Seeding with Costly Network Information

We study the task of selecting $k$ nodes in a social network of size $n$, to seed a diffusion with maximum expected spread size, under the independent cascade model with cascade probability $p$. Most of the previous work on this problem (known as influence maximization) focuses on efficient algorithms to approximate the optimal seed set with provable guarantees, given the knowledge of the entire network. However, in practice, obtaining full knowledge of the network is very costly. To address this gap, we first study the achievable guarantees using $o(n)$ influence samples. We provide an approximation algorithm with a tight (1-1/e){\mbox{OPT}}-\epsilon n guarantee, using $O_{\epsilon}(k^2\log n)$ influence samples and show that this dependence on $k$ is asymptotically optimal. We then propose a probing algorithm that queries ${O}_{\epsilon}(p n^2\log^4 n + \sqrt{k p} n^{1.5}\log^{5.5} n + k n\log^{3.5}{n})$ edges from the graph and use them to find a seed set with the same almost tight approximation guarantee. We also provide a matching (up to logarithmic factors) lower-bound on the required number of edges. To address the dependence of our probing algorithm on the independent cascade probability $p$, we show that it is impossible to maintain the same approximation guarantees by controlling the discrepancy between the probing and seeding cascade probabilities. Instead, we propose to down-sample the probed edges to match the seeding cascade probability, provided that it does not exceed that of probing. Finally, we test our algorithms on real world data to quantify the trade-off between the cost of obtaining more refined network information and the benefit of the added information for guiding improved seeding strategies

Modulation of p53 signalling and response to MDM2-p53 binding antagonists

PhD ThesisMutational inactivation of the p53 tumour suppressor protein, encoded by the TP53 gene, occurs in ≈50% of malignancies overall. Non-genotoxic activation of p53 signalling in the remaining TP53 wild-type malignancies is a promising therapeutic strategy. MDM2 inhibitors, such as Nutlin-3 and RG7388, can activate p53 in a nongenotoxic manner, mobilising p53-dependent signalling; however, sensitivity to these compounds varies widely among TP53 wild-type cell lines. In this study p53 signalling network components involved in the response to DNA damage and p53 homeostasis are investigated for their role as determinants of cellular sensitivity to MDM2 inhibitors. Deciphering determinants of sensitivity to this group of compounds will enable optimisation of their therapeutic potential. Chemical inhibition of kinases, ATM and DNA-PKcs, which are critical for DNA double strand break repair and activation of p53 signalling in response to DNA damage, did not affect the cellular sensitivity to Nutlin-3 in the absence of DNA damage. However, inhibition of these kinases enhanced the cellular sensitivity of TP53 wild-type cells to the combined effect of Nutlin-3 and DNA damage induced by ionising radiation, in a cell type dependent manner. In a neuroblastoma derived TP53 wild-type and mutant, otherwise isogenic, cell line pair, ionising radiation increased the growth inhibitory effect of Nutlin-3 in a p53-dependent manner and this was enhanced significantly in the presence of the DNA-PKcs inhibitor NU7441. In contrast, in the osteosarcoma derived TP53 wild-type and mutant, otherwise isogenic, cell line pair, exposure to ionising radiation decreased the growth inhibitory effect of Nutlin-3 in a p53-dependent manner and DNA-PKcs inhibition did not influence this protective effect. Given that ATM and DNA-PKcs activate p53 through phosphorylation of key residues, inhibition of the WIP1 phosphatase (encoded by the PPM1D gene) that dephosphorylates one such residue, was tested for the effect on cellular sensitivity to MDM2 inhibitors. Cellular growth/proliferation was assessed in TP53 wild-type and matched mutant/null cell line pairs, differing in their PPM1D genetic status, when treated with MDM2 inhibitors Nutlin-3/RG7388 + a highly selective WIP1 inhibitor GSK2830371 or transient siRNA knockdown of WIP1 expression. The effects of GSK2830371 and transient WIP1 siRNA knockdown on MDM2 inhibitor induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity and apoptosis II were also investigated. WIP1 transient siRNA knockdown increased p53Ser15 phosphorylation and sensitivity to MDM2 inhibitors in TP53 wild-type parental cell lines. TP53 wild-type and mutant cell line pairs were relatively insensitive to single agent GSK2830371 regardless of their PPM1D status. However, a non-growth inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harbouring PPM1D activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also concurred with significant increase in MDM2 inhibitor induced cell death endpoints which were preceded by a marked increase in phosphorylated p53Ser15, a WIP1 negatively regulated substrate, and known to increase p53 transcriptional activity. Microarray-based gene expression profiling showed that the combination treatment increases the subset of early RG7388 induced p53-transcriptional target genes involved in growth inhibition and apoptosis. Increased mRNA and protein expression of WIP1 has been associated with poor clinical outcome in various malignancies in which MDM2 inhibitors are being considered as a potential therapeutic strategy. For neuroblastoma mining the Amsterdam microarray databank showed WIP1 mRNA expression to correlate with worse survival. Therefore, WIP1 protein expression was assessed by immunohistochemical (IHC) staining of neuroblastoma tissue microarrays. A wide range of WIP1 IHC staining was found, however there was no significant association between high WIP1 staining and clinical outcome. Overall these findings show that manipulating p53 post-translational modification following its activation by MDM2 inhibitors or DNA damaging agents can increase cellular sensitivity to this class of compounds. Furthermore, these observations provide evidence to support the inhibition of WIP1 phosphatase activity as a strategy for enhancing the efficacy of MDM2 inhibitors, particularly in TP53 wild-type, PPM1D overexpressing/overactive malignancies

