This project focused on determining the effect of lithium on glucose uptake, glycogen synthesis, and insulin signaling proteins, protein kinase B (Akt1) and GSK-3, in isolated soleus muscle from female lean Zucker rats. We also investigated the role of the stress-activated p38 MAPK in the action of lithium to activate skeletal muscle glucose transport. In the absence of insulin, lithium (10 mM LiCl) increased basal glucose transport by 62% (p<0.05) and glycogen synthesis by 112%. Lithium did not alter phosphorylation of Akt ser473, but enhanced GSK-3β ser9 phosphorylation by 41%. Lithium further enhanced the effect of insulin on glucose transport (42%), glycogen synthesis (44%), and GSK-3ß phosphorylation (13%). Lithium increased phosphorylated p38 MAPK 31% without and 19% with insulin. Moreover, a selective p38 MAPK inhibitor, A304000, completely prevented the lithium-induced enhancement of glucose transport revealing the critical involvement of p38 MAPK phosphorylation in lithium-induced glucose transport in isolated skeletal muscle.

Terahertz (THz) frequency range (wavelength of 300-30 μm, frequency of 1-10 THz and photon energy of ~4-40meV), the gap between infrared and microwave electromagnetic waves, have remained relatively unexplored for a long time, due to lack of a high power, coherent, and compact source, as well as the lack of an appropriate detector and the transmission devices. THz wave has recently received considerable attention for potential applications in non-invasive medical imaging, detecting trace of gases in the environment, sensing of organic and biological molecules, security controls, local oscillators for heterodyne receiver systems, free space communication, etc. THz quantum cascade laser (QCL), as the relatively high power and coherent THz radiation source, was demonstrated in 2002. After near a decade of intense research, THz QCLs operate only up to 186K in pulse mode with maximum power of 250 mW at 10 K. This thesis discusses many aspects of theoretical and experimental design considerations for THz QCLs. The objective is to obtain a laser device that emits high powers and works towards the temperatures achievable by thermoelectric coolers. This work includes designing the active gain medium, and the engineering of the waveguide and heat removal structures. A density matrix based model is developed to explain the charge transport and gain mechanism in the intersubband devices, particularly for three well resonant phonon based THz QCLs. The model allows for designing of the optimum and novel active gain mediums that work at higher temperatures. The designed active gain mediums are fabricated using discussed low loss waveguide and efficient heat removal structures. The maximum operating temperatures as high as ~176 K is achieved. Finally a promising lasing scheme based on phonon-photon-phonon emissions is proposed that improves the population inversion and offers high gain peak.

Quantum cascade laser (QCL), as a unipolar semiconductor laser based on intersubband transitions in quantum wells, covers a large portion of the Mid and Far Infrared electromagnetic spectrum. The frequency of the optical transition can be determined by engineering the layer sequence of the heterostructure. The focus of this work is on Terahertz (THz) frequency range (frequency of 1 - 10 THz and photon energy of ~ 4 - 40 meV), which is lacking of high power, coherent, and efficient narrowband radiation sources. THz QCL, demonstrated in 2002, as a perfect candidate of coherent THz source, is still suffering from the empirical operating temperature limiting factor of T ≈ ħω/kB, which allows this source to work only under a cryogenic system. Most of high performance THz QCLs, including the world record design which lased up to ~ 200 K, are based on a resonant phonon (RP) scheme, whose population inversion is always less than 50%. The indirectly-pumped (IDP) QCL, nicely implemented in MIR frequency, starts to be a good candidate to overcome the aforementioned limiting factor of RP-QCL. A rate equation (RE) formalism, which includes both coherent and incoherent transport process, will be introduced to model the carrier transport of all presented structures in this thesis. The second order tunneling which employed the intrasubband roughness and impurity scattering, was implemented in our model to nicely predict the behavior of the QCL designs. This model, which is easy to implement and fast to calculate, could help us to engineer the electron wavefunctions of the structure with optimization tools. We developed a new design scheme which employs the phonon scattering mechanism for both injecting carrier to the upper lasing state and extracting carrier from lower lasing state. Since there is no injection/extraction state to be in resonance with lasing states, this simple design scheme does not suffer from broadening due to the tunneling. Finally, three different THz IDP-QCLs, based on phonon-photon-phonon (3P) scheme were designed, grown, fabricated, and characterized. The performance of those structures in terms of operating temperature, threshold current density, maximum current density, output optical power, lasing frequency, differential resistance at threshold, intermediate resonant current before threshold, and kBT/ħω factor will be compared. We could improve the kBT/ħω factor of the 3P-QCL design from 0.9 in first iteration to 1.3 and the output optical power of the structure from 0.9 mW in first design to 3.4 mW. The performance of the structure in terms of intermediate resonant current and the change in differential resistance at threshold was improved.

