Die Auswirkungen einer Loss-of-Function-Mutation des PKP2-Gens auf den Kalziumhaushalt in Kardiomyozyten aus induzierten pluripotenten Stammzellen von ARVC-Patienten

Im vorliegenden Promotionsprojekt wurde erstmals der cytosolische und nukleäre Kalziumhaushalt am Modell von patientenspezifischen, aus iPSC-induzierten Kardiomyozyten einer an ARVC-erkrankten PKP2-Mutationsträgerin, sowie einer asymptomatischen PKP2-Mutationsträgerin im Vergleich mit einer gesunden Kontrollperson ohne Mutation untersucht. Dies erfolgte mit dem Ziel, die bis dato nicht vollständig nachvollziehbare Pathogenese der ARVC weiter aufzuklären. In den Ergebnissen stellte sich heraus, dass die Kardiomyozyten der ARVC-Patientin komplexe Veränderungen aufweisen. Es zeigten sich eine gestörte elektromechanische Kopplung, eine auffällig stark erhöhte intrinsische Frequenz und eine deutlich erhöhte Neigung zu Arrhythmien. Da bei den Kardiomyozyten der asymptomatischen Mutationsträgerin ähnliche Veränderungen in deutlich abgeschwächter Form vorlagen, liegt der Verdacht nahe, dass das Vorliegen einer loss-of-function-PKP2-Mutation allein für diesen proarrhythmogenen Phänotyp nicht ursächlich sein kann. Unsere Ergebnisse deuten darauf hin, dass Veränderungen im Kalziumhaushalt die Grundlage für proarrhythmogenes Verhalten darstellen, aber erst die Kombination mit weiteren mutationsbedingten Funktionseinschränkungen wie z.B. an den Connexinen und am spannungsgesteuerten Natriumkanal zum Vollbild einer ARVC mit schweren Arrhythmien führt. Zum ersten Mal wird hier der Vergleich zweier Mutationsträger mit unterschiedlicher Symptomausprägung gezeigt, wodurch wertvolle Erkenntnisse zur Arrhythmogenese gewonnen werden konnten

LawSTRESS project: Additional Information

The LawSTRESS project is a controlled prospective-longitudinal study on psychological, endocrine, central nervous and genetic predictors of responses to long-lasting academic stress in a homogenous cohort. Law students from Bavarian universities (total n = 451) have been studied over a 13-months period at six sampling points starting 12 months prior to the exam. The stress group (SG) consisted of students experiencing a long-lasting and significant stress period, namely the preparation for the first state examination for German law students. Law students assigned to the control group (CG) were studied over an equally long period without particular and sustained stress exposure

LawSTRESS project: Additional Information (preliminary)

The LawSTRESS project is a controlled prospective-longitudinal study on psychological, endocrine, central nervous and genetic predictors of responses to long-lasting academic stress in a homogenous cohort. Law students from Bavarian universities (total n = 451) have been studied over a 13-months period at six sampling points starting 12 months prior exam. The stress group (SG) consisted of students experiencing a long-lasting and significant stress period, namely the preparation for the first state examination for German law students. Law students assigned to the control group (CG) were studied over an equally long period without particular and sustained stress exposure

Persistent spin splitting of a two-dimensional electron gas in tilted magnetic fields

By varying the orientation of the applied magnetic field with respect to the normal of a two-dimensional electron gas, the chemical potential and the specific heat reveal persistent spin splitting in all field ranges. The corresponding shape of the thermodynamic quantities distinguishes whether the Rashba spin-orbit interaction RSOI, the Zeeman term or both dominate the splitting. The interplay of the tilting of the magnetic field and RSOI resulted to an amplified splitting in weak fields. The effects of changing the RSOI strength and the Landau level broadening are also investigated.Comment: 10 pages, 5 figure

Experimental Separation of Rashba and Dresselhaus Spin-Splittings in Semiconductor Quantum Wells