Influence Of Transverse Elements On The Pullout Capacity Of Metal Strip Reinforcement In Sandy Soil

Interface friction angle between different materials is a very important parameter in the designs of mechanically stabilized earth (MSE) as it corresponds directly to pull out capacity of a reinforcement strip. In this research, anchorage elements have been added to normal reinforcement strip in order to increase interface friction angle and thus the pull out capacity. Sand was used as fill material. In the tests, one plain strip with smooth surface, two strips with simple ribs, and eighteen strips with transverse members of various depths and counts were subjected to pull out forces with normal stresses ranging from 50 kPa to 100 kPa applied. Also, π-Buchingham theorem and regression analysis using statistical software - SPSS v.14 - were used to obtain general equations relating pull out capacity to strip parameters and compare predicted strength values to actual outcomes of the tests. The results of the study indicate that the new method involving transverse members could generally offer saving of strip material or provide particular design criteria for MSE of limited construction space, since the increased capacity of each reinforcement strip would reduce the total length or amount of strips required in a project

Skin Cancer, Skin Biopsies and Mohs Surgery: Patient Education

Skin cancer is the most common cancer in the United States. There are three main types of skin cancer: Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma. While Melanoma is less common than Basal Cell and Squamous Cell Carcinoma, it has a higher mortality rate. If diagnosed in earlier stages, Melanoma has a significantly better prognosis and lower patient costs. Most skin cancers are diagnosed through skin biopsies. Vermont has one of the highest rates of skin cancer. The goal of this project was to develop a patient handout to bring patient awareness to skin cancer and describe the different types of skin biopsies (shave, punch and excisional), as well as Mohs surgery.https://scholarworks.uvm.edu/fmclerk/1823/thumbnail.jp

Development of staircase-output multilevel inverter

Due to several scenarios attached to the fossil fuel resources, the world has experienced a trend popularly towards alternative energy sources especially, renewable and clean in extraction as well as generation. This has raised the demand bar for the often popular solar and wind as the energy sources. As a result, renewable power conversion marketing has also dramatically increased during the past decade. Due to the application of inverters in power generation,the coinciding interest is shared equally and thus has created the basis of research interest on multi-level inverters. To acquire desired form of power, especially when precision, reliability and the economy of the project is considered upon, a multi-level inverter is a beneficial choice. They present ability to control higher amount of voltage and current, low THD, low cost, simple control methods, and compactness. Having exhibited its share of advantages in electronic power conversion, certain previous structures have indicated some limitations which risk hampering its fair deal of positive attributes. Such as the implementation of series connected switches (cascaded),a factor behind the inefficiency, operational heat generation and unreliability. A cascaded structure imposes two important limitations to the system: it limits the efficiency and reliability by increasing the on-state power dissipation in the converter; it directly limits the reliability by increasing the likelihood of failure. The selection of multi-level inverter configurations, on the basis of on-state voltage drop of switches is possible through developing a new mathematical method to calculate the comparative efficiency in staircase diode-clamped, H-bridge and the proposed inverter with pn junction and MOSFET switches. These calculations rely on the onstate voltage drop of p-n junction switches, conducting resistance of MOSFET switches, break down voltage, number of levels, peak output voltage, voltage steps magnitude and the load. The calculations show the important effect of on-state voltage drop of switches on the efficiency in staircase multi-level inverters. Using an affordable multi-winding transformer, a low frequency multi-level DC-AC-AC inverter is proposed and proves to be an advantageous choice. The most important advantage of this multilevel inverter is that only four switches conduct during each step,which means that it operates with lower number of serial conducting switches, resultantly increasing the efficiency and reliability. Higher reliability when switches fail in open-circuit and short-circuit behavior is another advantage of this inverter structure however, it is recommended to use switches that fail in open-circuit owning to higher reliability of the inverter in open-circuit failures. Furthermore, some important factors that affect the reliability of inverters have been improved in the proposed inverter, including:duty cycle of conducting switches, voltage stresses, switching frequency, switches temperature and dependency to capacitors. The system is controlled with a cheap microcontroller. A 5-kW 47-level prototype showed 97.4% ± 0.2% peak efficiency decreases to 91% under a full load and THD starts at 0.66% under a 50-W load increases to more than 7.5% under a full load. The novel proposed inverter, Switch-Ladder multi-level inverter, is a reliable and efficient choice for PV and renewable applications, where the output voltage peak is low and the volume and weight are not important parameters