In previous studies on heartbeat series, it has been proposed that the healthy heartbeat pattern represents complex nonlinear dynamics, and such cardiac nonlinearity may be used as a clinical indicator for the diagnosis of certain types of heart disease. However, it is still not quite clear whether there is any difference among the heartbeat series of patients with congestive heart failure (CHF), or whether cardiac nonlinearity represents a severe heart disease situation. In the present study, parallel cascade identification (PCI), which frequently requires only short stretches of data to obtain highly promising results, is used to distinguish severe congestive heart failure, a clinical situation associated with a high-risk of sudden death, from low-risk CHF. Parallel cascade identification is an accurate and robust method for identifying dynamic nonlinear systems. The PCI algorithm combined with a specified statistical test may be used as a severe congestive heart failure marker by comparing a nonlinear model with a “linear” model (more precisely, a first-order Volterra series). In this thesis, PCI is applied to distinguish R-R wave intervals of CHF patients who died from those of patients who survived in a 5-year study. The detection accuracy of the PCI detector is evaluated over a first set of 49 patients, and then over a larger set of a further 352 patients, and consistent results are obtained between the two sets. Over the larger set, Matthews' correlation coefficient of nonlinearity with unfavorable outcome (death) is , sensitivity for predicting unfavorable outcome is , while the specificity is . The R-R wave interval exhibits nonlinearity in patients who died during the 5-year study. However, typically nonlinearity cannot be detected in patients who survived during the study. These findings show that for patients with congestive heart failure, nonlinearity is associated with unfavorable outcome (death), while patients for whom nonlinearity cannot be detected overwhelmingly have good outcomes. This is significant for clinical diagnosis and prognosis of severe congestive heart failure. / Thesis (Master, Electrical & Computer Engineering) -- Queen's University, 2007-09-28 11:54:57.695

The temporal and spatial patterning that underlies morphogenetic events is controlled by gene regulatory networks (GRNs). These operate through a combinatorial code of DNA – binding transcription factor proteins, and non – coding DNA sequences (cis-regulatory elements, or CREs), that specifically bind transcription factors and regulate nearby genes. By comparatively studying the development of different species, we can illuminate lineage – specific changes in gene regulation that account for morphological evolution. The central nervous system of vertebrates is composed of diverse neural cells that undergo highly coordinated programs of specialization, migration and differentiation during development. Approximately 20% of neurons in the cerebral cortex are GABAergic inhibitory interneurons, which release the neurotransmitter gamma-aminobutyric acid (GABA). Diseases such as autism, schizophrenia and epilepsy are associated with defects in GABAergic interneuron function. Several members of the distal-less homeobox (Dlx) transcription factor family are implicated in a GRN underlying early GABAergic interneuron development in the forebrain. I examined the role played by orthologous dlx genes in the development of GABAergic interneurons in the zebrafish forebrain. I found that when ascl1a transcription factor is down-regulated through the micro-injection of translation – blocking morpholino oligonucleotides, Dlx gene transcription is decreased in the diencephalon, but not the telencephalon. Similarly, gad1a transcription is also decreased in this region for these morphants. As gad1a encodes an enzyme necessary for the production of GABA, these genes are implicated in a cascade underlying GABAergic interneuron development in the diencephalon.

No description available.

Proteolytic processes are often mediated by highly orchestrated cascades, through which protease enzymes function coordinately to ensure a stepwise activation. This thesis presents experimental data which supports and complements the previously postulated mechanism of KLK (kallikrein-related protease) activation through proteolytic cascades. Further examination of the seminal KLK cascade has revealed several of its key (patho) physiological roles in human reproductive system. Multiple members of the seminal KLK cascade, in particular KLK14, were shown to play a pivotal role in regulating semen liquefaction. The cascade was further shown to be tightly regulated through a series of highly orchestrated feedback loops, to prevent deleterious effects due to aberrant protease activation. Accordingly, a strong association was observed between the expression level of several seminal KLKs, delayed liquefaction, and other markers of semen quality, including semen hyperviscosity. Furthermore, a strong association was found between delayed liquefaction and abnormal sperm motility. Therefore, dysregulated KLK expressions and/or activities were proposed as an underlying cause of male subfertility. Finally, this thesis has provided initial insights into a novel potential function of multiple members of the seminal KLK cascade in activation of the key immune-deviating agent, TGFβ1, in seminal plasma. TGFβ1 activation is postulated to be mediated directly through complete fragmentation or indirectly through partial cleavage and conformational changes of the LAP propeptide motif of the latent TGFβ1. KLK- mediate proteolytic cleavage of the TGFβ1 binding protein, LTBP1, is also suggested as a potential physiological mechanism for release of the membrane-bound latent TGFβ1. Overall, the data provided here may suggest a common regulatory mechanism, involved co-temporally in the two key processes of semen liquefaction and immune-suppression. This might be critical in protecting motile sperms following their release from semen coagulum. Understanding KLK-mediated proteolytic events in seminal plasma can shed light not only on the physiological role of this family of enzymes, but also on some of causes of male subfertility. Accordingly, therapeutic induction of this cascade may be utilized to supplement the current clinical treatment of male subfertility. Conversely, targeted inhibition of key components of the cascade may have potential pharmaceutical utility as a novel topical contraceptive strategy.

