For each decision we make, we must first determine the degree of effort that we are going to exert, and this can range from no effort to full effort. To select a reasoning strategy (e.g., withholding or exerting effort), it has been proposed that we must first integrate internal and external factors to compute the degree of effort necessary and solve the problem at hand. In this dissertation, I sought to determine the mechanisms underlying selecting such reasoning strategies by leveraging electroencephalographic imaging techniques. My investigations began by exploring neural correlates of effortful contemplation and evolved to test assumptions of prediction errors as it became apparent that they were an influential factor. I then tied this mechanism to the strategy selection phase of reasoning and cost-benefit computations. From these findings, I proposed that prediction errors of decision demands function to lessen or remove the burden of cost-benefit computations. Specifically, repeated encounters of the same or similar decisions provide an opportunity to develop expectations of the prospective costs and benefits of those judgments and these expectations facilitate the reasoning process. I consider two possible explanations as to how prediction errors may influence reasoning: first, our expectations provide our cost-benefit computations with a starting point to be adjusted if necessary, and second, our expectations act as a gating mechanism for cost-benefit computations. Although more research is needed to test these hypotheses, I hope my work provides grounds for advancing this field of study. / Graduate

POLQ is a unique multifunctional replication and repair gene that encodes a multidomain protein with a N-terminal superfamily 2 helicase and a C-terminal A-family polymerase. Although the function of the polymerase domain has been investigated, little is understood regarding the helicase domain. Multiple studies have reported that polymerase θ-helicase (Polθ-helicase) is unable to unwind DNA. However, it exhibits ATPase activity that is stimulated by single-stranded DNA, which presents a biochemical conundrum. In contrast to previous reports, we demonstrate that Polθ-helicase (residues 1– 894) efficiently unwinds DNA with 3'–5' polarity, including DNA with 3' or 5' overhangs, blunt- ended DNA, and replication forks. Polθ-helicase also efficiently unwinds RNA-DNA hybrids and exhibits a preference for unwinding the lagging strand at replication forks, similar to related HELQ helicase. Finally, we find that Polθ-helicase can facilitate strand displacement synthesis by Polθ-polymerase, suggesting a plausible function for the helicase domain. Taken together, these findings indicate nucleic acid unwinding as a relevant activity for Pol theta in replication repair. DNA polymerase theta is a unique polymerase-helicase fusion protein that promotes microhomology-mediated end-joining of DNA double-strand breaks. How full-length human DNA polymerase theta performs microhomology-mediated end-joining and is regulated by the helicase and disordered central domain remains unknown. We find that the helicase upregulates DNA polymerase theta microhomology-mediated end-joining activity in an ATPase-independent manner. Using single-particle microscopy, we find that DNA polymerase theta forms large multimeric complexes that promote DNA accumulation and end-joining. We further find that the disordered central domain regulates DNA polymerase theta multimerization and governs its DNA substrate requirements for end-joining. In summary, these studies identify major regulatory functions for the helicase and central domains in DNA end-joining and the structural organization of DNA polymerase theta. / Biomedical Sciences

