A Dynamic Spectrum Access Framework (Bring Your Own Spectrum)

In this thesis, a unified and sustainable framework for spectrum allocation is presented. This multi-level operator-agnostic framework, Bring Your Own Spectrum (BYOS), is the result of a few thought experiments reflecting the ways in which spectrum could be bought and sold as an asset, similar to service models in cloud computing where every technical element can be traded via an "as-a-Service" model. BYOS architectural features form the major part of this thesis and cover four levels of abstraction as – contextual, conceptual, logical and physical. First, the contextual aspect of BYOS is covered, which addresses the question: "why is the framework needed?". To understand the reasons behind the need for a new framework an exhaustive survey of history of telecommunications policy development of 32 countries was conducted that included major economies in several key regions of the world. This research provided insight into the role of the government, mechanisms used for allocations, success/failure of allocations, and business models in the sector. Additionally, a review of existing and emerging technologies was done to understand various possible mechanisms of spectrum access. Next, the conceptual aspect of BYOS is presented, which addresses the question: "what does the framework look like?". For this, the information from the study above was converted into a skeleton framework, ensuring that it covers the requirements gathered. The framework has a three-level architecture with a quasi-static allocation scheme. The levels of architecture are designated based on periods of ownership and the thesis presents an original exponential-based-scale to determine the allocation periods (longest to shortest). The framework accommodates different types of operators, categorising in terms of their spectrum access privileges. Following this, the thesis focuses on the physical level of the framework, where the question: "with what?" i.e. the technical mechanisms are discussed. In this part, a novel analogy is presented where the wireless spectrum is compared to a multi-lane, multi-level highway. This analogy provides the basis for unit of information transport between two points, which in turn form the trading unit. In this thesis, "Interference (transmission power) spread over bandwidth" is chosen as the basic trading unit for the BYOS framework. Also included is a discussion on the required changes to the calculation of "population" – an inherent part of reserve price calculation – in view of the proliferation of device using different types of mobile technologies. A second part of the physical framework presents an original mechanism for competition management in view of the new framework and trading unit. Using the principles of network traffic management, a new tracking unit – token – is introduced, which helps the regulators keep track of the process of spectrum allocation, but in a hands-off manner. Multiple models of using tokens in the framework are presented. Tokens are intended only for the shortterm trades, though the initial number is determined by the total spectrum acquisitions and cumulative participation behaviour. Finally, the logical or system model of the framework is presented, which addresses the question: "how to structure and organise the architecture to achieve the desired requirements". This discussion is also divided into two parts. First, the discussion focuses on the multiple ways to use tokens and demonstrates the different use cases by way of competition games. Key novel points here are the discussion of competition management over multi-period allocation and addressing the needs of public safety services. Additionally, the discussion also focuses on unequal desirability of available spectrum lots based on spectrum characteristics, acquisition periods, and operator’s own requirements. The second part of the discussion focuses on various methods of implementation of this framework. A potential enterpriseblockchain based method is explored, though there may be other better solutions. Another focus of this thesis, which can be considered as a separate minor segment, came out of the initial policy research was to organize and analyse this information systematically. For this purpose, the theory of policy diffusion was explored, and the research provides evidence for the existence of, and analyses the mechanisms used for policy diffusion in different regions and countries.Thesis (Ph.D.) -- University of Adelaide, School of Electrical and Electronics, 202

In Vitro Assessment of Antioxidant Capacity, Potential to Induce Autophagy/Mitophagy, and Mitochondrial Turnover of Natural Compounds for Cytotoxicity Studies

The dynamic process of intracellular reduction-oxidation status (redox homeostasis) is influenced by various factors, with mitochondria being one of the most significant contributors. Mitochondria play a crucial role in the bioenergetic pathway, fulfilling the metabolic energy demands of cells. To maintain increased energy requirements, mitochondrial biogenesis and fusion are employed, while decreased energy demands or damaged mitochondria are addressed through fission and autophagic removal, known as mitophagy. Any disruption in these adaptive responses can compromise redox homeostasis and cellular function, and make cells more vulnerable to oxidative stress, resulting in oxidative DNA damage, inflammatory responses, and apoptotic/anti-apoptotic reactions. Such dysregulation contributes to the development of “free radical diseases” like metabolic disorders and cancer. Traditional medicines and herbs (possessing antioxidant and autophagic properties) have been utilized for centuries in the treatment of various diseases; however, it is only recently that researchers have begun to investigate their molecular, cellular, and tissue-level modes of action. Nevertheless, concerns about their cytotoxicity have also arisen. This manuscript focuses on the current technological advancements in assessing the properties of plant-based natural compounds. Both cell-free and cell-based methods are employed to evaluate the therapeutic potential of these compounds, allowing for their scientific evaluation and validation

Natural Terpenes Prevent Mitochondrial Dysfunction, Oxidative Stress and Release of Apoptotic Proteins during Nimesulide-Hepatotoxicity in Rats

Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1∶1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

10.3390/ijms21051645INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES21

Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management

O-hexadecyl-dextran entrapped berberine nanoparticles abrogate high glucose stress induced apoptosis in primary rat hepatocytes.

Nanotized phytochemicals are being explored by researchers for promoting their uptake and effectiveness at lower concentrations. In this study, O-hexadecyl-dextran entrapped berberine chloride nanoparticles (BC-HDD NPs) were prepared, and evaluated for their cytoprotective efficacy in high glucose stressed primary hepatocytes and the results obtained compared with bulk berberine chloride (BBR) treatment. The nanotized formulation treated primary hepatocytes that were exposed to high glucose (40 mM), showed increased viability compared to the bulk BBR treated cells. BC-HDD NPs reduced the ROS generation by ∼ 3.5 fold during co-treatment, prevented GSH depletion by ∼ 1.6 fold, reduced NO formation by ∼ 5 fold and significantly prevented decline in SOD activity in stressed cells. Lipid peroxidation was also prevented by ∼ 1.9 fold in the presence of these NPs confirming the antioxidant capacity of the formulation. High glucose stress increased Bax/Bcl2 ratio followed by mitochondrial depolarization and activation of caspase-9/-3 confirming involvement of mitochondrial pathway of apoptosis in the exposed cells. Co- and post-treatment of BC-HDD NPs prevented depolarization of mitochondrial membrane, reduced Bax/Bcl2 ratio and prevented externalization of phosphatidyl-serine confirming their anti-apoptotic capacity in those cells. Sub-G1 phase apparent in high glucose stressed cells was not seen in BC-HDD NPs treated cells. The present study reveals that BC-HDD NPs at ∼ 20 fold lower concentration are as effective as BBR in preventing high glucose induced oxidative stress, mitochondrial depolarization and downstream events of apoptotic cell death

Decreased autophagy and fuel switching occur in a senescent hepatic cell model system

10.18632/aging.103740AGING-US121413958-1397

Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression

Objective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD. Methods: We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured. Results: Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. Conclusion: Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression

Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression

Objective: Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T4) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T4 to the bioactive T3 and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD. Methods: We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Leprdb mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured. Results: Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T3/T4 ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation. Conclusion: Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression