Transcriptional Control of Oncogenic Processes in Breast Cancer Cells by the Estrogen Receptors

The estrogen receptors are fundamental factors in human biology. As transcriptional factors regulating gene programs controlling many processes in the body, they are key in both development and disease. Also, as nuclear receptors they can be activated or blocked by specific ligands, making them excellent targets for therapeutics. This dissertation focuses on the study of the estrogen receptors, both the alpha and beta isoforms (ERα and ERβ, respectively), and how they regulate gene transcription in human breast cancer. The proliferative role of ERα in breast cancer remains poorly understood. Here we show that the ion channel KCNK5 is a direct transcriptional target of ERα in breast cancer cell lines MCF7 and T47D. Also, we show that this is reflected by changes in the ion channel’s protein. Furthermore, silencing of the ion channels expression reduces cellular proliferation, as well as the estrogen-induction of proliferation. This uncovers ion channels as potential factors in the proliferation of breast cancer, as well as potential targets in novel treatment approaches. ERα’s role as a transcription factor has predominantly been studied in regards to its regulation of protein-coding genes. Herein, we show that ERα also regulates non-coding RNAs, such as long non-coding RNAs and pseudogenes. We also potentially uncover novel protein-coding targets, by the use of novel RNA- sequencing technology, and the use of microarrays. The other estrogen receptor, ERβ, is less characterized, but it is considered to be anti-proliferative in breast cancer and its activation suggested as a potential future therapy. However, discordant results of expression in breast tumors, correlation to prognosis, and tumor-suppressive function in cell lines have made this a debated field. We explore its role in breast cancer cells further and show that, in certain contexts, ERβ is not able to suppress breast cancer cell proliferation, nor, as often suggested, counteract ERα-mediated signaling. This warrants further studies into whether its activation in breast cancer is a desirable treatment.Biology and Biochemistry, Department o

Quality of life assessment after fibula free flap reconstruction for mandibular defects post benign tumour ablative surgery

Magister Chirurgiae Dentium (MChD)Introduction: Defects in the mandible and maxilla have various etiological factors. These include trauma, inflammatory diseases or pathology such as benign and malignant tumours. Patients that are exposed to these factors are often left with compromised function and aesthetics which could have a deleterious effects on the patients’ quality of life if not adequately restored with reconstructive surgery (Goh et al. 2008). Reconstruction should aim to allow rehabilitation of normal stomatognathic function, facial contour and aesthetics, obliteration of dead space left after ablation, and the need to examine the area for recurrence (Kim and Ghali 2011). The fibula free flap has become the gold standard for maxillofacial reconstruction. This flap offers various advantages that makes it suitable, especially for reconstructing defects of the mandible (Anne-Gaelle et al. 2011). The success of rehabilitation of these patients should however also take into consideration the patient’s ability to use a dental prosthesis (conventional or implant retained) post-operatively. This remains challenging (Kramer and Dempf 2005). The effective placement of a dental prosthesis relies on the basic principles of retention, stability and support. With the altered anatomy caused by the graft, placement of dental implants is used to enhance retention and stability. Quality of life (QoL) is a measure of a patient’s satisfaction with their current situation in regards to function and other factors compared to a perceived or expected ideal. The subjective component linked to quality of life means that it could vary from one locality to another, and therefore gathering data that will establish a baseline for these patients that have undergone tumour ablative surgeries. This could be invaluable to healthcare practitioners that operate in this specific field

Submillimetre galaxies in a hierarchical universe: number counts, redshift distribution and implications for the IMF

High-redshift submillimetre galaxies (SMGs) are some of the most rapidly star-forming galaxies in the Universe. Historically, galaxy formation models have had difficulty explaining the observed number counts of SMGs. We combine a semi-empirical model with 3D hydrodynamical simulations and 3D dust radiative transfer to predict the number counts of unlensed SMGs. Because the stellar mass functions, gas and dust masses, and sizes of our galaxies are constrained to match observations, we can isolate uncertainties related to the dynamical evolution of galaxy mergers and the dust radiative transfer. The number counts and redshift distributions predicted by our model agree well with observations. Isolated disc galaxies dominate the faint (S_(1.1) ≲ 1 or S_(850) ≲ 2 mJy) population. The brighter sources are a mix of merger-induced starbursts and galaxy-pair SMGs; the latter subpopulation accounts for ∼30–50 per cent of all SMGs at all S_(1.1) ≳ 0.5 mJy (S_(850) ≳ 1 mJy). The mean redshifts are ∼3.0–3.5, depending on the flux cut, and the brightest sources tend to be at higher redshifts. Because the galaxy-pair SMGs will be resolved into multiple fainter sources by the Atacama Large Millimeter/submillimeter Array (ALMA), the bright ALMA counts should be as much as two times less than those observed using single-dish telescopes. The agreement between our model, which uses a Kroupa initial mass function (IMF), and observations suggests that the IMF in high-redshift starbursts need not be top heavy; if the IMF were top heavy, our model would overpredict the number counts. We conclude that the difficulty some models have reproducing the observed SMG counts is likely indicative of more general problems – such as an underprediction of the abundance of massive galaxies or a star formation rate and stellar mass relation normalization lower than that observed – rather than a problem specific to the SMG population

P-glycoprotein-9 and macrocyclic lactone resistance status in selected strains of the ovine gastrointestinal nematode, Teladorsagia circumcincta

The Teladorsagia circumcincta P-glycoprotein-9 (Tci-pgp-9) gene has previously been implicated in multiple-anthelmintic resistance in this parasite. Here we further characterise genetic diversity in Tci-pgp-9 and its possible role in ivermectin (IVM) and multi-drug resistance using two UK field isolates of T. circumcincta, one susceptible to anthelmintics (MTci2) and the other resistant to most available anthelmintics including IVM (MTci5). A comparison of full-length Tci-pgp-9 cDNA transcripts from the MTci2 and MTci5 isolates (∼3.8 kb in both cases) indicated that they shared 95.6% and 99.5% identity at the nucleotide and amino acid levels, respectively. Nine non-synonymous SNPs were found in the MTci5 sequences relative to their MTci2 counterparts. Twelve genomic sequence variants of the first internucleotide binding domain of Tci-pgp-9 were identified and up to 10 of these were present in some individual worms, strongly supporting previous evidence that amplification of this gene has occurred in T. circumcincta. On average, fewer distinct sequence variants of Tci-pgp-9 were present in individual worms of the MTci5 isolate than in those of the MTci2 isolate. A further reduction in the number of sequence variants was observed in individuals derived from an IVM-treated sub-population of MTci5. These findings suggest that Tci-pgp-9 was under purifying selection in the face of IVM treatment in T. circumcincta, with some sequence variants being selected against

Submillimetre galaxies in a hierarchical universe: number counts, redshift distribution and implications for the IMF

High-redshift submillimetre galaxies (SMGs) are some of the most rapidly star-forming galaxies in the Universe. Historically, galaxy formation models have had difficulty explaining the observed number counts of SMGs. We combine a semi-empirical model with 3D hydrodynamical simulations and 3D dust radiative transfer to predict the number counts of unlensed SMGs. Because the stellar mass functions, gas and dust masses, and sizes of our galaxies are constrained to match observations, we can isolate uncertainties related to the dynamical evolution of galaxy mergers and the dust radiative transfer. The number counts and redshift distributions predicted by our model agree well with observations. Isolated disc galaxies dominate the faint (S_(1.1) ≲ 1 or S_(850) ≲ 2 mJy) population. The brighter sources are a mix of merger-induced starbursts and galaxy-pair SMGs; the latter subpopulation accounts for ∼30–50 per cent of all SMGs at all S_(1.1) ≳ 0.5 mJy (S_(850) ≳ 1 mJy). The mean redshifts are ∼3.0–3.5, depending on the flux cut, and the brightest sources tend to be at higher redshifts. Because the galaxy-pair SMGs will be resolved into multiple fainter sources by the Atacama Large Millimeter/submillimeter Array (ALMA), the bright ALMA counts should be as much as two times less than those observed using single-dish telescopes. The agreement between our model, which uses a Kroupa initial mass function (IMF), and observations suggests that the IMF in high-redshift starbursts need not be top heavy; if the IMF were top heavy, our model would overpredict the number counts. We conclude that the difficulty some models have reproducing the observed SMG counts is likely indicative of more general problems – such as an underprediction of the abundance of massive galaxies or a star formation rate and stellar mass relation normalization lower than that observed – rather than a problem specific to the SMG population

