Numerical solution of laminar compressible flow over a circular cylinder

M.S.Pandeli Durbetak

Radiosensitization of Head & Neck Carcinoma Cells by Linifanib, A Receptor Tyrosine Kinase Inhibitor

Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. Rapid growing tumors will cause hypoxia, which up-regulates tumor cell survival factors, such as VEGF and hypoxia-inducing factor-1α (HIF-1α), giving rise to more tumor proliferation, angiogenesis and increased radioresistance. Thus, agents that target new tumor vessel formation can modulate the tumor microenvironment to improve tumor blood flow and oxygenation, leading to enhanced radiosensitivity. Signal transducer and activator of transcription 3 (STAT3), is a potential modulator of VEGF expression and regulates cell-cycle progression, angiogenesis, metastasis and apoptosis. Approximately 80% of HNSCC exhibit up-regulation of STAT3 expression, which theoretically mediates radio-resistance and chemo-resistance. Therefore, inhibition of STAT3 may render tumor cells growth arrest and/or apoptosis. Recently it has been discovered that DNA damage can induce the expression and secretion of interleukin-6 (IL-6), resulting in the activation of STAT3 signaling pathway. Therefore, by inhibiting STAT3, one can also inhibit DNA damage repair and induce apoptosis in tumor cells. In this project, we tested the feasibility of Linifanib (ABT-869), a multi-receptor tyrosine kinase inhibitor of VEGF and platelet derived growth factor (PDGF) receptor families, on radio-sensitization of HNSCC. The results show that Linifanib (ABT-869) can induce an antitumor effect and radio-sensitize HNSCC cells via inhibition of STAT3 signaling pathway. Combining antiangiogenic targeted agent such as Linifanib (ABT-869) with radiation to enhance tumor killing and apoptosis may provide a novel therapeutic strategy and improve efficacy of radiation against HNSCC in the future

Environmental and Dietary Exposure to Copper and Its Cellular Mechanisms Linking to Alzheimer's Disease.

Metals are commonly found in the environment, household, and workplaces in various forms, and a significant segment of the population is routinely exposed to the trace amount of metals from variety of sources. Exposure to metals, such as aluminum, lead, iron, and copper, from environment has long been debated as a potential environmental risk factor for Alzheimer's disease (AD) for decades, yet results from in vitro, in vivo, and human population remain controversial. In the case of copper, the neurotoxic mechanism of action was classically viewed as its strong affinity to amyloid-beta (Aβ) to help its aggregation and increase oxidative stress via Fenton reaction. Thus, it has been thought that accumulation of copper mediates neurotoxicity, and removing it from the brain prevents or reverse Aβ plaque burden. Recent evidence, however, suggests dyshomeostasis of copper and its valency in the body, instead of the accumulation and interaction with Aβ, are major determinants of its beneficial effects as an essential metal or its neurotoxic counterpart. This notion is also supported by the fact that genetic loss-of-function mutations on copper transporters lead to severe neurological symptoms. Along with its altered distribution, recent studies have also proposed novel mechanisms of copper neurotoxicity mediated by nonneuronal cell lineages in the brain, such as capillary endothelial cells, leading to development of AD neuropathology. This review covers recent findings of multifactorial toxic mechanisms of copper and discusses the risk of environmental exposure as a potential factor in accounting for the variability of AD incidence

Bandwidth Improvement of MMIC Single-Pole-Double-Throw Passive HEMT Switches with Radial Stubs in Impedance-Transformation Networks

In this paper, we propose a new configuration for improving the isolation bandwidth of MMIC single-pole-double-throw (SPDT) passive high-electron-mobility transistor (HEMT) switches operating at millimeter frequency range. While the conventional configuration adopted open-stub loading for compensation of the off-state capacitance, radial stubs were introduced in our approach to improve the operational bandwidth of the SPDT switch. Implemented in 0.15 m GaAs pHEMT technology, the proposed configuration exhibited a measured insertion loss of less than 2.5 dB with better than 30 dB isolation level over the frequency range from 33 GHz to 44 GHz. In terms of the bandwidth of operation, the proposed configuration achieved a fractional bandwidth of 28.5% compared to that of 12.3% for the conventional approach. Such superior bandwidth performance is mainly attributed to the less frequency dependent nature of the radial stubs