Norzoanthamine is a complex heptacyclic marine alkaloid isolated from colonial zoanthids. It potently inhibits loss of bone weight and strength in a postmenopausal osteoporosis mouse model, but its mode-of-action remains unknown. The scarcity of this natural product from its natural source and the need to access analogs for structure-activity relationship (SAR) study make it necessary to chemically synthesize this compound. However, the complex molecular skeleton, especially the highly functionalized and stereochemically complex ABC core structure of the natural product poses a significant challenge. As part of our efforts to develop a practical synthetic route to norzoanthamine, we systematically explored a transannular Michael reaction cascade in the context of the synthesis of angular 6-6-6 tricyclic ring system, a mimic of the ABC core structure of norzoanthamine. Using 1,7-bis-enones in the form of 14-membered macrocyclic lactone as model substrates, we demonstrated that both E,Z- and E,E-macrocycles underwent facile transannular reactions to give cis-syn-cis and trans-anti-trans ring systems, respectively. However, Z,E- and Z,Z- macrocycles did not cyclize under similar reactions. The similarities and differences between transannular Diels-Alder reactions and this transannular cyclization process were also disclosed. Building upon these preliminary studies, we developed a 12-linear step synthesis of the ABC carbocyclic core of norzoanthamine. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling based on selective alkylation of a bis-enolate, and a transannular Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core. Subsequent Claisen rearrangement enabled installation of a handle for introduction of the bottom piece to complete the total synthesis. Other efforts toward the total synthesis have also been discussed.

This thesis quantitatively investigates gaseous electron-ion recombination in an environmental scanning electron microscope (ESEM) at a transient level by utilizing the dark shadows/streaks seen in gaseous secondary electron detector (GSED) images immediately after a region of enhanced secondary electron (SE) emission is encountered by a scanning electron beam. The investigation firstly derives a theoretical model of gaseous electron-ion recombination that takes into consideration transients caused by the time constant of the GSED electronics and external circuitry used to generate images. Experimental data of pixel intensity versus time of the streaks is then simulated using the model enabling the relative magnitudes of (i) ionization and recombination rates, (ii) recombination coefficients, and (iii) electron drift velocities, as well as absolute values of the total time constant of the detection system, to be determined as a function of microscope operating parameters. Results reveal the exact dependence that the effects of SE-ion recombination on signal formation have on reduced electric field intensity and time in ESEM. Furthermore, the model implicitly demonstrates that signal loss as a consequence of field retardation due to ion space charges, although obviously present, is not the foremost phenomenon causing streaking in images, as previously thought. Following that the generation and detection of gaseous scintillation and electro- luminescence produced via electron-gas molecule excitation reactions in ESEM is investigated. Here a novel gaseous scintillation detection (GSD) system is developed to efficiently detect photons produced. Images acquired using GSD are compared to those obtained using conventional GSED detection, and demonstrate that images rich in SE contrast can be achieved using such systems. A theoretical model is developed that describes the generation of photon signals by cascading SEs, high energy backscattered electrons (BSEs) and primary beam electrons (PEs). Photon amplification, or the total number of photons produced per sample emissive electron, is then investigated, and compared to conventional electronic amplification, over a wide range of microscope operating parameters, imaging gases and photon collection geometries. The main findings of the investigation revealed that detected electroluminescent signals exhibit larger SE signal-to-background levels than that of conventional electronic signals detected via GSED. Also, dragging the electron cascade towards the light pipe assemblage of GSD systems, or electrostatic focusing, dramatically increases photon collection efficiencies. The attainment of such an improvement being a direct consequence of increasing the `effective' solid angle for photon collection. Finally, in attempt to characterize the scintillating wavelengths arising from sample emissive SEs, PEs, BSEs, and their respective cascaded electrons, such that future photon filtering techniques can be employed to extract nominated GSD imaging signals, the emission spectra of commonly utilized electroluminescent gases in ESEM, such as argon (Ar) and nitrogen (N2), were collected and investigated. Spectra of Ar and N2 reveal several major emission lines that occur in the ultraviolet (UV) to near infrared (NIR) regions of the electromagnetic spectrum. The major photon emissions discovered in Ar are attributed to occur via atomic de-excitation transitions of neutral Ar (Ar I), whilst for N2, major emissions are attributed to be a consequence of second positive band vibrational de-excitation reactions. Major wavelength intensity versus gas pressure data, for both Ar and N2, illustrate that wavelength intensities increase with decreasing pressure. This phenomenon strongly suggesting that quenching effects and reductions in excitation mean free paths increase with imaging gas pressure.

A study into the reconstruction of cascade like events in the IceCube neutrino detector was performed by utilizing in-situ flasher devices. Reconstruction analysis was done with two different flasher settings at each optical module on string 63 at varying depths in the ice. Three different reconstruction algorithms were used to estimate the characteristics of these cascade type events. The characteristics included the estimated vertex position, and the number of photons produced by each flasher. The number of photons produced can be related to the energy for the cascade event via the detailed knowledge of the cascade physics. Results from the analysis show the strengths of using the center of gravity type approaches to estimating the vertex positions of very bright events, and the inability to reconstruct to an accurate position in z which can occur when using more complicated vertex algorithms on the same events. Analysis using the energy reconstruction modules demonstrated the strengths of using methods that take into account the ice properties inside the detector.