sowohl der Grad der Anreicherung als auch die Fluoreszenzintensität vom mitochondrialen Membranpotential abhängen. Um den Mechanismus der Fluoreszenz von DASPMI aufzuklären wurden zunächst zeitaufgelöste Spektren in unterschiedlich polaren Lösungsmitteln aufgenommen: In Ethanol und Chloroform konnte der Fluoreszenzabfall global durch ein bi-exponentielles Modell beschrieben werden, wogegen in Glycerin ein tri-exponentielles Modell notwendig war. In Wasser, das stark polar und niedrig viskös ist war ein mono-exponentielles Modell hinreichend. Der Einfluss der Lösungsmittelviskosität wurde in Ethanol / g-Mischungelyzerinn unterschiedlicher Verhältnisse untersucht. Mit zunehmender Viskosität des Lösungsmittels stieg auch die Fluoreszenz-Abklingzeit. Das Auftreten einer negativen Amplitude der kurzen Abklingzeit in Chloroform und Glycerol bei größeren Wellenlängen belegt die Entstehung eines weiteren angeregten Zustandes aus dem anfänglichen angeregten Zustand. Die zeitaufgelösten Emissionsspektren in Chloroform und Glycerol zeigten einen biphasischen Anstieg des Emissionsmaximums und der spektralen Breite. Die spektrale Breite stieg anfänglich stark an und blieb nach 150 ps nahezu konstant. Um die Kinetik des angeregten Zustands zu erklären, wurde ein zweistufiges Modell entwickelt, das auf der Solvation des initialen angeregten Zustands und des TICT Zustands basiert. Die Untersuchung von einzelnen Mitochondrien bzw. wenigen Organellen von XTH2-Zellen zeigte eine tri-exponentielle Kinetik des Fluoreszenzabfalls. Auf Basis der photophysikalischen Eigenschaften von DASPMI in verschiedenen Lösungsmitteln wurden die gefundenen Fluoreszenz-Abklingzeiten drei unterschiedlichen angeregten Zuständen zugeordnet (locally excited (LE), intramolecular charge transfer (ICT) und twisted intramolecular charge transfer (TICT) state. Eine bemerkenswerte Variation in der Abklingzeit von Mitochondrien unterschiedlicher Form innerhalb einer Zelle war offensichtlich, was den hohen Variabilitaten der Zellphysiologie entspricht. Die starke Verringerung der kurzen Abklingzeit (&#61556;1) unter Bedingungen hohen Membranpotentials, wie z. B. in Anwesenheit von ATP oder Substrat entsprach dem Quenching und der dramatischen Abnahme der Abklingzeit in polarem Lösungsmittel. Unter diesen Bedingungen nahmen &#61556;2 und &#61556;3 mit abnehmendem Beitrag zu. Nach Behandlung mit dem Ionophor Nigericin, führte die Hyperpolarisation der Mitochondrien zu einer bemerkenswerten Verkürzung von &#61556;1 von 159 ps auf 38 ps. Die Hemmung der Zellatmung mit Cyanid führte zu einer beachtlichen Zunahme der Abklingzeit und einer Abnahme der mitochondrialen Fluoreszenz. Die Zunahme der DASPMI Fluoreszenz unter Bedingungen eines erhöhten mitochondrialen Membranpotentials ist einer Aufnahme entsprechend einer Nernst-Verteilung, der Delokalisation von &#61552;-Elektronen, Quenching der Methylpyridinium-Gruppe und der eingeschränkten Torsionsdynamik an der inneren Mitochondrienmembran zugeschrieben worden. Dementsprechend enthüllte die Bestimmung der Anisotropie von DASPMI-markierten Mitochondrien in lebenden XTH2-Zellen, die Abhängigkeit der Anisotropie vom Membranpotential. Solche Änderungen in der Anisotropie, die der Beschränkung der Torsionsdynamik um die flexiblen Einzelbindungen in Nachbarschaft der olefinischen Doppelbindung zugeschrieben werden, erwiesen die bereits vorher bekannten submitochondrialen Zonen erhöhten Membranpotentials entlang des Mitochondriums. Der direkte Einfluss des lokalen elektrischen Feldes auf das Übergangsdipolmoment des Farbstoffs und seiner Torsionsdynamik spiegelt Veränderungen des mitochondrialen Energiestatus in lebenden Zellen wieder. Membranpotential-abhängige Veränderungen der Anisotropie wurden darüber hinaus in seneszenten Hühnerembryo-Fibroblasten nachgewiesen. Zusammenfassend wurden spektroskopische Beobachtungen der Kinetik des angeregten Zustands von DASPMI in verschiedenen Lösungsmitteln sowie in lebenden Zellen durchgeführt. Damit konnte zum ersten Mal die genaue Lokalisierung, der Mechanismus spannungssensitiver Fluoreszenz und die Membranpotential-abhängige Anisotropie in lebenden Zellen gezeigt werden

