Experimental and Numerical Investigation of the Seismic Performance of RC Moment Resisting Frames

The rehabilitation of concrete structures has been a subject of extensive investigation, exploring various facets. One such avenue involves the incorporation of fiber additives into concrete materials. In parallel, the construction of reinforced concrete structures inevitably encounters construction errors, necessitating constant efforts from researchers to devise solutions for mitigating their impact. In the context of this research, a series of experiments was conducted involving the construction and testing of five reinforced concrete moment-resisting frames. The initial sample served as the control, while two additional samples were integrated with polypropylene and metal fibers. The subsequent two samples deliberately introduced a manufacturing error through the application of air-entraining admixture materials at the beam-to-column connection. This deliberate error aimed to assess the influence of additive fibers on frames affected by manufacturing errors. Several critical parameters were subjected to evaluation, including ultimate strength, stiffness, ductility, energy dissipation capacity, and strength reduction factor. The results of these assessments demonstrated that the utilization of additive fibers contributes to an enhanced overall performance of the frames, as inferred from the aforementioned seismic parameters. Furthermore, it was established that the incorporation of these additive fibers substantially alleviates the impact of manufacturing errors on moment-resisting reinforced concrete frames. Although a significant reduction in energy dissipation capacity was observed in samples with manufacturing errors, the other seismic parameters remained relatively unaffected. Subsequently, numerical models were generated in ABAQUS software to validate the experimental findings, and their outcomes were compared with the results derived from the physical experiments

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