Sexual differentiation of the brain : investigating the role of Sry using animal models

Recent findings have challenged the dogma that gonadal hormones are the sole factor mediating sexual differentiation of the mammalian brain, and have highlighted the importance of sex-linked genes in this process, either independently, or in combination with, gonadal hormones. Using two rodent models, this thesis investigated the roles of the Y-linked (male-specific) gene Sry and other sex chromosome-linked genes on emotional behaviour. Using an established murine ‘four core genotype’ (FCG) model an attempt was made to dissociate, ‘Sry-dependent effects’ (due to direct effects of Sry brain expression, or to downstream hormonal factors) and effects due to ‘sex chromosome complement’ (i.e. sex-linked genes other than Sry). The mouse work was augmented by the development of a novel rat Sry antisense ‘knockdown’ model permitting investigation of the behavioural effects of direct manipulation of Sry expressed in discrete brain areas.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Targeting histone deacetylase (HDACs) enzymes with novel bisnaphthalimidopropyl derivatives (BNIPs) as alternative breast cancer therapies.

Breast cancer is the most commonly occurring cancer in women, with incidence rates approaching 1.38 million cases per year worldwide. Over the last few decades, there have been numerous attempts to develop, synthesise and advance into the clinic novel and selective breast cancer therapies. Research work has shown that bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM) exerts potent in vitro anti-cancer activities and strong DNA binding properties. The aim of this thesis was to synthetise novel bisnaphthalimidopropyl derivatives (BNIPs) and investigate their subsequent modes of action within two human metastatic breast cancer cell lines, MDA-MB-231 and SKBR-3. A series of novel BNIPs, bisnaphthalimidopropyl-piperidylpropane (BNIPPiProp), bisnaphthalimidopropyl- ethylenedipiperidine (BNIPPiEth) and (trans(trans))-4,4-methylenebis-cyclohexylamine (trans,trans-BNIPDaCHM) were synthesised, characterised and studied in comparison to BNIPDaCHM for their DNA binding and anti-cancer activities against MDA-MB-231 and SKBR-3 cells. Thermal denaturation studies have shown that BNIPs can intercalate and stabilize the double helix of Calf Thymus, each BNIP can competitively displace EtBr from DNA in a dose dependent manner and by UV binding studies, high affinity was found for the three novel BNIPs. After 24 hours treatment, all novel BNIPs, exhibited strong cytotoxicity with IC50 values ranging from 1.4 μM to 3.3 μM in MDA-MB-231 cells and 0.2 - 0.7 μM in SKBR-3 cells, confirming the importance of bisnaphthalimidopropyl functionality. BNIPs were also found to increase intracellular ROS levels after 8 hours treatment and induce a significant increase in DNA strand breaks compared to endogenous levels, after 24 hour treatment in both cell lines. After cell synchronisation, cell cycle distribution was studied, revealing that trans,trans-BNIPDaCHM induces sub-G1 cell population arrest in MDA-MB-231 and SKBR-3 cells, after 24 hours treatment. In addition, BNIPs induced apoptotic phosphatidylserine exposure, after 0.5 hours treatment, inhibited Caspase-3 activity and increased autophagy, after 24 hour treatment in MDA-MB-231 and SKBR-3 cells. Moreover, BNIPs inhibited histone deacetylases (HDAC) activity after 24 hours treatment in MDA-MB-231 and SKBR-3 cells and BNIPDaCHM was identified as a potential SIRT2 inhibitor, in SKBR-3 cells. According to Proteome Profiler Arrays, BNIPDaCHM and BNIPPiEth altered the expression of cell stress-related proteins in a cell dependent manner and bioinformatic analysis revealed two novel, putative pathways for BNIP-induced oxidative stress-mediated cell death in MDA-MB-231 and SKBR-3 cells. The above findings indicate that BNIPs represent promising candidates for future breast cancer studies and cancer treatment