Investigation of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis

The emergence of antibiotic resistant strains of Mycobacterium tuberculosis, coupled with the time it takes to perform phenotypic drug susceptibility testing of this organism, makes the treatment of tuberculosis increasingly difficult. Several genotypic assays for the rapid detection of drug resistance in M. tuberculosis have been developed, but the sensitivity with which these assays identify resistance differs geographically. Additionally, the identification of phenotypically resistant isolates with no identifiable genotypic marker suggests that other factors, such as differential gene expression, may play a role in the development of drug resistance in M. tuberculosis. This investigation aims to both develop and evaluate rapid genotypic assays for the detection of resistance to both first- and second-line drugs in M. tuberculosis, and to investigate the role of alternative sigma factors in the progression to multidrug resistant M. tuberculosis

De novo design of a transmembrane Zn²⁺-transporting four-helix bundle.

The design of functional membrane proteins from first principles represents a grand challenge in chemistry and structural biology. Here, we report the design of a membrane-spanning, four-helical bundle that transports first-row transition metal ions Zn(2+) and Co(2+), but not Ca(2+), across membranes. The conduction path was designed to contain two di-metal binding sites that bind with negative cooperativity. X-ray crystallography and solid-state and solution nuclear magnetic resonance indicate that the overall helical bundle is formed from two tightly interacting pairs of helices, which form individual domains that interact weakly along a more dynamic interface. Vesicle flux experiments show that as Zn(2+) ions diffuse down their concentration gradients, protons are antiported. These experiments illustrate the feasibility of designing membrane proteins with predefined structural and dynamic properties

Mitochondrial and autophagic alterations in human-derived cell models of Parkinson's disease related to LRRK2 (G2019S) and GBA (N370S) mutations

