En el presente estudio se realizó un modelamiento de un hospital de base aislada con el aislador elastomérico núcleo de plomo (LRB) de 6 pisos, como medida de protección para obtener menores daños y pérdidas económicas en cuanto a la estructura, ya que un hospital debe garantizar una funcionabilidad continua a cualquier evento sísmico, además, de ser un establecimiento muy importante que alberga a muchas personas. Esta investigación está formulada bajo las pautas del código ASCE 7-16 y SISCF. La investigación está validada por modelos informáticos de hospitales aislados, en lo que se detallara el modelamiento y las propiedades correspondientes del aislador núcleo de plomo, mejorando así su rendimiento sísmico. Los resultados son favorables, con reducciones en las derivas y cortantes de base / In the present study, an isolated base hospital was modeled with the 6-story lead core elastomeric insulator (Lead Rubber Bearing), as a protection measure to obtain less damage and economic losses in terms of structure, since a hospital must guarantee continuous functionality to any seismic event, in addition to being a very important establishment that houses many people. This research is formulated under the ASCE 7-16 and SISCF code guidelines. The research is validated by computer models from isolated hospitals, detailing the modeling and the corresponding properties of the lead core insulator, thus improving its seismic performance. The results are favorable, with reductions in drifts and base shear. / Trabajo de investigación

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Breast cancer is one of the most common malignancy diagnosed in women and is the primary cause of cancer-related deaths in women worldwide. It is a heterogeneous group of diseases that have a different response, prognosis, and clinical outcomes. Estrogen, progesterone and HER2 negative breast cancer, known as triple negative breast cancer (TNBC), does not respond to hormonal therapy. Basal-like breast cancer (BLBC) has shorter overall survival rate among other subtypes. Tumors sharing both TNBC and BLBC are considered less responsive to currently available treatment. Chemoresistance to treatment has been a challenge in cancer biology and force investigation toward developing new targeted therapies, which selectively target specific subtypes. Sphingolipid metabolites have an important physiological role in determining cell fate. Sphingolipid metabolites, ceramide, sphingosine, and sphingosine-1-phosphate (S1P), are implicated in cancer. S1P exerts its functions via extracellular and intracellular targets. S1P synthesized inside the cell is exported outside and binds to G-protein coupled receptors, the sphingosine-1-phosphate receptors 1-5 (S1PR1-5). Although the intracellular function is not well defined, its suggested intracellular S1P promotes cell apoptosis. The S1P pathway has received great attention recently due its function in cell survival and death. This effect was reported to be concentration dependent. In this research, I focused on S1P effect on nine TNBC/BLBC cell lines. I examined the in-vitro effects of S1P on apoptosis, proliferation, and cytotoxicity in triple negative/ basal-like breast cancer cell lines. Moreover, I studied the co-administration of S1P with currently used chemotherapeutic agents in these cell lines. Data show that S1P can selectively induce cell death in TNBC/BLBC cell lines at a specific concentration. In this research, I found that the mechanism of cell death following treatment with different S1P concentrations was mainly due to apoptosis. Results show that S1P leads to cell shrinkage, rounding and detachment in the nine TNBC/BLBC cell lines. S1P combination with doxorubicin and docetaxel at different concentrations shows no beneficial effect of the combination compared to the chemotherapeuitc agent alone. In some cell lines, the combination showed a protective effect. Further studies are required to determine the mechanism by which S1P induces cell apoptosis, inhibits cell growth, and demonstrates lack of responsiveness in combination studies.

In this thesis we model two very different movement-related neuronal circuits, both of which produce oscillatory patterns of activity. In one case we study oscillatory activity in the basal ganglia under both normal and Parkinsonian conditions. First, we used a detailed Hodgkin-Huxley type spiking model to investigate the activity patterns that arise when oscillatory cortical input is transmitted to the globus pallidus via the subthalamic nucleus. Our model reproduced a result from rodent studies which shows that two anti-phase oscillatory groups of pallidal neurons appear under Parkinsonian conditions. Secondly, we used a population model of the basal ganglia to study whether oscillations could be locally generated. The basal ganglia are thought to be organised into multiple parallel channels. In our model, isolated channels could not generate oscillations, but if the lateral inhibition between channels is sufficiently strong then the network can act as a rhythm-generating ``pacemaker'' circuit. This was particularly true when we used a set of connection strength parameters that represent the basal ganglia under Parkinsonian conditions. Since many things are not known about the anatomy and electrophysiology of the basal ganglia, we also studied oscillatory activity in another, much simpler, movement-related neuronal system: the spinal cord of the Xenopus tadpole. We built a computational model of the spinal cord containing approximately 1,500 biologically realistic Hodgkin-Huxley neurons, with synaptic connectivity derived from a computational model of axon growth. The model produced physiological swimming behaviour and was used to investigate which aspects of axon growth and neuron dynamics are behaviourally important. We found that the oscillatory attractor associated with swimming was remarkably stable, which suggests that, surprisingly, many features of axonal growth and synapse formation are not necessary for swimming to emerge. We also studied how the same spinal cord network can generate a different oscillatory pattern in which neurons on both sides of the body fire synchronously. Our results here suggest that under normal conditions the synchronous state is unstable or weakly stable, but that even small increases in spike transmission delays act to stabilise it. Finally, we found that although the basal ganglia and the tadpole spinal cord are very different systems, the underlying mechanism by which they can produce oscillations may be remarkably similar. Insights from the tadpole model allow us to predict how the basal ganglia model may be capable of producing multiple patterns of oscillatory activity.

