The Dual Role of HIF Hydroxylase PHD3 in Cancer Cell Survival

Most advanced tumours face periods of reduced oxygen availability i.e. hypoxia. During these periods tumour cells undergo adaptive changes enabling their survival under adverse conditions. In cancer hypoxia-induced cellular changes cause tumour progression, hinder cancer treatment and are indicative of poor prognosis. Within cells the main regulator of hypoxic responses is the hypoxia-inducible factor (HIF). HIF governs the expression of over a hundred hypoxia-inducible genes that regulate a number of cellular functions such as angiogenesis, glucose metabolism and cell migration. Therefore the activity of HIF must be tightly governed. HIF is regulated by a family of prolyl hydroxylase enzymes, PHDs, which mark HIF for destruction in normoxia. Under hypoxic conditions PHDs lose much of their enzymatic activity as they need molecular oxygen as a cofactor. Out of the three PHDs (PHD1, 2 and 3) PHD2 has been considered to be the main HIF-1 regulator in normoxic conditions. PHD3 on the other hand shows the most robust induction in response to oxygen deprivation and it has been implied as the main HIF-1 regulator under prolonged hypoxia. SQSTM1/p62 (p62) is an adaptor protein that functions through its binding motifs to bring together proteins in order to regulate signal transduction. In non-stressed situations p62 levels are kept low but its expression has been reported to be upregulated in many cancers. It has a definitive role as an autophagy receptor and as such it serves a key function in cancer cell survival decisions. In my thesis work I evaluated the significance of PHD3 in cancer cell and tumour biology. My results revealed that PHD3 has a dual role in cancer cell fate. First, I demonstrated that PHD3 forms subcellular protein aggregates in oxygenated carcinoma cells and that this aggregation promotes apoptosis induction in a subset of cancer cells. In these aggregates an adaptor protein SQSTM1/p62 interacts with PHD3 and in so doing regulates PHD3 expression. SQSTM1/p62 expression is needed to keep PHD3 levels low in normoxic conditions. Its levels rapidly decrease in response to hypoxia allowing PHD3 protein levels to be upregulated and the protein to be diffusely expressed throughout the cell. The interaction between PHD3 and SQSTM1/p62 limits the ability of PHD3 to function on its hydroxylation target protein HIF-1alpha. Second, the results indicate that when PHD3 is upregulated under hypoxia it protects cancer cells by allowing cell cycle to proceed from G1 to S-phase. My data demonstrates that PHD3 may either cause cell death or protect the cells depending on its expression pattern and the oxygen availability of tumours.

Battled nerves : Finnish soldiers' war experience, trauma, and military psychiatry, 1941–44

I min avhandling undersöker jag av kriget framkallade psykiska störningar hos finländska soldater under fortsättningskriget. Vilka var de psykiskt invalidiserade soldaterna och hurudana var deras traumatiska erfarenheter? Vilken var den bredare upplevelsevärlden vid fronten där störningarna uppstod, och hur kan man förklara att majoriteten av soldaterna ändå klarade sig utan mentala rubbningar i denna av våld präglade miljö? Hur förhöll sig Finlands armé i allmänhet och den krigspsykiatri som utvecklades under kriget specifikt till soldaternas psykiska störningar? Som Matti Ponteva redan 1977 utredde, det totala antalet psykiatriska soldatpatienter under fortsättningskriget var ca 15 700 män. I min undersökning betonar jag att den siffran omfattar endast en del av fenomenet: långt ifrån alla finländska soldater som uppvisade psykiska symptom förpassades från fronten i psykiatrisk vård. De finländska psykiatrerna hade före vinterkriget inte kommit i direkt kontakt med av krig orsakade psykiska störningar. Deras kunskaper kom nästan uteslutande från den tyska krigspsykiatrin, där den ledande tanken framför allt efter första världskriget var att förklara psykiska störningar med soldaternas personliga brister och svagheter. Slutligen resonerar jag, varför synen på soldaternas psykiska störningar på ett så markant sätt skilde sig från synen på andra krigsskador. Att soldater stupade eller sårades fysiskt kunde framställas som yttringar av manligt hjältemod och offervillighet. Att brytas ner psykiskt av kriget blev däremot en tom symbol för våldet och saknade annat innehåll än uttryckligen en meningslöshet. Psykiska störningar associerades med ett moraliskt fördömande och ett stigma av skam, och förutom att man tenderade att förneka och marginalisera deras existens försökte man göra en skillnad mellan dem och den egentliga krigsupplevelsen. Det har varit problematiskt att inkludera de psykiskt rubbade soldaterna i den nationella historieskrivningen fram till våra dagar.