[eng] Parkinson's disease (PD) is the second most common neurodegenerative disease, and the most common movement disorder in the world population. In most cases its aetiology is still unknown, however, mitochondrial alterations and autophagy deregulations are some of the molecular mechanisms that are altered in this disease. These molecular alterations of PD are not limited only to the destruction of dopaminergic neurons in the substantia nigra pars compacta, but they have also been described in the peripheral nervous system and the organs that it innervates. There is also evidence of the presence of other molecular alterations in diverse tissues, such as dysfunction of Complex I of the mitochondrial respiratory chain and accumulation of alpha synuclein in fibroblasts of patients with PD. One of the great difficulties the research and understanding of the mechanisms that lead to PD is the inaccessibility of the target tissue of the disease. In the best of cases, autopsy tissue from patients with advanced PD is available, leaving a question mark about the molecular processes of prodromal and early stages of the disease. Animal models have helped to unravel some questions, but the development of accessible and replicable cell models, preferably at low cost, is much needed. It is in this context that the cellular models obtained from PD patients and from asymptomatic carriers of genes associated with the disease are of great importance and require validation. The present thesis consists of the study of two cell models obtained from patients with PD associated with the LRRK2 mutation (G2019S), asymptomatic carriers of LRRK2 (G2019S) and homozygous and heterozygous carriers of GBA (N370S); which are the genes most frequently associated with familial PD and the most important genetic risk factor for PD, respectively. First, the mitochondrial and autophagic profile of fibroblasts derived from the skin of asymptomatic carriers of the LRRK2 (G2019S) mutation and with PD were analysed. The analysis was carried out under two conditions, keeping the fibroblasts in a standard culture medium (DMEM with 25mM glucose) and after subjecting them to a mitochondrial challenge for 24 hours (DMEM with 10mM galactose), in order to simulate the oxidative environment of neurons. dopaminergic. In this study, a genotype-phenotype correlation was confirmed in fibroblasts obtained from asymptomatic carriers of the LRRK2 (G2029S) mutation and patients with PD linked to this same mutation, and it was demonstrated that a mitochondrial and autophagic function profile allows to differentiate between groups. The second study explored the genotype-phenotype correlation in a cellular model characterized by neurospheres, a conglomerate of cells obtained from the dedifferentiation of human adipocytes into neuronal stem cells, and its relationship with the onset of macroautophagy in subjects carrying the mutation GBA (N370S). The main finding of this study is that mitochondrial dysfunction preceded alterations of macroautogphagic flux in subjects carrying the GBA (N370S) mutation. In conclusion, the study of asymptomatic subjects carrying mutations associated with PD represents a relevant study method that shows initial molecular alterations and the presence of compensatory mechanisms that can be studied for the development of preventive strategies and treatments in early stages of the disease.[spa] La enfermedad de Parkinson (EP) es el trastorno de movimiento más frecuente en la población mundial. Considerada mayoritariamente idiopática y multifactorial, alteraciones mitocondriales y en la regulación autofagica son algunos de los mecanismos moleculares que se han encontrado alterados en la etiopatología de la enfermedad. El descubrimiento de genes relacionados a formas familiares de EP, del cual LRRK2 es el más frecuente, y los genes que aumentan el riesgo de padecer la enfermedad, como GBA, han abierto un campo de estudio en el cual se pueden analizar los mecanismos moleculares que llevan a la neurodegeneración en formas genéticas de la EP. La presente tesis consiste en el estudio de dos modelos celulares obtenidos a partir de portadores asintomáticos de LRRK2(G2019S) (NMLRRK2(G2019S)), pacientes con EP asociada a la mutación LRRK2(G2019S) (PDLRRK2(G2019S)), así como de portadores homozigotos y heterozigotos de GBA(N370S). El primer estudio analizó el perfil mitocondrial y autofágico de fibroblastos NMLRRK2(G2019S) y PDLRRK2(G2019S). El análisis se realizó en dos condiciones, en un medio de cultivo estándar (DMEM, glucosa 25mM) y tras someterlos 24 horas a un reto mitocondrial (DMEM, galactosa 10mM), simulando el ambiente oxidativo de las neuronas dopaminérgicas. En este estudio se confirmó una correlación genotipo-fenotipo en fibroblastos obtenidos de ambos grupos y una función mitocondrial y autofágica que permite diferenciarlos entre ellos. El segundo estudio exploró la correlación genotipo-fenotipo en un modelo celular caracterizado por neuroesferas, un conglomerado de células obtenido a partir de la desdiferenciación de adipocitos humanos en células madres neuronales, y su relación con el inicio de la macroautofagia en sujetos portadores de la mutación GBA(N370S). El hallazgo principal de este segundo estudio es que la disfunción mitocondrial precede a las alteraciones del flujo macroautofágico en sujetos portadores de la mutación GBA(N370S). El estudio de sujetos asintomáticos portadores de mutaciones asociadas a PD representa un relevante método de estudio que evidencia alteraciones moleculares iniciales y la presencia de mecanismos compensatorios que pueden ser estudiados para el desarrollo de estrategias preventivas y tratamientos en lateabas tempranas de la enfermedad

Trends in Infectious Diseases

This book gives a comprehensive overview of recent trends in infectious diseases, as well as general concepts of infections, immunopathology, diagnosis, treatment, epidemiology and etiology to current clinical recommendations in management of infectious diseases, highlighting the ongoing issues, recent advances, with future directions in diagnostic approaches and therapeutic strategies. The book focuses on various aspects and properties of infectious diseases whose deep understanding is very important for safeguarding human race from more loss of resources and economies due to pathogens

Investigating putative pathogenic mechanisms within a family in which a chromosomal translocation confers risk of major mental illness

