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Pronounced seasonal adaptations in physiology and behaviour are exhibited by mammals living in polar and temperate habitats. These include the development of a winter coat, altered fat reserves, reproductive quiescence and food hoarding. Maintaining constant body temperature (Tb) during winter is energetically very costly, and so many small mammals periodically abandon homeothermy in favour of heterothermy. The two principal heterothermic strategies are daily torpor and seasonal hibernation, in which bouts of profound hypothermia range from a few hours to several days (respectively). It is now clear that hypothalamic thyroid hormone (TH) regulation, and specifically the availability of the active metabolite triiodothyronine (T3), is a critical regulator of seasonal reproductive cycles in many species including birds and mammals. The impact of this signal as a switch for seasonal changes in physiology has been highlighted by the demonstration that blockade of this pathway prevents seasonal adaption in hamsters. Peripheral TH signalling is also a principle regulator of metabolic rate in mammals. Despite these findings nothing is yet known about the involvement of central (hypothalamic) and peripheral TH cycles in the expression of torpor and hibernation. Within this thesis, the role of TH dynamics both in the brain and peripheral circulation is examined within three models of heterothermia: the Siberian (Phodopus sungorus) and European (Cricetus cricetus) hamsters, which employ daily torpor and hibernation, respectively, and the laboratory mouse (Mus Musculus) which exhibits torpor in response to metabolic stress such as food restriction. To delineate TH regulation and signalling in the context of both seasonal and acute physiological responses, the expression of genes involved in thyroid hormones conversion (e.g. Deiodinase type II (Dio2) and type III (Dio3) and transport (e.g. Monocarboxylate transporter 8, Mct8) within the ependymal layer of the ventral 3rd ventricle have been detailed across seasonal (long (LD) and short day (SD)) photoperiods, and during normothermic and hypothermic conditions. Furthermore, TH concentrations have been directly measured within the hypothalami of P. sungorus and C. cricetus, and TH responsive genes (e.g. Hairless (Hr) and Thyrotropin releasing hormone (TRH) to determine the potential impact of regional T3 signalling. As expected, Dio2 and Dio3 expression in P. sungorus exhibited a strong seasonal cycle indicative of elevated T3 production during SD (reduced Dio2 and elevated Dio3). Unexpectedly, total T3 measures from hypothalamic extracts revealed no significant alteration either seasonally or during torpor/hibernation in hamsters. However, Hr expression in the ependymal layer and TRH expression in the paraventricular nucleus (PVN) suggests low T3 concentrations during SD are localised to specific regions and does not encompass the whole hypothalamus per se. In addition, altered serum TH concentrations implicate seasonal and torpor associated dynamics that may play a role in seasonal adaptation and hypothermia. Finally, data from transgenic mice strongly implicate the melatonin-related receptor (GPR50) in leptin signalling and aberrant thermogenesis in mice.

The sympathetic nervous system, a subdivision of the autonomic nervous system, innervates glands, smooth and cardiac muscle of the body and drives the “fight or flight” response. The objective of this study is to use anatomical and radiological methods to definitively identify and investigate the sympathetic chain, specifically ganglia from stellate through T5. The overarching goal of this research is to help guide clinical treatments, including nerve block and ligation procedures, for various disorders of the sympathetic nervous system, including cardiac arrhythmias, hyperhidrosis and pain syndromes. This study uses anatomical methods, including cadaveric dissection, optical tracking, anatomic relationships and landmarks, to investigate the characteristics of the sympathetic chain. This study also uses radiologic methods, including conventional radiography and 3 Tesla (T) magnetic resonance imaging (MRI) with a high-resolution 3D constructive interference in steady state (CISS) sequence, to provide a clinically applicable comparison to gross anatomic observations and measurements.

Hypothyroidism is a chronic medical condition that results in the inadequate production of thyroid hormones. Thyroid hormones are essential for the metabolism of almost every organ in the body. The prominent symptoms of hypothyroidism include lack of energy, weight gain, constipation, and intolerance to cold temperatures. Medical therapies aim to replenish thyroid hormones enough to meet the body's metabolic demands. Unfortunately, many individuals experience persistent symptoms despite stable thyroid hormone levels. Current treatment options for hypothyroidism include Levothyroxine, Liothyronine, and Desiccated Thyroid Extract (DTE). Levothyroxine contains synthetic T4 and is the current gold-standard medical therapy in hypothyroid patients. Liothyronine, synthetic T3, can be added to Levothyroxine to improve symptomatology. DTE is a natural form of T3 and T4 and the historical first-line medical treatment. Combination therapy with Liothyronine or DTE is an option for symptomatic euthyroid patients on Levothyroxine monotherapy. Unfortunately, most primary care providers do not feel comfortable managing alternative regimens. This article’s focus is to review hypothyroidism treatment modalities while discussing their efficacy and reviewing current practice guidelines.

Local varieties of Mandarin Chinese have been underdocumented. This study focuses on Mandarin high falling fourth tone (T4), as pronounced in connected speech by four female speakers native to Nanning City and its surrounding areas, in Guangxi Zhuang Autonomous Region. Surface forms of T4 and the high level tone (T1) often exhibit minimal difference, most likely due to the strong Cantonese influence in the area. I compare the pronunciation of T4 in multiple environments to the predictions about Standard Mandarin T4 surface forms in those same positions. Nanning T4 is flatter overall than Standard Mandarin T4 in all positions, with two-thirds to three-fourths of the T4s which were predicted to exhibit full falls actually exhibiting blocked falls. In this study I also propose a subdivision of blocked falls into two subcategories of partially blocked and completely blocked. This division helps to more accurately describe the surface forms of blocked falls, creating the ability to distinguish T4 falls with narrower ranges from T4s with completely flattened contours or even positive slopes. A perception test accompanies the acoustic analysis. Twenty-six Chinese living in Nanning were asked to identify T4 and T1 syllables extracted from the recordings. Test prompts included syllables, words, phrases, and sentences. Results show a unidirectional confusion of T4 with T1, which is consistent with findings from other perception studies. Onset height is a vital T4 perceptual cue, often more powerful than contour for some listeners. Regardless of the acoustic flattening of T4 in Nanning Mandarin, the underlying form of T4 remains distinct from T1, and onset height is a more important determiner of range than the position of T4 in the sentence or the tonal context surrounding the T4.