Dual light barrier method for six degrees of freedom tool center point calibration of an industrial robot

Tool center point calibration is a known problem in industrial robotics. The major focus of academic research is to enhance the accuracy and repeatability of next generation robots. However, operators of currently available robots are working within the limits of the robot´s repeatability and require calibration methods suitable for these basic applications. This study was conducted in association with Stresstech Oy, which provides solutions for manufacturing quality control. Their sensor, based on the Barkhausen noise effect, requires accurate positioning. The accuracy requirement admits a tool center point calibration problem if measurements are executed with an industrial robot. Multiple possibilities are available in the market for automatic tool center point calibration. Manufacturers provide customized calibrators to most robot types and tools. With the handmade sensors and multiple robot types that Stresstech uses, this would require great deal of labor. This thesis introduces a calibration method that is suitable for all robots which have two digital input ports free. It functions with the traditional method of using a light barrier to detect the tool in the robot coordinate system. However, this method utilizes two parallel light barriers to simultaneously measure and detect the center axis of the tool. Rotations about two axes are defined with the center axis. The last rotation about the Z-axis is calculated for tools that have different width of X- and Y-axes. The results indicate that this method is suitable for calibrating the geometric tool center point of a Barkhausen noise sensor. In the repeatability tests, a standard deviation inside robot repeatability was acquired. The Barkhausen noise signal was also evaluated after recalibration and the results indicate correct calibration. However, future studies should be conducted using a more accurate manipulator, since the method employs the robot itself as a measuring device.

Effect of training on the ability of dual-task coordination

Within the framework of the working memory model proposed by A. Baddeley and G. Hitch, a dual-task paradigm has been suggested to evaluate the capacity to perform simultaneously two concurrent tasks. This capacity is assumed to reflect the functioning of the central executive component, which appears to be impaired in patients with dysexecutive syndrome. The present study extends the investigation of an index ("mu"), which is supposed to indicate the capacity of coordination of concurrent auditory digit span and tracking tasks, by testing the influence of training on the performance in the dual task. The presentation of the same digit sequence lists or always-different lists did not differently affect the performance. The span length affected the mu values. The improved performance in the tasks under the dual condition closely resembled the improvement in the single-task performance. So, although training improved performance in the single and dual conditions, especially for the tracking component, the mu values remained stable throughout the sessions when the single tasks were performed first. Conversely, training improved the capacity of dual-task coordination throughout the sessions when dual task was performed first, addressing the issue of the contribution of the within-session practice to the mu index.

Effect of practice and span length on the dual-task coordination executive test

The measure "mu", proposed as an index of the ability to coordinate concurrent box-crossing (BC) and digit-span (DS) tasks in the dual task (DT), should reflect the capacity of the executive component of the working memory system. We investigated the effect of practice in BC and of a change in the digit span on mu by adding previous practice trials in BC and diminishing, maintaining or increasing the digit sequence length. The mu behavior was evaluated throughout three trials of the test. Reported strategies in digit tasks were also analyzed. Subjects with diminished span showed the best performance in DT due to a stable performance in DS and BC in the single- and dual-task conditions. These subjects also showed a more stable performance throughout trials. Subjects with diminished span tended to employ effortless strategies, whereas subjects with increased span employed effort-requiring strategies and showed the lowest means of mu. Subjects with initial practice trials showed the best performance in BC and the most differentiated performance between the single- and dual-task conditions in BC. The correlation coefficient between the mu values obtained in the first and second trials was 0.814 for subjects with diminished span and practice trials in BC. It seems that the within-session practice in BC and the performance variability in DS affect the reliability of the index mu. To control these factors we propose the introduction of previous practice trials in BC and a modification of the current method to determine the digit sequence length. This proposal should contribute to the development of a more reliable method to evaluate the executive capacity of coordination in the dual-task paradigm.

