Non-Orthogonal Signal and System Design for Wireless Communications

The thesis presents research in non-orthogonal multi-carrier signals, in which: (i) a new signal format termed truncated orthogonal frequency division multiplexing (TOFDM) is proposed to improve data rates in wireless communication systems, such as those used in mobile/cellular systems and wireless local area networks (LANs), and (ii) a new design and experimental implementation of a real-time spectrally efficient frequency division multiplexing (SEFDM) system are reported. This research proposes a modified version of the orthogonal frequency division multiplexing (OFDM) format, obtained by truncating OFDM symbols in the time-domain. In TOFDM, subcarriers are no longer orthogonally packed in the frequency-domain as time samples are only partially transmitted, leading to improved spectral efficiency. In this work, (i) analytical expressions are derived for the newly proposed TOFDM signal, followed by (ii) interference analysis, (iii) systems design for uncoded and coded schemes, (iv) experimental implementation and (v) performance evaluation of the new proposed signal and system, with comparisons to conventional OFDM systems. Results indicate that signals can be recovered with truncated symbol transmission. Based on the TOFDM principle, a new receiving technique, termed partial symbol recovery (PSR), is designed and implemented in software de ned radio (SDR), that allows efficient operation of two users for overlapping data, in wireless communication systems operating with collisions. The PSR technique is based on recovery of collision-free partial OFDM symbols, followed by the reconstruction of complete symbols to recover progressively the frames of two users suffering collisions. The system is evaluated in a testbed of 12-nodes using SDR platforms. The thesis also proposes channel estimation and equalization technique for non-orthogonal signals in 5G scenarios, using an orthogonal demodulator and zero padding. Finally, the implementation of complete SEFDM systems in real-time is investigated and described in detail

Optical Communication

Optical communication is very much useful in telecommunication systems, data processing and networking. It consists of a transmitter that encodes a message into an optical signal, a channel that carries the signal to its desired destination, and a receiver that reproduces the message from the received optical signal. It presents up to date results on communication systems, along with the explanations of their relevance, from leading researchers in this field. The chapters cover general concepts of optical communication, components, systems, networks, signal processing and MIMO systems. In recent years, optical components and other enhanced signal processing functions are also considered in depth for optical communications systems. The researcher has also concentrated on optical devices, networking, signal processing, and MIMO systems and other enhanced functions for optical communication. This book is targeted at research, development and design engineers from the teams in manufacturing industry, academia and telecommunication industries

Spectrally efficient FDM communication signals and transceivers: design, mathematical modelling and system optimization

This thesis addresses theoretical, mathematical modelling and design issues of Spectrally Efficient FDM (SEFDM) systems. SEFDM systems propose bandwidth savings when compared to Orthogonal FDM (OFDM) systems by multiplexing multiple non-orthogonal overlapping carriers. Nevertheless, the deliberate collapse of orthogonality poses significant challenges on the SEFDM system in terms of performance and complexity, both issues are addressed in this work. This thesis first investigates the mathematical properties of the SEFDM system and reveals the links between the system conditioning and its main parameters through closed form formulas derived for the Intercarrier Interference (ICI) and the system generating matrices. A rigorous and efficient mathematical framework, to represent non-orthogonal signals using Inverse Discrete Fourier Transform (IDFT) blocks, is proposed. This is subsequently used to design simple SEFDM transmitters and to realize a new Matched Filter (MF) based demodulator using the Discrete Fourier Transforms (DFT), thereby substantially simplifying the transmitter and demodulator design and localizing complexity at detection stage with no premium at performance. Operation is confirmed through the derivation and numerical verification of optimal detectors in the form of Maximum Likelihood (ML) and Sphere Decoder (SD). Moreover, two new linear detectors that address the ill conditioning of the system are proposed: the first based on the Truncated Singular Value Decomposition (TSVD) and the second accounts for selected ICI terms and termed Selective Equalization (SelE). Numerical investigations show that both detectors substantially outperform existing linear detection techniques. Furthermore, the use of the Fixed Complexity Sphere Decoder (FSD) is proposed to further improve performance and avoid the variable complexity of the SD. Ultimately, a newly designed combined FSD-TSVD detector is proposed and shown to provide near optimal error performance for bandwidth savings of 20% with reduced and fixed complexity. The thesis also addresses some practical considerations of the SEFDM systems. In particular, mathematical and numerical investigations have shown that the SEFDM signal is prone to high Peak to Average Power Ratio (PAPR) that can lead to significant performance degradations. Investigations of PAPR control lead to the proposal of a new technique, termed SLiding Window (SLW), utilizing the SEFDM signal structure which shows superior efficacy in PAPR control over conventional techniques with lower complexity. The thesis also addresses the performance of the SEFDM system in multipath fading channels confirming favourable performance and practicability of implementation. In particular, a new Partial Channel Estimator (PCE) that provides better estimation accuracy is proposed. Furthermore, several low complexity linear and iterative joint channel equalizers and symbol detectors are investigated in fading channels conditions with the FSD-TSVD joint equalization and detection with PCE obtained channel estimate facilitating near optimum error performance, close to that of OFDM for bandwidth savings of 25%. Finally, investigations of the precoding of the SEFDM signal demonstrate a potential for complexity reduction and performance improvement. Overall, this thesis provides the theoretical basis from which practical designs are derived to pave the way to the first practical realization of SEFDM systems