This thesis investigated the modulation of approach-avoidance behavior using neurofeedback (NF), focusing specifically on Frontal Midline Theta (FMT) as a target oscillation. The main goal was to determine whether reducing FMT through NF could enhance approach behavior in conflict situations while increasing FMT would promote avoidance. To provide an overview of the current state of the art, the first study focused on a systematic review and meta-analysis of existing studies on FMT modulation by NF. The results indicated a medium effect size, suggesting the feasibility of FMT-NF. However, sub-analyses showed only successful upregulation of FMT, with no evidence supporting FMT downregulation. Although the synthesis was complicated by substantial variability in study design, the number of NF sessions emerged as a moderator of effect size. This comprehensive review provided guidance for future NF protocols and introduced new responder nomenclature to facilitate cross-study comparisons. The next study aimed to integrate the findings into an efficient NF protocol to inhibit FMT. Based on the previous review, we individualized the feedback band to the FMT peak frequency (ITF) elicited during an approach-avoidance task. However, pilot data revealed substantial ITF variability between sessions. Therefore, we analyzed data from an additional 151 participants, confirming that ITF is highly variable over time, with low reliability within and across sessions. This suggests that a single calibration is insufficient for multi-session NF. Lastly, based on the processes related to FMT and the lack of supporting evidence for its downregulation, we proposed the "FMT inhibition dilemma," which suggests that FMT is challenging to downregulate due to its association with cognitive effort during NF. Analysis of two distinct datasets showed that FMT activity increased during NF, even when attempts were made to inhibit it. This indicates a severe dilemma and the need for alternative NF protocols that reduce cognitive engagement or adjust feedback mechanisms. In summary, while FMT-targeted neurofeedback presents a promising avenue for influencing approach-avoidance behavior, there are significant methodological and theoretical challenges that need to be addressed. Key recommendations include embracing multi-session protocols, systematically reporting and investigating individual peak frequencies, and considering inherent processes of FMT when designing and aiming at FMT inhibition. The adoption of open science practices and rigorous replication are highlighted as critical to advancing the reliability and efficacy of neurofeedback research. / In dieser Arbeit wurde die Modulation von Annäherungs-Vermeidungs-Verhalten mittels Neurofeedback (NF) untersucht. Im Speziellen wurde sich dabei auf Frontal Midline Theta (FMT) als Modulationsziel konzentriert. Das Hauptziel war es, festzustellen, ob eine Verringerung der FMT-Aktivität durch NF das Annäherungsverhalten in Konfliktsituationen erhöhen könnte, während eine Erhöhung der FMT das Vermeidungsverhalten fördern würde. Um einen Überblick über den aktuellen Stand der Forschung zu erhalten, fokussiert die erste Studie eine systematische Überprüfung und Meta-Analyse bestehender Studien zur Modulation von FMT durch. Die Ergebnisse weisen auf eine mittlere Effektstärke hin, was auf ihre Durchführbarkeit von FMT-NF schließen lässt. Die Subanalysen zeigten jedoch nur eine erfolgreiche Hochregulierung von FMT, während es keine Belege für eine FMT-Runterregulierung gab. Obwohl die Synthese durch die erhebliche Variabilität der Studiendesigns erschwert wurde, erwies sich die Anzahl der NF-Sitzungen als Moderator der Effektstärke. In dieser umfassenden Übersicht liefern wir Leitlinien für künftige NF-Protokolle und führen eine neue Nomenklatur für Personen die auf NF ansprechen ein, um den künftigen Vergleich zwischen verschiedenen Studien zu erleichtern. Ziel der nächsten Studie war es, die Erkenntnisse in ein effizientes NF-Protokoll zur Verringerung von FMT zu integrieren. Auf der Grundlage der vorangegangenen Übersichtsarbeit haben wir das Feedbackband an die individuelle FMT-Spitzenfrequenz (ITF) angepasst, die während einer Annäherungs-Vermeidungs-Aufgabe ausgelöst wurde. Pilotdaten zeigten jedoch eine erhebliche ITF-Variabilität zwischen den Sitzungen. Daher analysierten wir die Daten von weiteren 151 Teilnehmern und bestätigten, dass die ITF im Laufe der Zeit sehr variabel ist, mit geringer Zuverlässigkeit innerhalb und zwischen den Sitzungen. Dies legt nahe, dass eine einzige Kalibrierung für eine NF-Intervention, die mehrere Sitzungen umfasst, unzureichend ist. Basierend auf den Prozessen, die mit FMT assoziert sind, und dem Mangel an unterstützenden Beweisen für die Herunterregulierung von FMT, schlugen wir das „FMT-Inhibitionsdilemma“ vor. Dieses besagt, dass es schwierig ist, FMT herunterzuregulieren, da es durch kognitive Anstrengung während der NF erhöht wird. Die Analyse von zwei verschiedenen Datensätzen zeigte, dass die FMT-Aktivität während der NF zunahm, selbst wenn versucht wurde, sie zu hemmen. Dies deutet auf ein schwerwiegendes Dilemma und die Notwendigkeit alternativer NF-Protokolle hin, die das kognitive Engagement reduzieren oder die Feedback-Mechanismen anpassen. Zusammenfassend lässt sich sagen, dass FMT-gezieltes Neurofeedback zwar einen vielversprechenden Weg zur Beeinflussung des Annäherungs-/Vermeidungsverhaltens darstellt, es jedoch erhebliche methodische und theoretische Herausforderungen gibt, die es zu bewältigen gilt. Zu den wichtigsten Empfehlungen gehören die Verwendung von Protokollen mit mehreren Sitzungen, die systematische Erfassung und Untersuchung individueller Spitzenfrequenzen und die Berücksichtigung inhärenter Prozesse der FMT bei der Entwicklung von FMT-Hemmungen. Die Integration von „Open-Science“ Praktiken und rigoroser Replikation werden als entscheidend für die Verbesserung der Zuverlässigkeit und Wirksamkeit der Neurofeedbackforschung hervorgehoben.