Transcranial direct current stimulation and repetitive transcranial magnetic stimulation in consultation-liaison psychiatry

Patients with clinical diseases often present psychiatric conditions whose pharmacological treatment is hampered due to hazardous interactions with the clinical treatment and/or disease. This is particularly relevant for major depressive disorder, the most common psychiatric disorder in the general hospital. In this context, nonpharmacological interventions could be useful therapies; and, among those, noninvasive brain stimulation (NIBS) might be an interesting option. The main methods of NIBS are repetitive transcranial magnetic stimulation (rTMS), which was recently approved as a nonresearch treatment for some psychiatric conditions, and transcranial direct current stimulation (tDCS), a technique that is currently limited to research scenarios but has shown promising results. Therefore, our aim was to review the main medical conditions associated with high depression rates, the main obstacles for depression treatment, and whether these therapies could be a useful intervention for such conditions. We found that depression is an important and prevalent comorbidity in a variety of diseases such as epilepsy, stroke, Parkinson's disease, myocardial infarction, cancer, and in other conditions such as pregnancy and in patients without enteral access. We found that treatment of depression is often suboptimal within the above contexts and that rTMS and tDCS therapies have been insufficiently appraised. We discuss whether rTMS and tDCS could have a significant impact in treating depression that develops within a clinical context, considering its unique characteristics such as the absence of pharmacological interactions, the use of a nonenteral route, and as an augmentation therapy for antidepressants.

Characterization of the filter media used in the dual media filter

The removal of organics from copper electrolyte solutions after solvent extraction by dual media filtration is one of the most efficient ways to ensure the clean electrolyte flow into the electrowinning. The clean electrolyte will ensure the good quality cathode plate production. Dual media filtration uses two layers of filter media for filtration as anthracite and garnet respectively. The anthracite layer will help the coalescing of the entrained organic droplets which will then float to the top of the filter, and back to the solvent extraction process. The garnet layer will catch any solids left in the electrolyte traveling through the filter media. This thesis will concentrate on characterization of five different anthracites in order to find some differences using specific surface area analysis, particle size analysis, and morphology analysis. These results are compared to the pressure loss values obtained from lab column tests and bed expansion behavior. The goal of the thesis was to find out if there were any differences in the anthracite which would make the one perform better than the other. There were no big differences found on any aspect of the particle characterization, but some found differences should be further studied in order to confirm the meaning of the porosity, surface area, intensity mean and intensity SD (Standard Deviation) on anthracites and their use in dual media filtration. The thesis work analyzed anthracite samples the way that is not found on any public literature sources, and further studies on the issue would bring more knowledge to the electrolyte process.

The dual role of students with behavioural problems: an analysis of their experiences as bullies and victims /

The present study examined the bullying experiences of a group of students, age 10-14 years, identified as having behaviour problems. A total often students participated in a series of mixed methodology activities, including self-report questionnaires, story telling exercises, and interview style joumaling. The main research questions were related to the prevalence of bully/victims and the type of bullying experiences in this population. Questionnaires gathered information about their involvement in bullying, as well as about psychological risk factors including normative beliefs about antisocial acts, impulsivity, problem solving, and coping strategies. Journal questions expanded on these themes and allowed students to explain their personal experiences as bullies and victims as well as provide suggestions for intervention. The overall results indicated that all of the ten students in this sample have participated in bullying as both a bully and a victim. This high prevalence of bully/victim involvement in students from behavioural classrooms is in sharp contrast with the general population where the prevalence is about 33%. In addition, a common thread was found that indicated that these students who participated in this study demonstrate characteristics of emotionally dysregulated reactive bullies. Theoretical implication and educational practices are discussed.