A PROANGIOGENIC STRATEGY TO PROMOTE DIABETIC WOUND CLOSURE

Ph.DDOCTOR OF PHILOSOPH

Identification of Epigenetic Mechanisms Regulating NCX3 in in Vivo Model of Brain Ischemic Preconditioning

Variations of the isoform 3 expression of the sodium / calcium exchanger play an important role in the response to neuronal damage after an ischemic insult. I found that the transcription factor (GATA binding protein) 3 GATA3 activates the transcription of ncx3 in rat cortical cultures. In fact, the overexpression of GATA3, obtained as a result of transient transfection of the plasmid containing the GATA3 cDNA in neurons, leads to a significant increase in the luciferase activity of the ncx3 promoter, in parallel with an increase in mRNA and protein expression of ncx3. In contrast, the transfection of a siRNA capable of reducing the protein expression of GATA3 by about 60% causes a reduction of the luciferase activity of the ncx3 promoter and a decrease in the ncx3 mRNA. The site-specific mutagenesis of the binding sequence of GATA3 on the ncx3 promoter demonstrates that the mechanism by which GATA3 activates NCX3 is site-specific. More important, in vivo, GATA3 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to Preconditioning (PC) followed by transient middle cerebral artery occlusion (tMCAO), with an increase of histone 3 lysine 3 trimethylation of the ncx3 promoter region. Interestingly, in the same experimental conditions histone acetylation on ncx3 promoter was unmodified. Furthermore, Re-ChIP experiments demonstrated that GATA3 forms a functional complex with the histone lysine methyl transferase KMT2A on the ncx3 gene during PC+tMCAO. Therefore, increasing KMT2A expression or activity might represent a new possible strategy in stroke intervention

Study of Combinatorial Cell Therapy and Neuroprotective Agents for the Treatment of Spinal Cord Injury in Experimental Models