Modeling Mid-infrared Diagnostics of Obscured Quasars and Starbursts

We analyze the link between active galactic nuclei (AGNs) and mid-infrared flux using dust radiative transfer calculations of starbursts realized in hydrodynamical simulations. Focusing on the effects of galaxy dust, we evaluate diagnostics commonly used to disentangle AGN and star formation in ultraluminous infrared galaxies (ULIRGs). We examine these quantities as a function of time, viewing angle, dust model, AGN spectrum, and AGN strength in merger simulations representing two possible extremes of the ULIRG population: one is a typical gas-rich merger at z ~ 0, and the other is characteristic of extremely obscured starbursts at z ~ 2-4. This highly obscured burst begins star-formation-dominated with significant polycyclic aromatic hydrocarbon (PAH) emission, and ends with a ~10^9 yr period of red near-IR colors. At coalescence, when the AGN is most luminous, dust obscures the near-infrared AGN signature, reduces the relative emission from PAHs, and enhances the 9.7 μm absorption by silicate grains. Although generally consistent with previous interpretations, our results imply none of these indicators can unambiguously estimate the AGN luminosity fraction in all cases. Motivated by the simulations, we show that a combination of the extinction feature at 9.7 μm, the PAH strength, and a near-infrared slope can simultaneously constrain the AGN fraction and dust grain distribution for a wide range of obscuration. We find that this indicator, accessible to the James Webb Space Telescope, may estimate the AGN power as tightly as the hard X-ray flux alone, thereby providing a valuable future cross-check and constraint for large samples of distant ULIRGs

D4.3: Digital Twin supported lean project planning, control and risk management

There is a considerable opportunity to improve the planning and control of construction work. The construction industry is still struggling to adopt to the digital revolution’s concepts due to complexity, uncertainty, the fragmented supply chain, the short-term thinking, and the culture of ad hoc solutions. The main purpose of this document is to describe the business and decision-making processes to support lean project planning, control, and risk management with digital twin data.There is a considerable opportunity to improve the planning and control of construction work. The construction industry is still struggling to adopt to the digital revolution’s concepts due to complexity, uncertainty, the fragmented supply chain, the short-term thinking, and the culture of ad hoc solutions. The main purpose of this document is to describe the business and decision-making processes to support lean project planning, control, and risk management with digital twin data. Additionally, this document also presents and describes a process model that has been developed for the construction phase. In this task, three demo-sites have been investigated. All three projects were building construction projects hence no infrastructure projects have been researched. To describe the designed process model, IDEF0-notation was used. A vital part of using digital twins to support process management and agile planning is the capture of data from the site. The produced process model contains five different process groups: initiating, planning, implementing, controlling, and closing and is generally based on the demonstration sites within the ASHVIN project and applicable to constructions sites worldwide. From each demonstration site information was gathered considering how data-collection had been conducted on each site using various digital tools and how they corresponded to the different KPI’s within the project. The methods were then analysed and evaluated how they could be implemented in a work breakdown structure (WBS) and location breakdown structure (LBS). These methods in combination with the process model allows the team to detect issues, react and adjust the schedule to make the whole process smoother. It can assist them in planning when to take in certain disciplines and when to order materials. During this task the demonstration projects were already in the construction phase, which meant that it was mainly controlling activities that could be conducted according to the process model. It would be interesting to be able to test the process model from the beginning of a construction project, in other words from the initiating phase. Multiple findings have been made throughout this study. The main takeaway from is how vital it is for a project to decide in an early stage the prerequisites that will be needed to control and affect the project during the construction phase. This is the reason why it is essential to make sure that the process model as well as the digital tools are applied in depth. The second point to be made is to understand that all the KPI’s mentioned in the results section can be collected using a multitude of different tools and methods. This report has met its main purpose of describing the business and decision-making processes to support lean project planning, control, and risk management with digital twin data.Objectius de Desenvolupament Sostenible::9 - Indústria, Innovació i InfraestructuraPreprin