Spot friction welding (SFW) is solid state joining process using a rotating tool with the pin at the tip plunged into a two overlapping sheets to create plastic flow of the material and create a spot welded joint. Based on literature survey, the following gaps in research are identified and addressed in this thesis: (1) effects of process parameters on specimen temperature, specimen geometry and their impacts on the SFW joint strength and failure mode, (2) effects of stamping lubricant on the SFW joint strength, and (3) improve the joint strength by creating Metal Matrix Composite (MMC) in-situ at the joint during the welding process. The effects of key process parameters, cycle time, tool rotational speed, and axial force, on the specimen temperature and joint strength is studied to establish a relationship between the specimen temperature to the maximum lap shear load. When the specimen temperature met or exceeded a threshold temperature of 340°C, an acceptable joint strength of 2.4 kN or higher as specified by Society of Automotive Engineers (SAE) is achieved. The specimen temperature greater than 340°C can be accomplished by adjusting cycle time and/or tool speed and/or axial force. In this study, cross-sectional macrographs of SFW joints are studied to establish a relationship between joint geometric feature and joint failure mode. A geometric feature, identified as the ratio of distance from the point at which metallurgical bond start to free edge of the pin and to free edge of the shoulder, has demonstrated to be a factor to determine the failure mode of SFW joints. When this ratio was below 1.3, the specimens failed by shear fracture and when it was above 1.8, the specimens failed by mixed mode fracture. The SFW joint area is maximized to achieve highest joint strength when this ratio is between 1.4 and 1.8. This study conducts a design of experiment (DOE) to establish the effect of stamping lubricant on the joint strength. The maximum lap shear load increased by approximately 10% when the lubricant presents at the top surface compared to that of the baseline (no lubricant) whereas the maximum lap shear load decreased by 10% when the lubricant presents in the middle and at the bottom surfaces compared to that of the baseline. The weld nugget sizes of the tested specimens were measured and the average nugget size loosely correlated to the lap shear strength. The localized particle reinforced MMC in SFW has demonstrated that using the >45 mum size steel particle in 6111-T4 aluminum, the improvement in maximum lap shear load by 25% and the displacement to failure by 55% compared to that of the baseline (homogeneous material). Cross-sectional macrographs of SFW joints show the increase in length of the crack path due to the torturous crack path which leads to the increase in maximum lap shear load for the particle reinforced MMC SFW specimen. An analytical model was developed based on Ramberg-Osgood equation to calculate the tensile failure stress for the experimental setup with steel particle reinforced SFW in 6111-T4 aluminum. The estimated tensile stress of particle reinforced MMC increased by 14 to 30% compared to that of homogeneous material. The model is applied to provide the guideline for selection of type of particles that can be applied to further improve the strength of MMC reinforced SFW joint. Based on the variables used in the modeling, the SFW joint strength can be increased by increasing the volume fraction, using stronger reinforcement material, distributing the reinforcement particles uniformly, and using smaller particles.

The time of initiation of T4 DNA replication is dependent on the initiation of deoxyribonucleotide synthesis. It is our thesis that the turn-on of synthesis of the limiting enzyme, ribonucleoside diphosphate reductase, completes the deoxyribonucleotide synthetase complex and initiates deoxyribonucleotide and DNA synthesis. This thesis examines the expression of the nrdA and $B$ genes, coding for the $\alpha$ and $\beta$ chains of the enzyme, respectively. The translational frame of nrdA begins 558 base pairs downstream of the 3$\sp\prime$ terminus of the td gene (thymidylate synthase). In turn, nrdB initiates 700 base pairs from the termination of nrdA. A high degree of similarity is found between the deduced amino acid sequence of the 754-residue $\alpha$ chain and the corresponding chain of Escherichia coli. Thus, 56% of the residues are identical. A newly discovered gene expressed in infection, the Y gene codes for an unusual 87-amino acid chain (10 kDa) lacking alanine, but containing elevated levels of threonine and proline. It is 24 bases downstream of the td gene. A potential open reading frame corresponding to a very basic 141-residue polypeptide chain also initiates within the translational termination codon of nrdA. nrdA is transcribed onto three mRNAs. Two of these transcripts are form prereplicative promoters: T$\sb{\rm U}$, a multi-cistronic message initiating upstream of the frd gene (dihydrofolate reductase) and T$\sb3$, formed in low concentrations, whose 5$\sp\prime$ terminus lies upstream of nrdA, and the third (T$\sb{\rm L}$) is a transcript of a late promoter found upstream of nrdA. These nrdA transcripts are effectively terminated about 80 nucleotides downstream of nrdA. A separate transcript initiating about 162 nucleotides upstream of nrdB was found by the S1 nuclease protection method. This transcript appears to be rather stable. Thus, unlike the host's nrd gene, the phage nrdA and $B$ genes are not coordinately regulated. The nrdA, nrdB, and $Y$ genes were cloned into expression vectors, these resulting plasmids expressed large amounts of the corresponding protein products; these proteins constituted over 20% of the soluble protein.