Tesis por compendio[ES] La lesión medular (LM) es un trastorno neurológico devastador y debilitante que se caracteriza por un grado variable de disfunción motora, sensorial y/o autonómica permanente. El trasplante de células madre neurales (NSC) ofrece una herramienta terapéutica prometedora para el tratamiento de la LM al proporcionar neuroprotección y neuroregeneración. Sin embargo, el entorno generado tras la lesión limita el potencial terapéutico de las terapias celulares al dar lugar a una escasa supervivencia y engraftment de las células y a una diferenciación inadecuada. Además, las terapias celulares han mostrado hasta la fecha una recuperación funcional limitada en los ensayos clínicos. Por lo tanto, se ha postulado el uso de terapias combinatorias para superar estas limitaciones y potenciar los beneficios terapéuticos de las terapias celulares. En esta tesis doctoral, se han estudiado distintas estrategias de combinación con el trasplante de NSC, como el uso de fármacos y biomateriales, con el objetivo de mejorar y potenciar el efecto de la terapia celular en el rescate de la actividad neuronal, en la modulación del proceso inflamatorio, en la supervivencia del trasplante, así como en su integración y diferenciación en el tejido medular. Así, En el capítulo 1 evaluamos la terapia combinada de células madre neurales humanas derivadas de células madre pluripotentes inducidas (iPSC-NSCs), células madre mesenquimales (MSCs) y un nanoconjugado de curcumina (PA-C) en un modelo de LM subagudo, proporcionando un mayor grado de neuroprotección en comparación con los tratamientos individuales. En el capítulo 2 desarrollamos una estrategia mínimamente invasiva mediante el uso de un scaffold de ácido hialurónico en forma de semi-luna para el transplante de iPSC-NSCs combinado con PA-C. Así, los análisis histológicos demostraron que el tratamiento combinado de iPSC-NSCs y la PA-C presentaban una mayor preservación de fibras neuronales en la zona de la lesión y una reducción de la extensión de la cicatriz fibrótica. Por último, en el capítulo 3 se describe una estrategia terapéutica que se aproxima más a la traslación clínica mediante el trasplante de progenitores neurales fetales humanos (hfNPCs) condicionados previamente con una forma conjugada del inhibidor de Rho/Rock fasudil (PGA-SS-FAS). Así, la combinación de las hfNPCs con el PGA-SS-FAS favoreció la migración del transplante en el tejido medular, la preservación de las interneuronas somatosensoriales Lbx1 inhibitorias y las Tlx3 excitatorias, así como la activación neuronal alrededor del epicentro de la lesión. Así pues, en la presente tesis doctoral se estudia y describe el beneficio aportado por tres estrategias combinatorias, que incrementan los efectos neuroprotectores proporcionados por la terapia celular en el tratamiento de lesiones medulares agudas y sub-agudas.[CA] La lesió medul·lar (LM) és un trastorn neurològic devastador i debilitant que es caracteritza per un grau variable de disfunció motora, sensorial i/o autonòmica permanent. El trasplantament de cèl·lules mare neurals (NSC) ofereix una eina terapèutica prometedora per al tractament de la LM proporcionant neuroprotecció i neuroregeneració. Tot i això, l'entorn generat després de la lesió limita el potencial terapèutic de les teràpies cel·lulars donant lloc a una escassa supervivència i engraftment de les cèl·lules i a una diferenciació inadequada. A més, les teràpies cel·lulars han mostrat fins ara una recuperació funcional limitada als assajos clínics. Per tant, s'ha postulat l'ús de teràpies combinatòries per superar aquestes limitacions i potenciar els beneficis terapèutics de les teràpies cel·lulars. En aquesta tesi doctoral, s'han estudiat diferents estratègies de combinació amb el trasplantament de NSC, com ara l'ús de fàrmacs i biomaterials, amb l'objectiu de millorar i potenciar l'efecte de la teràpia cel·lular en el rescat de l'activitat neuronal, en la modulació del procés inflamatori, en la supervivència del trasplantament, així com en la seva integració i diferenciació al teixit medul·lar. Així, Al capítol 1 avaluem la teràpia combinada de cèl·llules mare neurals humanes derivades de cèl·lules mare pluripotents induïdes (iPSC-NSCs), cèl·lules mare mesenquimals (MSCs) i un nanoconjugat de curcumina (PA-C) en un model de LM subagut, proporcionant un major grau de neuroprotecció en comparació dels tractaments individuals. Al capítol 2 desenvolupem una estratègia mínimament invasiva mitjançant l'ús d'un scaffold d'àcid hialurònic en forma de semilluna per al trasplantament d'iPSC-NSC combinat amb PA-C. Així, els anàlisis histològics mostraren que el tractament combinat d'iPSC-NSCs i la PA-C incrementaba la preservació de fibres neuronals a la zona de la lesió i reduïa l'extensió de la cicatriu fibròtica. Finalment, al capítol 3 es descriu una estratègia terapèutica que s'aproxima més a la translació clínica mitjançant el trasplantament de progenitors neurals fetals humans (hfNPCs) condicionats prèviament amb una forma conjugada de l'inhibidor de Rho/Rock fasudil (PGA-SS-FAS. Així, la combinació de les hfNPCs amb el PGA-SS-FAS va afavorir la migració del trasplantament al teixit medul·lar, la preservació de les interneurones somatosensorials Lbx1 inhibitòries i les Tlx3 excitatòries, així com l'activació neuronal al voltant de l'epicentre de la lesió. Així doncs, en aquesta tesi doctoral s'estudia i descriu el benefici aportat per tres estratègies combinatòries, que incrementen els efectes neuroprotectors proporcionats per la teràpia cel·lular en el tractament de lesions medul·lars agudes i sub-agudes.[EN] Spinal cord injury (SCI) is a devastating and debilitating neurological disorder characterized by a variable degree of permanent motor, sensory and/or autonomic dysfunction. Neural stem cell (NSC) transplantation offers a promising therapeutic tool for the treatment of SCI by providing neuroprotection and neuroregeneration. However, the environment generated after injury limits the therapeutic potential of cell therapies by resulting in poor cell survival and engraftment and inadequate differentiation. In addition, cell therapies have shown limited functional recovery in clinical trials to date. Therefore, the use of combinatorial therapies has been postulated to overcome these limitations and enhance the therapeutic benefits of cell therapies. In this doctoral thesis, we have studied different combination strategies with NSC transplantation, such as the use of drugs and biomaterials, with the aim of improving and enhancing the effect of cell therapy in the rescue of neuronal activity, in the modulation of the inflammatory process, in the survival of the transplant, as well as in its integration and differentiation in the medullary tissue. Thus, In Chapter 1 we evaluated the combined therapy of human induced pluripotent stem cell-derived neural stem cells (iPSC-NSCs), mesenchymal stem cells (MSCs) and a curcumin nanoconjugate (PA-C) in a subacute LM model, providing a higher degree of neuroprotection compared to single treatments. In Chapter 2, we developed a minimally invasive strategy by using a demilune hyaluronic acid scaffold for combined transplantation of iPSC-NSCs with PA-C. Thus, histological analyses demonstrated that the combined treatment of iPSC-NSCs and PA-C exhibited increased preservation of neuronal fibers in the lesion area and a reduction in the extension of the fibrotic scar. Finally, Chapter 3 describes a therapeutic strategy that more closely approximates clinical translation by transplanting human fetal neural progenitors (hfNPCs) preconditioned with a conjugated form of the Rho/Rock inhibitor fasudil (PGA-SS-FAS). Thus, the combination of hfNPCs with PGA-SS-FAS favored transplant migration within the spinal parenchyma, preservation of endogenous inhibitory Lbx1 and excitatory Tlx3 somatosensory interneurons, as well as endogenous neuronal activation around the lesion epicenter. Thus, this PhD thesis studies and describes the benefit provided by three combinatorial strategies, which increase the neuroprotective effects provided by cell therapy in the treatment of acute and sub-acute spinal cord injury.This research was funded by Fundació Marató TV3 2017/refs.20172230, 20172231 and 20172110; FEDER/Ministerio de Ciencia e Innovación–Agencia Estatal de Investigación “RTI2018- 095872-B-C21/ERDF”, Agencia Valenciana de Innovación (AVI) INNVAL10/19/047 and TERCEL (RD12/0019/0011) funds from the Instituto de Salud Carlos III of Spain; Science by Women program, Women for Africa Foundation to HE and the grants FEDER/Ministerio de Ciencia e Innovación – Agencia Estatal de Investigación [RTI2018-095872-B-C21 and –C22/ERDF]; RISEUP project FetOpen in H2020 Program: H2020-FETOPEN-2018-2019-2020-01 and by Grants RTI2018-095872-B- C21 and PDI2021-1243590B-I00/ERDF funded by MCIN/AEI//10.13039/501100011033 and by ERDF A way of making Europe). This project was also funded by Project 964562 (RISEUP), H2020 FetOpen programBonilla Villamil, P. (2022). Study of Combinatorial Cell Therapy and Neuroprotective Agents for the Treatment of Spinal Cord Injury in Experimental Models [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/191500Compendi