Schizophrenia remains an enigmatic disorder with unclear neuropathology. Recent advances in neuroimaging and genetic research suggest alterations in glutamate-dopamine interactions adversely affecting synaptic plasticity both intracortically and subcortically. Relating these changes to the manifestation of symptoms presents a great challenge, requiring a constrained framework to capture the most salient elements. Here, a biologically-grounded computational model of basal ganglia-mediated action selection was used to explore two pathological processes that hypothetically underpin schizophrenia. These were a drop in the efficiency of cortical transmission, reducing both the signal-to-noise ratio (SNR) and overall activity levels; and an excessive compensatory upregulation of subcortical dopamine release. It was proposed that reduced cortical efficiency was the primary process, which led to a secondary disinhibition of subcortical dopamine release within the striatum. This compensation was believed to partly recover lost function, but could then induce disorganised-type symptoms - summarised as selection ”Instability” - if it became too pronounced. This overcompensation was argued to be countered by antipsychotic medication. The model’s validity was tested during an fMRI (functional magnetic resonance imaging) study of 16 healthy volunteers, using a novel perceptual decision-making task, and was found to provide a good account for pallidal activation. Its account for striatum was developed and improved with a small number of principled model modifications: the inclusion of fast spiking interneurons within striatum, and their inhibition by the basal ganglia’s key regulatory nucleus, external globus pallidus. A key final addition was the explicit modelling of dopaminergic midbrain, which is dynamically regulated by both cortex and the basal ganglia. This enabled hypotheses concerning the effects of cortical inefficiency, compensatory dopamine release and medication to be directly tested. The new model was verified with a second set of 12 healthy controls. Its pathological predictions were compared to data from 12 patients with schizophrenia. Model simulations suggested that Instability went hand-in-hand with cortical inefficiency and secondary dopamine upregulation. Patients with high Instability scores showed a loss of SNR within decision-related cortex (consistent with cortical inefficiency); an exaggerated response to task demands within substantia nigra (consistent with dopaminergic upregulation); and had an improved fit to simulated data derived from increasingly cortically-inefficient models. Simulations representing the healthy state provided a good account for patients’ motor putamen, but only cortically-inefficient simulations representing the ill state provided a fit for ventral-anterior striatum. This fit improved as the simulated model became more medicated (increased D2 receptor blockade). The relative improvement of this account correlated with patients’ medication dosage. In summary, by distilling the hypothetical neuropathology of schizophrenia into two simplified umbrella processes, and using a computational model to consider their effects within action selection, this work has successfully related patients’ fMRI activation to particular symptomatology and antipsychotic medication. This approach has the potential to improve patient care by enabling a neurobiological appreciation of their current illness state, and tailoring their medication level appropriately.

Thinning is performed today with essentially two thinning methods, with strip-roads or stand-thinning machines. The result after thinning affects the stands future development. In this study, the two thinning methods was compared with regard to distribution of basal area, resulting damage, the distribution of stems, actual thinning intensity and the impact that these differences may provide in the future. The survey was conducted in Sundsvall, Sweden in two different stands where basal area- surfaces, number of stems, damage and thinning strength was measured. The result shows that stand-thinning machines produce less damage to the stems and a more even distribution of the basal area. The strip-road method carried out a thinning of excessive thinning intensity of 50 % compared to 30 % for stand-thinning method. From a quality point of view the stand-thinning machines performed a better result. These machines have a lower production (harvested volume per hour) which probably results in lower financial gains in thinnings. Keywords: stand-thinning, basal area, thinning strength, Vimek, soil damage.