In a large Scottish family a high incidence of schizophrenia, bipolar disorder and major depressive disorder co-segregates with a balanced autosomal translocation (t(1;11)(q42.1;q14.3). The translocation disrupts Disrupted-in-Schizophrenia-1 (DISC1) and DISC2 on chromosome 1, and DISC1FP1 (Disrupted-in-Schizophrenia-Fusion-Partner-1), also known as Boymaw, on chromosome 11. DISC1 is a leading candidate gene for major mental illness and is involved in neurodevelopment and cellular signalling, whilst DISC2 and DISC1FP1 are apparently non-coding RNA genes that undergo alternative splicing and that are expressed in the brain. This thesis aimed to investigate putative mechanisms of pathogenesis that may result from the t(1;11), with the hope that pathogenic mechanisms identified in the t(1;11) pedigree might shed light upon mechanisms conferring risk for psychiatric illness in the wider population. Previous work had identified DISC1/DISC1FP1 chimeric transcripts in t(1;11)-family derived lymphoblastoid cell lines. The detected transcripts include CP60 and CP69 which encode DISC1 aa1-597 plus an additional 60 or 69 amino acids from DISC1FP1, respectively. In this thesis a novel DISC1/DISC1FP1 transcript, CP1, was identified in t(1;11) lymphoblastoid cell lines. The CP1 transcript encodes DISC1 aa1-597 plus one glycine. A truncated form of DISC1 comprising aa1-597 was previously suggested to be a putative product of the translocation and, as such, has been the focus of multiple studies. The identification of the CP1 species is of interest as it differs from DISC1 aa1-597, by only a glycine. As glycines are simple uncharged aa’s, it is likely that these two DISC species share similar properties. In vitro exogenous expression of the three DISC1/DISC1FP1 protein species in both COS-7 and primary neuron cultures revealed contrasting cellular phenotypes. CP1 showed a diffuse cellular localisation pattern with cells containing readily visible tubular mitochondria. This is indistinguishable from the staining pattern of DISC1 aa1-597, highlighting the high degree of similarity between these species. CP60 and CP69, however, appeared to be clustered in the perinuclear region of the cell. Initial staining attempts with MitoTracker Red to visualise mitochondria in CP60 and CP69 expressing cells resulted in fewer than 30% of cells being stained. In those that did stain, the mitochondria appeared clustered. The absence of MitoTracker Red staining in mitochondria may be due to the loss of the mitochondrial membrane potential, Δψm. The adoption of a co-staining protocol with antibodies for mitochondrial proteins enabled the visualisation of mitochondrial structure in all of the cells exogenously expressing CP60 and CP69. All of these mitochondria possessed a clustered morphology, with which CP60 and CP69 expression was substantially co-localised. To see if MitoTracker staining was perturbed, in t(1;11) lymphoblastoid cell lines, as may occur if the DISC1/DISC1FP1 chimeras are expressed endogenously, the fluorescence of MitoTracker Red staining was investigated by FACS. Pooled analysis of experimental replicates revealed a negative result, with MitoTracker Red staining in t(1;11) lymphoblastoid cell lines not differing from controls. These findings indicate a need for further research using the mitochondrial membrane potential, Δψm as a metric as this would enable variations in mitochondrial mass to be accounted for. Prior to my arrival, an expression microarray had been carried out on lymphoblastoid cell line cDNA to assess gene expression differences resulting from the t(1;11). In order to identify putative pathogenic mechanisms, I carried out functional enrichment analysis of the expression array data using multiple analysis programs. Several programs detected dysregulation of the cell cycle and enrichment of altered expression of genes involved in the immune response and inflammation in t(1;11) carriers. The use of a rare variant investigative paradigm in this thesis furthers understanding of the putative pathogenic mechanisms that might act to increase risk for psychiatric illness in t(1;11) carriers. Moreover, it may aid the biological understanding of the aetiology of psychiatric illness in the general population. As such, improved understanding of the mechanisms of risk in the t(1;11) pedigree may eventually lead to the development of better treatments. In the intervening time since some of the research for thesis was published, two studies have emerged that may serve to highlight potential mechanisms of pathogenic action mediated by CP60 and CP69 expression. It has recently been observed that WT-DISC1 couples to the adaptor protein TRAK1 and the mitochondrial membrane anchor Miro1, which are part of the mitochondrial transport complex (Ogawa et al, 2014; Norkett et al, 2016). Furthermore, the exogenous expression of CP60 impairs bidirectional mitochondrial trafficking (Norkett et al, 2016). This suggests that CP60 expression may impair interactions with TRAK1 and Miro1. Given the sequence homology between CP60 and CP69, mitochondrial transport deficits also likely arise with CP69 expression. It is therefore possible that the exogenously expressed CP60 and CP69 proteins could be docked on stationary mitochondria, which may contribute to the clustered expression patterns observed