Consumer-Resource Body-Size Relationships in Natural Food Webs

It has been suggested that differences in body size between consumer and resource species may have important implications for interaction strengths, population dynamics, and eventually food web structure, function, and evolution. Still, the general distribution of consumer–resource body-size ratios in real ecosystems, and whether they vary systematically among habitats or broad taxonomic groups, is poorly understood. Using a unique global database on consumer and resource body sizes, we show that the mean body-size ratios of aquatic herbivorous and detritivorous consumers are several orders of magnitude larger than those of carnivorous predators. Carnivorous predator–prey body-size ratios vary across different habitats and predator and prey types (invertebrates, ectotherm, and endotherm vertebrates). Predator–prey body-size ratios are on average significantly higher (1) in freshwater habitats than in marine or terrestrial habitats, (2) for vertebrate than for invertebrate predators, and (3) for invertebrate than for ectotherm vertebrate prey. If recent studies that relate body-size ratios to interaction strengths are general, our results suggest that mean consumer–resource interaction strengths may vary systematically across different habitat categories and consumer types

A Physical Model for z~2 Dust Obscured Galaxies

We present a physical model for the origin of z~2 Dust-Obscured Galaxies (DOGs), a class of high-redshift ULIRGs selected at 24 micron which are particularly optically faint (24/R>1000). By combining N-body/SPH simulations of high redshift galaxy evolution with 3D polychromatic dust radiative transfer models, we find that luminous DOGs (with F24 > 0.3 mJy at z~2 are well-modeled as extreme gas-rich mergers in massive (~5x10^12-10^13 Msun) halos, with elevated star formation rates (~500-1000 Msun/yr) and/or significant AGN growth (Mdot > 0.5 Msun/yr), whereas less luminous DOGs are more diverse in nature. At final coalescence, merger-driven DOGs transition from being starburst dominated to AGN dominated, evolving from a "bump" to a power-law shaped mid-IR (IRAC) spectral energy distribution (SED). After the DOG phase, the galaxy settles back to exhibiting a "bump" SED with bluer colors and lower star formation rates. While canonically power-law galaxies are associated with being AGN-dominated, we find that the power-law mid-IR SED can owe both to direct AGN contribution, as well as to a heavily dust obscured stellar bump at times that the galaxy is starburst dominated. Thus power-law galaxies can be either starburst or AGN dominated. Less luminous DOGs can be well-represented either by mergers, or by massive ($M_{\rm baryon} ~5x10^11 Msun) secularly evolving gas-rich disc galaxies (with SFR > 50 Msun/yr). By utilising similar models as those employed in the SMG formation study of Narayanan et al. (2010), we investigate the connection between DOGs and SMGs. We find that the most heavily star-forming merger driven DOGs can be selected as Submillimetre Galaxies (SMGs), while both merger-driven and secularly evolving DOGs typically satisfy the BzK selection criteria.Comment: Accepted by MNRAS; major changes include better description of dependency on ISM specification and updated models allowing dust to evolve with metallicity