Micromagnetic Modeling of Magnetic Storage Devices

University of Minnesota Ph.D. dissertation. March 2021. Major: Electrical Engineering. Advisor: Randall Victora. 1 computer file (PDF); ix, 92 pages.Hard disk drives (HDDs) are the dominant mass storage devices for personal and cloud storage due to their low cost and high capacity. Heat-assisted magnetic recording (HAMR) is considered to be next-generation recording technology for HDDs. While HAMR shows the potential for areal density to go beyond one terabit per square inch, this new recording mechanism requires further understanding and optimization before commercialization. First, I examine the relationship between media noise power and linear density in HAMR. I observe that there is a noise plateau at intermediate recording density and show that the plateau can be shifted to different recording density regions depending on the temperature profile. This effect is argued to be a consequence of the competition between transition noise and remanence noise in HAMR. To extend the recording density limit, heat-assisted shingled magnetic recording is studied. The transitions are no longer symmetric about the track center after shingled writing, especially when the transitions are highly curved as a result of the temperature profile generated by the near-field transducer. I propose a new reading scheme by rotating the read head to match the curved transitions. For a single rotated head, more than 10% improvement in user density over that of a single non-rotated head is achieved. I found that the optimal rotation angle generally follows the transition shape. With an array of two rotated heads, a track pitch of 15 nm, and a minimum bit length of 6.0 nm, the user areal density reaches 6.2 terabits per square inch, more than 30% above previous projections for recording on granular media. Magnetoresistive random-access memory (MRAM) is another type of magnetic storage device that is mainly used as computer memory. As semiconductor-based memory begins to hit physical limits, spin-transfer torque (STT) MRAM and spin-orbit torque (SOT) MRAM appear to be strong candidates for future memory applications. I start first by studying SOT switching in magnetic insulators. Magnetic insulators (MIs), in particular rare-earth iron garnets, have low damping compared to metallic ferromagnetic materials due to lack of conduction electrons. Analogous to STT devices, their low-damping nature is presumed to be an advantage for SOT applications. I report that perpendicular magnetic anisotropy (PMA) material with low damping does not favor reliable SOT switching, but increased damping, interfacial Dzyaloshinskii–Moriya interactions, or field-like torques may help SOT switching in some cases. Notches in a nanometer-scale element, which is a more realistic size for practical applications, can also improve switching stability. To fully utilize low damping MIs with SOT, an in-plane exchange-coupled composite free layer SOT-MRAM is proposed. The free layer consists a low-damping soft MI and a high anisotropy material. The adoption of high anisotropy materials, such as L10 alloy, not only facilitates the achievement of ultra-high-density memory but also allows for the reduction of heavy metal layer volume and thus a reduction in write energy not seen in previous CoFeB-based SOT-MRAM. A write energy of 18 attojoules per bit for 1 ns switching is achieved which is only 72 times more than the theoretical limit of 60kBT. It also represents a factor of more than five hundred times improvement relative to state-of-the-art dynamic RAM