Drug Delivery Technology Development in Canada

Canada continues to have a rich history of ground-breaking research in drug delivery within academic institutions, pharmaceutical industry and the biotechnology community

GENE THERAPY STRATEGIES FOR TREATMENT OF MUCO-OBSTRUCTIVE LUNG DISEASES

Knowledge of genetic origins and associations of muco-obstructive lung diseases has made inhaled gene therapy an attractive alternative to the current standards of care that are limited to managing disease symptoms. However, despite over two decades of intensive research and development, gene therapy has yet to help patients with cystic fibrosis (CF) or any other muco-obstructive lung diseases. The slow progress is due in part to poor understanding of the biological barriers to inhaled gene therapy. In this dissertation, I first introduce the pathobiology of representative muco-obstructive lung diseases and examine pitfalls of clinically investigated gene vectors of the past and of current options. I then review key components for successful execution of inhaled gene therapy, including gene delivery systems, physiological barriers and strategies to overcome them, and advances in preclinical models with which the most promising systems may be vetted for clinical trials. Secondly, I demonstrate that adeno-associated vectors (AAV), which are more commonly used gene vectors for clinical settings, differ in their ability to diffuse through the CF sputum barrier and mediate various levels of transduction depending on the surface chemistry. Specifically, I compared three AAV vectors in their ability to i) diffuse in CF sputum, ii) provide transgene expression in ALI culture of primary human CF bronchial epithelial cells, and iii) provide transgene expression in a mouse model of muco-obstructive lung diseases. Thirdly, I present the application of a synthetic biodegradable gene vector in ex vivo, in vitro, and in vivo models relevant to muco-obstructive diseases. This gene vector is composed of engineered poly(β-amino ester) polymers and nucleic acid that encodes reporter or therapeutically relevant genes. I found that this gene vector, compared to conventional gene vector, is able to i) efficiently diffuse through CF sputum, ii) safely mediate higher magnitude of and widespread transgene expression in healthy and muco-obstructive lung mouse model, and iii) apically transfer reporter gene to mucus-covered air-liquid interface (ALI) culture of primary human CF bronchial epithelial cells harvested from CF patient lungs with F508del homozygous mutation, the most common form of mutation in the CF patient population