7 pp. / Preventing catastrophic stand replacing events are best accomplished through thinning. Lower tree densities result in greater tree growth. Stands with lower tree densities have greater plant diversity. Determining stand conditions will provide a baseline for formulating a plan to improve stand conditions. Thinning around individual trees can improve individual tree health reducing the likelihood of damage from bark beetles, fire or drought.

<p>Breast cancers with a basal-like gene signature are primarily triple-negative, are frequently metastatic, and carry the worst prognosis. Basal-like breast cancers are frequently enriched for markers of breast cancer stem cells as well as markers of epithelial-mesenchymal transition (EMT). While EMT is generally thought to be important in the process of metastasis, direct in vivo evidence of EMT in human disease remains rare. Here we report a novel model of human triple-negative breast cancer, the DKAT cell line, which was isolated from an aggressive, treatment-resistant triple-negative breast cancer that demonstrated morphological and biochemical evidence of epithelial-mesenchymal plasticity in the patient.</p><p>In culture, the DKAT cell line exhibits a basal epithelial phenotype under normal culture conditions in serum-free MEGM, and can undergo a reversible EMT in response to serum-containing media, a unique property among the breast cancer cell lines we tested. This EMT is marked by increased expression of the transcription factor Zeb1, and Zeb1 is required for the enhanced migratory ability of DKAT cells in the mesenchymal state. Additionally, we find that expression of the cytokine IL-6 is dramatically increased in mesenchymal DAKT cells, and blocking IL-6 signaling reduces expression of Zeb1. DKAT cells also express progenitor-cell markers, and single DKAT cells are able to generate tumorspheres containing both epithelial and mesenchymal cell types. In vivo, as few as ten DKAT cells are capable of forming xenograft tumors which display a range of epithelial and mesenchymal phenotypes. Finally, we also show evidence of vimentin expression in mammary epithelial cell clusters from asymptomatic women at high risk for breast cancer, suggesting that changes characteristic of epithelial-mesenchymal plasticity may be inherent to some breast cancers from their earliest stages.</p><p>Our results provide evidence that the aggressive behavior of a subset of triple-negative breast cancers is driven by inherent epithelial-mesenchymal plasticity. The novel finding that IL-6 regulates Zeb1 expression adds further rationale for the development of anti-IL-6 therapeutics, which will have the potential to target pathways at the intersection of metastasis and tumor recurrence. The DKAT cell line represents a novel model for further study of the molecular mechanisms that regulate plasticity in highly aggressive triple-negative breast cancers. An improved understanding of the pathways that are critical for this plasticity may lead to improved treatment options for highly aggressive and deadly breast cancers.</p> / Dissertation

This thesis aims to better understand the relationships between basal water pressure, friction, and sliding mechanisms at ice sheet scales. In particular, it develops a new subglacial hydrology model (Hydro) to explicitly predict water pressures in response to basal water production and water injection from the surface. Recent research suggests that the Greenland ice sheet (gis) is losing a substantial volume of ice through dynamic thinning. This process must be modelled to accurately assess the contribution of the gis to sea-level rise in future warming scenarios. A key control on dynamic thinning is the presence of water at the ice-bed interface; Zwally et al. (2002) highlight the importance of supraglacial lakes' impact on basal ice dynamics, a process now con rmed by Das et al. (2008) and Shepherd et al. (2009). Many studies focus on the effects of surface meltwater reaching the bed of the gis but the underlying processes are often ignored. Geothermal, strain, and frictional melting, which evolves with basal hydrology, provide the background basal pressure profile that surface meltwater perturbates. Without understanding how these heat terms affect the background profile it is difficult to define basal boundary conditions in models and therefore difficult to model the dynamic response of the gis to surface melting. Hydro tracks subglacial water pressures and the evolution of efficient drainage networks. Coupled with the existing 3D thermomechanical ice sheet model Glimmer, model outputs include effective pressure N and the efficient hydraulic area. Defining frictional heat flux and basal traction as functions of N allow the modelling of seasonal dynamic response to randomly draining supraglacial lakes. Key results are that frictional heat flux, as a function of N, caps potential runaway feedback mechanisms and that water converges in topographic troughs under Greenland's outlet glaciers. This leads to a background profile with low N under outlet glaciers. Therefore, outlet glaciers show a muted dynamic speedup to the seasonal surface signal reaching the bed. Land-terminating ice does not tend to have subglacial troughs and so has higher background N and consequently a larger seasonal response. This, coupled with effects of ice rheology, can explain the hitherto puzzling lack of observed seasonal velocity change on Jakobshavn Isbræ and other outlet glaciers.