Detta arbete jämför Theta* och en genetisk algoritm för att undersöka ifall en genetisk algoritm ger mer förutsägbara vägar i dynamiska miljöer än en deterministisk sökteknik. Den valda genetiska algoritmen är inte begränsad till vägval till närliggande noder, den nod som är näst i tur kan ligga var som helst i miljön. Theta* valdes för att matcha detta beteende och anses vara en bra representation av en deterministisk sökteknik då den är en vidareutveckling av standarden A*. Resultaten angående förutsägbarheten samlades in genom en enkätundersökning där fyra aspekter efterfrågades i jämförelser mellan Theta* och den genetiska algoritmen: vilken väg är mjukast, vilken väg är rakast, vilken väg är mest direkt, och vilken väg är kortast. Resultaten visade att den genetiska algoritmen presterat 0,6-2,0% bättre än Theta* och anses därför kunna ge mer förutsägbara vägar. Dock krävs mer forskning för att fastställa hur väsentliga de olika kriterierna är för förutsägbarheten. / This work compares Theta* and a genetic algorithm in order to investigate whether a genetic algorithm gives more predictable paths in dynamic environments than a deterministic search algorithm. The chosen genetic algorithm is not restricted to moving to nearby nodes - the next node may be located anywhere in the environment. Theta* was chosen to match this behaviour and is considered to be a good representation of a deterministic search technique as it is based upon the industry standard A*. Results related to the predictability were collected through a survey where four aspects were asked in comparisons between Theta* and the genetic algorithm: which path is smoother, which path is straighter, which path is more direct, and which path is shorter. The results showed that the genetic algorithm performed 0,6-2,0% better than Theta* and is thereby considered to be able to give more predictable paths. There is however a need for further studies in order to establish how important the criteria are for the predictability.

Binaural Beats är ett fenomen som undersöks av diverse forskare kring dess påverkan på hjärnaktivitet och välmående. Kan detta påverka vår prestation i spel? Denna undersökning fokuserar på Theta-zonen som är en av hjärnans tillståndszoner. Med hjälp av specifika ljudfrekvenser (Binaural Beats) kan hjärnvågor stimuleras och bestämt börja arbeta i valfritt tillstånd, i det här fallet Theta-zonen somrepresenterar det lugna och djupt avslappnande stadiet hos människan. För att ta reda på svaret till denna frågeställning skapades en artefakt/ett spel som mätte spelarens prestation genom poänginsamling. Undersökningen samlade in värden i poäng och puls under spelsessionen, som därefter avslutades med en intervju. Resultaten analyserades och sammanfattades till en slutsats i koppling till arbetets frågeställning. Undersökningen och slutsatsen diskuteras och dras vidare till framtida arbeten om förbättringar och utökning av metoden, samt fortsatta studier inom liknande områden.