Fitness to stand trial : how discourses of rationality, reasonableness and culpability inform the law and psychiatry to create standards of normal

The objective of this thesis is to demonstrate the importance of the concepts of rationality, reasonableness, culpability and autonomy that inform and support our conception of both the person and the punishable subject. A critical discourse analysis tracing these concepts through both the law and psychological tools used to evaluate the fitness of a person reveals that these concepts and their implied values are inconsistently applied to the mentally disordered who come into conflict with the law. I argue that the result of this inconsistency compromises a person's autonomy which is a contradiction to this concept as a foundational principle of the law. Ultimately, this thesis does not provide a solution to be employed in policy making, but its analysis leaves open possibilities for further exploration into the ways legal and social justice can be reconciled.

Generator Matrix Based Search for Extremal Self-Dual Binary Error-Correcting Codes

Self-dual doubly even linear binary error-correcting codes, often referred to as Type II codes, are codes closely related to many combinatorial structures such as 5-designs. Extremal codes are codes that have the largest possible minimum distance for a given length and dimension. The existence of an extremal (72,36,16) Type II code is still open. Previous results show that the automorphism group of a putative code C with the aforementioned properties has order 5 or dividing 24. In this work, we present a method and the results of an exhaustive search showing that such a code C cannot admit an automorphism group Z6. In addition, we present so far unpublished construction of the extended Golay code by P. Becker. We generalize the notion and provide example of another Type II code that can be obtained in this fashion. Consequently, we relate Becker's construction to the construction of binary Type II codes from codes over GF(2^r) via the Gray map.

TGA2 dual activity: N-terminus regulation of reversible DNA binding influenced by NPRI and CK2

TGA2 is a dual-function Systemic Acquired Resistance (SAR) transcription factor involved in the activation and repression of pathogenesis-related (PR) genes. Recent studies have shown that TGA2 is able to switch from a basal repressor to activator, likely, through regulatory control from its N-terminus. The N-terminus has also been shown to affect DNA binding of the TGA2 bZIP domain when phosphorylated by Casein Kinase II (CK2). The mechanisms involved for directing a switch from basal repressor to activator, and the role of kinase activity, have not previously been looked at in detail. This study provides evidence for the involvement of a CK2-like kinase in the switch of TGA2 activity from repressor to activator, by regulating the DNA-binding activity of TGA2 by phosphorylating residues in the N terminus of the protein.

New Building Blocks for Dual-Property Molecule-Based Magnets

Two classes of compounds have been prepared and characterized as building blocks for chiral magnets and ferromagnetic conductors. In the fIrst project, the organic framework of a pentadentate, (N302) macro cycle has been synthetically modifIed to introduce phenyl substituents into its organic framework and the synthesis of four new [Fe(In(N302)(CN)2] complexes (I) - (IV) is presented. [Molecular diagram availble in pdf] This work represents the fIrst structural and magnetic studies of a family of spin crossover macrocycles that comprise of both structural and stereo-isomers. Magnetic susceptibility and Mossbauer data for the R,R-complex (I) is consistent with both a thermal and a light induced spin crossover transition. The X-ray data supports a change in geometry accompanying the thermal spin transition, from a high spin (HS) 7 -coordinate complex at room temperature to a low spin (LS) 5-coordinate complex at 100 K. The crystal structure ofthe racemic complex (III) reveals a HS, 7-coordinate complex at 200 K that undergoes no signifIcant structural changes on cooling. In contrast, the magnetic - susceptibility and Mossbauer data collected on a powder sample of the racemic complex are consistent with a LS complex. Finally, the meso complex (IV) was prepared and its structure and magnetic properties are consistent with a 5-coordinate LS complex that remains low spin, but undergoes conformational changes on cooling in solution. The chiral [Fe(H)(N302)(CN)2] macro cycle (I), together with its Mn(H) and Fe(H) derivatives have also been exploited as building blocks for the self-assembly of chiral magnets. In the second project, a synthetic route for the preparation of tetrathiafulvalene (TTF) donors covalently attached to a diisopropyl verdazyl radical via a cross conjugated pyridyl linker IS presented. Following this strategy, four new TTF-py- (diisopropyl)verdazyl radicals have been prepared and characterized (V) - (VIII) . [Molecular diagram available in pdf] The first (2:1) charge transfer complex ofa TTF-py-(diisopropyl)verdazyl radical donor and a TCNQ acceptor has been prepared and structurally characterized. The crystal packing shows that the donor and acceptor molecules are organized in a mixed stacking arrangement consistent with its insulating behaviour. EPR and magnetic susceptibility data support intramolecular ferromagnetic interactions between the TTF and the verdazyl radicals and antiferromagnetic interactions between TTF donors within a stack. In an attempt to increase the intramolecular exchange interaction between the two radicals, a TTF-x-(diisopropyl)verdazyl radical (IX) was prepared, where the two radicals are connected ia a conjugated divinylene linker. The neutral radical donors stack in a more favourable head-to-head arrangement but the bulky isopropyl groups prevent the donor radicals from stacking close enough together to facilitate good orbital overlap. [Molecular diagram available in pdf].