Analysis of a masonry viaduct of Parc Güell in Barcelona by funicular modeling

Park Güell is one of the most visited and characteristic monuments in the city of Barcelona designed by the modernist architect Antoni Gaudi. Park Güell was designed as a real estate project but due to economic reasons the project failed and opened as a public park in 1922. The main purpose of the thesis is the analysis of the stability of the lower viaduct of the three main viaducts of the Park Güell that can be found at the south-east side of the park. Since the lower viaduct is a masonry structure it is important the presentation of all the methods used historically for the analysis of the stability of historic masonry structures. Among them the method of graphic statics and the method of funicular analysis are applied for the calculation of the thrust line of the structure in order to investigate its stability. The general information regarding the historic and artistic significance of Park Güell is important in order to understand the significance of the whole structure where the viaduct is contained. Also reporting the architectural arrangement of the viaduct, its structural characteristics and its materials is necessary for a deeper understanding of the function of the structure before its stability analysis. Also a previous structural study by BIS architects offers conclusions on the structural capacity of the viaduct. The three-dimensional model of the structure in AutoCAD 3D allows the better understanding of the geometry of the structure and uses for the application of the graphic statics method. The graphic statics method is applied in two dimensions and is taking into account all the loads applied on the structure in order to investigate its stability. The results of the graphic statics method is the thrust line of the viaduct that must fit inside the limits of the geometry of the structure in order to consider that the structure is stable according to safe theorem. The application of the funicular analysis with the MASONRISK application of program GID for a characteristic part of the viaduct is another method for the investigation of the stability of the viaduct. The objective of the method is to create a catenary net that its deformed shape due to its loading is contained within the limits of the structure in order to prove that the structure is stable according to safe theorem. The solution obtained is a three dimensional catenary network. Finally some general conclusions regarding the two methods are made presenting their advantages and disadvantages for the analysis of the stability of historic masonry structures and also some recommendations for the improvement of the methods

Sexual differentiation of the brain: investigating the role of Sry using animal models

Recent findings have challenged the dogma that gonadal hormones are the sole factor mediating sexual differentiation of the mammalian brain, and have highlighted the importance of sex-linked genes in this process, either independently, or in combination with, gonadal hormones. Using two rodent models, this thesis investigated the roles of the Y-linked (male-specific) gene Sry and other sex chromosome-linked genes on emotional behaviour. Using an established murine ‘four core genotype’ (FCG) model an attempt was made to dissociate, ‘Sry-dependent effects’ (due to direct effects of Sry brain expression, or to downstream hormonal factors) and effects due to ‘sex chromosome complement’ (i.e. sex-linked genes other than Sry). The mouse work was augmented by the development of a novel rat Sry antisense ‘knockdown’ model permitting investigation of the behavioural effects of direct manipulation of Sry expressed in discrete brain areas

Real-time simulation of construction workers using combined human body and hand tracking for robotic construction worker system

Construction is an inherently less safe sector than other sectors because it exposes workers to harsh and dangerous working environments. The nature of the construction industry results in a comparatively high incidence of serious injuries and death caused by falls from a height, musculoskeletal disorders and being struck by objects. This paper presents a new concept that can tackle this problem in the future. The central hypothesis of this study is that it is possible to eliminate injuries if we move the human construction worker off-site and remotely link his/her motions to a Robotic Construction Worker (RCW) on-site. As a first steppingstone towards this ultimate goal, two systems essential for the RCW were developed in this study. First, a novel system that combines 3D body and hand position tracking was developed to capture the movements of human construction worker. This combination of tracking enables the capture of changes in the orientations and articulations of the entire human body. Second, a real-time simulation system that connects a human construction worker off-site to a virtual RCW was developed to demonstrate the proposed concept in a variety of construction scenarios. The simulation results demonstrate the future viability of the RCW concept and indicate the promise of this system for eliminating the health and safety risks faced by human construction workers

Novel bisnaphthalimidopropyl (BNIPs) derivatives as anticancer compounds targeting DNA in human breast cancer cells.