The goal of this thesis is to design a scanning system for method of laser induced breakdown spectroscopy. The thesis contains research about laser induced breakdown spectroscopy, scanning system including all used components and chemical mapping of sample´s surface. In this thesis, the scanning system is combined with F-theta lens. The construction and optical design of the scanning system, evaluation of measured results and comparison with original motorized positioning is included.

Les états de veille sont composés d’états cérébraux distincts, corrélés avec différents comportements et caractérisés par des oscillations spécifiques observables dans le potentiel de champ local (Local Field Potential, LFP). Bien que les différents états cérébraux et leur signature dans le LFP aient été caractérisés, les mécanismes cellulaires sous-jacents restent à ce jour peu connus. Des changements des propriétés de neurones uniques seraient corrélés avec, et pourraient participer à la génération de ces changements d’états cérébraux. L’activité coordonnée et synchronisée de neurones facilite certains processus cognitifs tels que la mémoire. L’hippocampe joue un rôle essentiel dans les mémoires spatiale et épisodique, et dans l’hippocampe, CA3 est important pour la formation d’associations facilitant l’encodage rapide de la mémoire. De plus, les informations provenant du cortex entorhinal, du gyrus denté, et de CA3 même sont comparées et intégrées dans CA3 avant d’être transmises à CA1. Lors de périodes de repos, le LFP hippocampique présente une activité large et irrégulière (Large Irregular Activity, LIA), ponctuée par des oscillations plus rapides, les sharp-wave ripples, jouant un rôle dans la consolidation de la mémoire. Lors de périodes exploratoires, le LFP hippocampique oscille aux fréquences theta (6-12 Hz) et gamma (30-100 Hz). Les cellules pyramidales (CP) de CA3 jouent un rôle important dans chacun de ces états ; elles sont nécessaires pour les sharp wave lors de périodes de repos, et les oscillations gamma lors de comportements exploratoires. Dans le but d’étudier les modulations intracellulaires des CP de CA3, nous avons réalisé des enregistrements de patch-clamp en configuration cellule entière chez l’animal éveillé. Nous avons associé ces enregistrements avec des mesures du diamètre pupillaire et de la vitesse de locomotion de l’animal, ainsi qu’avec l’enregistrement de l’activité oscillatoire du LFP dans l’hippocampe. Nos résultats montrent que certaines CP de CA3 sont sensibles à la modulation intracellulaire lors de différents rythmes hippocampiques, et ont tendance à diminuer leur potentiel de membrane moyen, leur excitabilité, leur variance et leur décharge de potentiel d’action lors des oscillations theta par rapport aux périodes de LIA. De futures études permettront de déterminer si ces changements sont dus à des changements d’entrées synaptiques et/ou de neuromodulateurs. Ces modulations pourraient jouer un rôle dans l’émergence des rythmes oscillatoires du LFP, et permettre à CA3 de réaliser différentes fonctions mnésiques à différents moments. / Wakefulness is comprised of distinct brain states, correlated with different behaviors and characterized by specific oscillatory patterns in the local field potential (LFP). While much work has characterized different brain states and their LFP signatures, the underlying cellular mechanisms are less known. Changes in single cell properties are thought to correlate with and possibly result in these changes in brain state. Synchronized and coordinated activity among distributed neurons supports cognitive processes such as memory. The hippocampus is essential for spatial and episodic memory, and within the hippocampus, area CA3 is important for rapid encoding of one-trial memory. Additionally, CA3 is the site where information from the entorhinal cortex, dentate gyrus, and CA3 itself is compared and integrated before output to CA1. During quiet wakefulness, the hippocampal LFP displays large irregular activity (LIA) punctuated by sharp-wave ripples, which play a role in memory consolidation. During exploratory behaviors, hippocampal LFP oscillates at both theta and gamma frequencies. CA3 pyramidal cells (PCs) play an important role in each of these brain states; they are necessary for both sharp waves during quiet wakefulness and for gamma oscillations during exploratory behavior. We explored the changes that occur in the intracellular dynamics of CA3 PCs during changes in brain state, by using whole-cell patch-clamp recordings from CA3 PCs in awake head-fixed mice. We combined those recordings with measurements of pupil diameter, treadmill running speed and LFP recordings of oscillatory activity. Our findings show that some CA3 PCs are prone to intracellular modulation during brain rhythms, and tend to decrease their average membrane potential, excitability, variance and output firing during theta as compared to LIA. Future studies will demonstrate whether these effects are due to changes in synaptic and/or neuromodulatory inputs. This modulation at the single-cell level in CA3 could play a role in the emergence of oscillations, and underlie the ability of CA3 to perform different memory functions during different brain states.