Forgiveness in Two Minds: Understanding Forgiveness Through Dual-Process Theory

In this thesis, I examined the relevance of dual-process theory to understanding forgiveness. Specifically, I argued that the internal conflict experienced by laypersons when forgiving (or finding themselves unable to forgive) and the discrepancies between existing definitions of forgiveness can currently be best understood through the lens of dual-process theory. Dual-process theory holds that individuals engage in two broad forms of mental processing corresponding to two systems, here referred to as System 1 and System 2. System 1 processing is automatic, unconscious, and operates through learned associations and heuristics. System 2 processing is effortful, conscious, and operates through rule-based and hypothetical thinking. Different definitions of forgiveness amongst both lay persons and scholars may reflect different processes within each system. Further, lay experiences with internal conflict concerning forgiveness may frequently result from processes within each system leading to different cognitive, affective, and behavioural responses. The study conducted for this thesis tested the hypotheses that processing within System 1 can directly affect one's likelihood to forgive, and that this effect is moderated by System 2 processing. I used subliminal conditioning to manipulate System 1 processing by creating positive or negative conditioned attitudes towards a hypothetical transgressor. I used working memory load (WML) to inhibit System 2 processing amongst half of the participants. The conditioning phase of the study failed and so no conclusions could be drawn regarding the roles of System 1 and System 2 in forgiveness. The implications of dual-process theory for forgiveness research and clinical practice, and directions for future research are discussed.

The effect of perturbation warning on attention switching abilities during dual-task performance in young and older adults

This study examined whether providing an auditory warning would facilitate attention switching abilities in older adults during dual-tasking. Fifteen young and 16 older adults performed a tracking task while recovering their balance from a support surface translation. For half of the trials, an auditory warning was presented to inform participants of the upcoming translation. Performance was quantified through electromyographic (EMG) recordings of the lower limb muscles, while the ability to switch attention between tasks was determined by tracking task error. Providing warning of an upcoming loss of balance resulted in both young and older adults increasing their leg EMG activity by 10-165% (p<0.05) in preparation for the upcoming translation. However, no differences in the timing of attention switching were observed with or without the warning (p=0.424). Together, these findings suggest that providing a perturbation warning has minimal benefits in improving attention switching abilities for balance recovery in healthy older adults.

Capacity to Attend to the Needs of Persons with Dual Diagnoses in the Criminal Justice System: Views of Mental Health and Criminal Justice Professionals

Currently, individuals with intellectual disabilities are overrepresented within the Criminal Justice System (Griffiths, Taillon-Wasmond & Smith, 2002). A primary problem within the Criminal Justice System is the lack of distinction between mental illness and intellectual disabilities within the Criminal Code. Due to this lack of distinction and the overall lack of identification procedures in the Criminal Justice System, individuals with disabilities will often not receive proper accommodations to enable them to play an equitable role in the justice system. There is increasing evidence that persons with intellectual disabilities are more likely than others to have their rights violated, not use court supports and accommodations as much as they should, and be subject to miscarriages of justice (Marinos, 2010). In this study, interviews were conducted with mental health (n=8) and criminal justice professionals (n=8) about how individuals with dual diagnosis are received in the Criminal Justice System. It was found that criminal justice professionals lack significant knowledge about dual diagnosis, including effective identification and therefore appropriate supports and accommodations. Justice professionals in particular were relatively ill-prepared in dealing effectively with this population. One finding to highlight is that there is misunderstanding between mental health professionals and justice professionals about who ought to take responsibility and accountability for this population.