Signalling mechanisms underlying priming and tolerance of T cells

The primary mission of the immune system is to defend against invading pathogens. The normal healthy body can distinguish self from non-self antigens. When a new antigen is encountered, such discriminatory capacity would generate a productive immune response against invasive pathogens or exert antigen-specific tolerance, the latter to prevent harmful immune responses against self-components or non-dangerous food or environmental antigens. Peripheral tolerance plays an important role in preventing T cells response to self or harmless antigens. A breakdown in tolerance within an individual can result in the development of a variety of autoimmune disorders. Full T cell activation requires at least two signals. The first one is provided by the TcR recognizing cognate peptides derived from antigen in the context of appropriate MHC molecules expressed by antigen presenting cells (APC). The second is mediated by “co-stimulation” via interaction of CD28 on the T cell with CD80/86 on the APC. The clonal anergy is induced when the TcR is ligated in the absence of co-stimulation, one of the proposed mechanisms of peripheral tolerance, describes a state of long lasting unresponsiveness to antigen, in the T cell. Despite widely studies in this area, however, the mechanisms of induction of anergy and the efficient markers for diagnosis of anergy are still not clear. One of the mechanisms which contributes to forming tolerance is anergy, which can be defined as defect in cellular proliferation and IL-2 production. Furthermore, GTPase Rap1 has been reported to inhibit the generation of pERK signals and to accumulate in tolerant cells. However, most of previous studies have done by biochemical assessment of signaling in T cell lines or clones upon polyclonal stimulations in vitro, and thus has generated some conflicting data. For solving this problem, our lab has developed the technique, laser scanning cytometry (LSC), for observation of responses in individual antigen-specific T cells within their environmental niche within primary or secondary lymphoid tissue. By LSC, it has reported that there are significant differences in the amplitude and cellular localization of phosphorylated ERK signals when naïve and in vitro-primed and tolerized T cells respond to Ag. To further investigate the role of Rap1 by LSC, it revealed that counter regulation in Rap1 and phosphor-ERK expression during the maintenance phase of tolerance and priming of antigen-specific CD4+ T cells in vitro and in vivo. In T cells, the maintenance phase of anergy has been reported to reflect defective activation of transcription factor, such as c-Jun/c-Fos, that are involved in formation of the AP-1 complex, which is required for inducing transcription of the IL-2 gene and optimal activation and effector function of T cells. In turn, this appears to be determined by the lack of recruitment of the ERK, JNK and p38 MAPK signaling cascades. The small GTPase, Rap1, has long been implicated in such desensitisation of ERK, and the consequent reduced IL-2 production, observed in tolerised T cells. However, the most of these studies were processed with T cell lines or clones in vitro and as such are not necessarily representative of physiological responses of primary antigen-specific T cells. Consistent with the previous finding, we have extended these studies to investigate whether Rap1 plays a role in determining commitment to anergy and priming during induction and maintenance phases. As expected, analysis in the DNA synthesis during maintenance phase reported that the primed T cells exhibited a higher response than either naïve or anergic T cells, whilst the anergic T cells displayed an even lower DNA synthesis than naïve T cells undergoing a primary response. To further investigation in cytokine production of IL-2 and IFNγ at 24, 48 and 96 hour during the maintenance phase, consistent with previous studies, the primed T cells produced the highest levels of IL-2, relative to anergic cells with the lowest levels, at the first 24 hours after challenge with antigen. However, the IL-2 production from primed and anergic T cells both drop down from 48 hours and to very low level at 96 hours but accompanying with gradual increase of IFNγ production. This implicates both anergic and primed cells consumed IL-2 secreted in the early stage of maintenance phase for supporting following cellular differentiation. The assessment of cellular proliferation also indicates that both primed and anergic cells had undergone several rounds of division. Whereas the primed cells proliferated more and faster than anergic cells over the first two days, after that anergic cells were able to catch up with primed cells. Consistent with above proliferative responses, the primed T cells showed higher levels of ERK activation than anergic cells at day 1 but lower levels of ERK activation than anergic cells at day 3. Surprisingly, there is no difference in Rap1 activation between primed and anergic T cells during maintenance phase. The additional finding from cellular proliferation during maintenance phase revealed that both primed and anergic cells undergo clonal expansion during induction of priming and tolerance, which leads the further investigation in functional outcomes, MAPK signaling and mTOR pathways studies during induction phase. The primed cells exhibited higher levels of DNA synthesis than anergic cells at 48 hours whereas they had similar levels of DNA synthesis at 96 hours. The IL-2 and IFNγ production were only detectable within the first 48 hours but not 96 hour. Collaborating with the data from cellular proliferation indicates the IL-2 were consumed for promoting the cells survival and proliferation since both populations showed clear peaks representing differential numbers of cell division from day 2 (48 hour) onwards, whereas the primed cells proliferated more and faster than anergic cells during whole induction phase. Moreover, cyclic activation of ERK was seen in the primed T cells and at higher levels of activation than in the anergic population, which did not exhibit these kinetics in western blotting. Interestingly, the primed T cells exhibited slightly higher levels of Rap1 than anergic cells from 48 hour until 96 hour during induction phase. Consistent with data from in vitro, the proliferation response in mimicking physiological model also can be replicated. Additionally, the counter regulation in ERK and Rap1 activation also occurred during the induction of priming and tolerance, which is investigated by adenoviral gene transfer of Ad Rap1 S17N, an inactive mutant of Rap1. Furthermore, modulation of Rap1 expression with Ad Rap1 S17N in cells during induction of anergy, revealed that Rap1 activity acts to limit cellular proliferation and thus switching off Rap1 activity upregulates cellular proliferation to generate a phenotype more resembling priming of normal (or GFP-) T cells by antiCD3+anti-CD28, which showed higher proliferation that GFP- cells stimulated with anti-CD3 only. However, when these adenoviral transfer experiments were repeated in the more physiological model, the higher proliferation exhibited in anergic Ad Rap1 S17N transduced cells were not replicated, suggesting that the enhancing effect of Ad Rap1 S17N might be substituted by signals generated under these more physiological conditions. There did not appear any difference between anergic and primed cells in terms of ERK/Rap1 signalling during the induction phase and introduction of Ad Rap1 S17N did not modulate ERK activity in transduced cells treated with anti-CD3 or anti-CD3+anti-CD28, suggesting that Rap may target some other effector during the induction phase. To sum up these data, Rap signaling in anergy and priming as well as the use of the dominant negative construct suggested that Rap was not acting to suppress ERK activation during induction of anergy. The further investigation in the downstream targets, c-Myc, did not see any direct connection with ERK/Rap1 activation during induction of anergy and priming. Moreover, the primed T cells tend to skew to catabolic rather anabolic metabolic pathways, when compared to anergic T cells during the induction phase, as evidenced by the primed cells exhibiting upregulation and phosphorylation of AMPK and Raptor to inhibit mTORC1 funtion and in turn, lower levels of pp70 S6K. However, the expression of phosphorylated Rictor in anergic t cells was higher than that of primed T cells, indicating inhibition of mTORC2 in anergic T cells resulting in downregulation of AKT activation during this induction phase