Bisnaphthalimidopropyl (BNIP) derivatives are a family of compounds that exert anti-cancer activities in vitro and, according to previous studies, variations in the linker sequence have increased their DNA binding and cytotoxic activities. By modifying the linker sequence of bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM), a previously synthesised BNIP derivative with anti-cancer properties, three novel BNIP derivatives were designed. Bisnaphthalimidopropyl-piperidylpropane (BNIPPiProp), a structural isomer of BNIPDaCHM, bisnaphthalimidopropyl ethylenedipiperidine dihydrobromide (BNIPPiEth), an isoform of BNIPDaCHM with a shorter linker chain, and (trans(trans))-bisnaphthalimidopropyl diaminodicyclohexylmethane (trans,trans-BNIPDaCHM), a stereoisomer of BNIPDaCHM, were successfully synthesised (72.3-29.5% yield) and characterised by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Competitive displacement of ethidium bromide (EtBr) and UV binding studies were used to study the interactions of BNIP derivatives with Calf Thymus DNA. The cytotoxicity of these derivatives was assessed against human breast cancer MDA-MB-231 and SKBR-3 cells by MTT assay. Propidium iodide (PI) flow cytometry was conducted in order to evaluate the cellular DNA content in both breast cancer cell lines before and after treatment with BNIPs. The results showed that all novel BNIPs exhibit strong DNA binding properties in vitro, and strong cytotoxicity, with IC50 values in the range of 0.2-3.3 μM after 24 hours drug treatment. Two of the novel BNIP derivatives, BNIPPiEth and trans,trans-BNIPDaCHM, exhibited greater cytotoxicity against the two breast cancer cell lines studied, compared to BNIPDaCHM. By synthesising enantiopures and reducing the length of the linker sequence, the cytotoxicity of the BNIP derivatives was significantly improved compared to BNIPDaCHM, while maintaining DNA binding and bis-intercalating properties. In addition, cell cycle studies indicated that trans,trans-BNIPDaCHM, the most cytotoxic BNIP derivative, induced sub-G1 cell cycle arrest, indicative of apoptotic cell death. Based on these findings, further investigation is under way to assess the potential efficacy of trans,trans-BNIPDaCHM and BNIPPiEth in treating human breast cancer

Testosterone and Human Behavior: The role of individual and contextual variables

The study of testosterone and aggression originated in experimental studies of animals, showing a direct causal link in some species. Human studies showed an overall weak correlation between testosterone and aggression. A theoretical framework (“the challenge hypothesis”) enabled testosterone-behavior interactions in humans to be framed within a theory that emphasized hormonal responses to competition influencing subsequent aggressive behavior. The short-term administrations of testosterone to young women and to young men showed influences on behavioral and neural processes associated with aggression. Other findings are that testosterone influences aggression in high dominance men, and in those with low cortisol levels; and that testosterone can affect both aggressive and prosocial behavior, within the context of an experimental gam

Cognitive, Behavioral, and Neural Consequences of Sex Chromosome Aneuploidy

The X chromosome has played a critical role in the development of sexually selected characteristics for over 300 million years, and during that time it has accumulated a disproportionate number of genes concerned with mental functions. There are relatively specific effects of X‐linked genes on social cognition, language, emotional regulation, visuospatial, and numerical skills. Many human X‐linked genes outside the X–Y pairing pseudoautosomal regions escape X‐inactivation. Dosage differences in the expression of such genes (which constitute at least 15% of the total) are likely to play an important role in male–female neural differentiation, and in cognitive deficits and behavioral characteristics, particularly in the realm of social communication, that are associated with sex chromosome aneuploidies

Automated Progress Monitoring Using Mixed Reality

This thesis presents a real-time automated building progress monitoring solution for indoor environments using a mobile device. Such a system could prompt accurate and timely assessment of work progress that would allow managers to make adjustments and minimise both time and cost overrun when deviations from the schedule occur. Although many researchers have proposed approaches for progress monitoring in outdoor scenes, these cannot perform in real-time and shift into the complex interior environment. Research efforts for indoor environments are not fully automated and lead to errors in more complex scenes. Systems based on mobile devices could potentially enhance the inspection process and reduce the required time by allowing the inspector to acquire progress data by simply walking around the site. The main challenge of these systems is the tracking of the pose of the camera to achieve accurate alignment between the 3D design model and the real-world scene. Methods for estimating the user’s pose rely on a) tags on each target of interest, which require additional time and cost for installation and maintenance; b) pre-selected user locations, which restricts the user to those locations only; or c) GPS on the augmented reality headset, which only applies to outdoor inspections. Additionally, current mobile-based inspection systems do not perform any comparison between the captured as-built and the as-planned data. In this research, different marker-less Augmented Reality (AR) potential methods were implemented and tested for finding the most robust tracking solution. The Microsoft HoloLens was found to be the top performer for tracking the user’s pose and for overall user-experience. Next, a semi-automated method was developed for initially registering the 3D model to the real environment by exploiting information from detected floor and wall surfaces. Results showed that this method reduces the time of the initial registration by 58%. Having the 3D model aligned to the real environment and knowing the pose of the camera at every moment, an automated method was developed that exploits the captured as-built surface mesh data from the mobile device, compares it against the 3D design model and identifies in real-time whether an object has been built according to plan. Different parameters were tested for finding the optimum combination based on the current quality of mesh data. If quality of mesh data changes, then new parameters should be explored. Finally, the proposed solution was tested in real site conditions resulting in 76.6% precision, 100.0% recall, and 83.5% accuracy