No description available.

Abstract Academic Leadership and Development Academy (ALDA) was instituted by the Tau Lambda-at-Large Chapter Sigma Theta Tau International (STTI). In 2011-2012 ALDA intended goal was to emancipate participants to be able to take professional leadership positions, generate a funded research project, professional networking muscle and collaboration, including publishing in an accredited journal. The purpose of the study was to explore and describe the needs of the fellows enrolled for the 2011-2012 ALDA leadership programme. The word ‘fellow’ refers to all candidates who were selected to participate in the ALDA programme. The programme was tailor-made to develop and prepare professional nurses for middle or high level leadership positions within the academic environment. Four African universities and colleges were involved. The research design was qualitative, exploratory, and descriptive in nature. The target population included all 2011-2012 fellows of the ALDA of the Sigma Theta Tau Lambda-at-Large Chapter Africa. The sample consisted of all 14 fellows of the 2011-2012 ALDA who were involved in programme. This programme was the first of its kind in Africa engineered by ALDA in Africa in 2011. Data gathering was a self-report through naïve sketches. Tesch’s eight steps of data analysis were applied. An independent coder was engaged to improve trustworthiness of the data. The results showed that fellows needed professionalism and recognition; communication and setting the stage; and more collaboration with research expects. At first the programme did not have a clear curriculum content outlined and as such fellows were dissatisfied for some time which affected the progress as expected by both the fellows and the faculty. Faculty refers to experts involved in the programme. However, fellows managed to work cooperatively with one another, thus promoting a social learning environment and providing opportunities of collaborative research studies in the future.

The effectiveness of radiotherapy treatment could be significantly improved if tumour cells could be rendered more sensitive to ionising radiation without altering the sensitivity of normal tissues. However, many of the key mechanisms that determine intrinsic tumour radiosensitivity are largely unknown. This thesis is concerned with the identification of novel determinants of tumour radiosensitivity. A siRNA screen of 200 genes involved in DNA damage repair was conducted using γH2AX foci post-irradiation as a marker of cell damage. This screen identified POLQ as a potential tumour-specific contributor to radioresistance. Subsequent investigations demonstrated that POLQ knockdown resulted in radiosensitisation of a panel of tumour cell lines, whilst having little or no effect on normal tissue cell lines. It was subsequently shown that POLQ depletion rendered tumour cells significantly more sensitive to several classes of cytotoxic agents. Following exposure to etoposide, it was found that tumour cells depleted of POLQ had reduced RAD51 foci formation, suggesting that POLQ is involved in homologous recombination. A homologous recombination assay was used to confirm that POLQ depletion does indeed result in reduced homologous recombination efficiency. These findings led to the investigation of the clinical significance of tumour overexpression of POLQ. The clinical outcomes of patients with early breast cancer were correlated with tumour expression levels of POLQ. It was found that POLQ overexpression was correlated with ER negative disease and high tumour grade, both of which are associated with poor clinical outcomes. POLQ overexpression was associated with extremely poor relapse free survival rates, independently of any other clinical or pathological feature. The mechanism that causes this adverse outcome may in part arise from resistance to adjuvant chemotherapy and radiotherapy treatment. These findings, combined with the limited normal tissue expression of POLQ, make it an appealing target for possible clinical exploitation.