Emerging Leaderships in an Online Community: A Longitudinal Network Analysis

Online communities have brought great benefits to society; however, relatively few of them are successful in sustaining community activities. It is necessary to have a better understanding of the contextual development of online communities. This study adopts the theory of networked influence to address the research objective. Data is collected from an online community which has been in operation for ten years. We investigate the community’s sustainability on a longitudinal basis, focusing on its dynamic temporal development, with regard to how it was formed, became robust, and either declined or was sustained. Adopting social network analysis with a qualitative approach, we identify several types of emerging leaders and how the relay events between them had a significant impact on communication prolongation. Their influence is found to extend across discussion entities, resulting in communication homogeneity, and leading to significant network effects that are relevant to participants’ interactions

Silicon microaccelerometer fabrication technologies

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1997.Includes bibliographical references (leaves 275-282).by Charles Heng-Yuan Hsu.Ph.D

Cytotoxicity in the Age of Nano: The Role of Fourth Period Transition Metal Oxide Nanoparticle Physicochemical Properties

A clear understanding of physicochemical factors governing nanoparticle toxicity is still in its infancy. We used a systematic approach to delineate physicochemical properties of nanoparticles that govern cytotoxicity. The cytotoxicity of fourth period metal oxide nanoparticles (NPs): TiO2, Cr2O3, Mn2O3, Fe2O3, NiO, CuO, and ZnO increases with the atomic number of the transition metal oxide. This trend was not cell-type specific, as observed in non-transformed human lung cells (BEAS-2B) and human bronchoalveolar carcinoma-derived cells (A549). Addition of NPs to the cell culture medium did not significantly alter pH. Physiochemical properties were assessed to discover the determinants of cytotoxicity: (1) point-of-zero charge (PZC) (i.e., isoelectric point) described the surface charge of NPs in cytosolic and lysosomal compartments; (2) relative number of available binding sites on the NP surface quantified by X-ray photoelectron spectroscopy was used to estimate the probability of biomolecular interactions on the particle surface; (3) band-gap energy measurements to predict electron abstraction from NPs which might lead to oxidative stress and subsequent cell death; and (4) ion dissolution. Our results indicate that cytotoxicity is a function of particle surface charge, the relative number of available surface binding sites, and metal ion dissolution from NPs. These findings provide a physicochemical basis for both risk assessment and the design of safer nanomaterials

An analysis of P\mathbb{P}-invariance and dynamical compensation properties from a control perspective

Dynamical compensation (DC) provides robustness to parameter fluctuations. As an example, DC enable control of the functional mass of endocrine or neuronal tissue essential for controlling blood glucose by insulin through a nonlinear feedback loop. Researchers have shown that DC is related to structural unidentifiability and $\mathbb{P}$-invariance property, and $\mathbb{P}$-invariance property is a sufficient and necessary condition for the DC property. In this article, we discuss DC and $\mathbb{P}$-invariancy from an adaptive control perspective. An adaptive controller is a self-tuning controller used to compensate for changes in a dynamical system. To design an adaptive controller with the DC property, it is easier to start with a two-dimensional dynamical model. We introduce a simplified system of ordinary differential equations (ODEs) with the DC property and extend it to a general form. The value of the ideal adaptive control lies in developing methods to synthesize DC to variations in multiple parameters. Then we investigate the stability of the system with time-varying input and disturbance signals, with a focus on the system's $\mathbb{P}$-invariance properties. This study provides phase portraits and step-like response graphs to visualize the system's behavior and stability properties