The relative strengths of Rashba and Dresselhaus terms describing the spin-orbit coupling in semiconductor quantum well (QW) structures are extracted from photocurrent measurements on n-type InAs QWs containing a two-dimensional electron gas (2DEG). This novel technique makes use of the angular distribution of the spin-galvanic effect at certain directions of spin orientation in the plane of a QW. The ratio of the relevant Rashba and Dresselhaus coefficients can be deduced directly from experiment and does not relay on theoretically obtained quantities. Thus our experiments open a new way to determine the different contributions to spin-orbit coupling

Dissociation of behavioral and neural responses to provocation during reactive aggression in healthy adults with high versus low externalization

The externalizing spectrum describes a range of heterogeneous personality traits and behavioral patterns, primarily characterized by antisocial behavior, disinhibition, and substance (mis)use. In psychopathology, abnormalities in neural threat, reward responses and the impulse-control system may be responsible for these externalizing symptoms. Within the non-clinical range, mechanisms remain still unclear. In this fMRI-study, 61 healthy participants (31 men) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure (TriPM) performed a monetary modified Taylor-Aggression-Paradigm (mTAP). This paradigm consisted of a mock competitive-reaction-time-task played against a fictional opponent with preprogrammed win- and lose-trials. In lose-trials, participants were provoked by subtraction of an amount of money between 0 and 90 cents. As a manipulation check, provocation induced a significant rise in behavioral aggression levels linked with an increased activation in the anterior cingulate cortex (ACC). High externalization predicted reduced ACC responses to provocation. However, high externalizing participants did not behave more aggressively than the low externalization group. Additionally, the high externalizing group showed a significantly lower positive affect while no group differences emerged for negative affect. In conclusion, high externalization in the non-clinical range was related to neural alterations in regions involved in affective decision-making as well as to changes in affect but did not lead to higher behavioral aggression levels in response to the mTAP. This is in line with previous findings suggesting that aberrations at multiple levels are essential for developing externalizing disorders

Two-dimensional electron gas tilt-induced Landau level crossings

This work elucidates the novel behavior found in a two-dimensional electron gas (2DEG) under a tilted magnetic field in which the field's angle becomes the dominant factor in tuning the spin-splitting rather than the strength of the spin-orbit interaction. The 2DEG eigenvalues are derived with Rashba and Zeeman interactions for various tilt angles and they show crossing-free levels except at very high tilt. Moreover, concomitant with the crossings is the appearance of beats in the 2DEG density of states. The crossings from different levels occur consecutively at around 87^{\circ}. Similar new observations in Shubnikov-de Haas experimental measurements by Hatke et al. [1] attributed such phenomena to an in-plane-magnetic-field-induced increase in the effective mass. We show here that this behavior is inherent to a 2DEG where spin-orbit interaction and the in-plane magnetic field contribution are taken into account.Comment: 5 pages, 5 figure

Quantum states and linear response in dc and electromagnetic fields for charge current and spin polarization of electrons at Bi/Si interface with giant spin-orbit coupling

An expansion of the nearly free-electron model constructed by Frantzeskakis, Pons and Grioni [Phys. Rev. B {\bf 82}, 085440 (2010)] describing quantum states at Bi/Si(111) interface with giant spin-orbit coupling is developed and applied for the band structure and spin polarization calculation, as well as for the linear response analysis for charge current and induced spin caused by dc field and by electromagnetic radiation. It is found that the large spin-orbit coupling in this system may allow resolving the spin-dependent properties even at room temperature and at realistic collision rate. The geometry of the atomic lattice combined with spin-orbit coupling leads to an anisotropic response both for current and spin components related to the orientation of the external field. The in-plane dc electric field produces only the in-plane components of spin in the sample while both the in-plane and out-of-plane spin components can be excited by normally propagating electromagnetic wave with different polarizations.Comment: 10 pages, 9 figure

Sex-Specific Interaction Between Cortisol and Striato-Limbic Responses to Psychosocial Stress

Although women and men differ in psychological and endocrine stress responses as well as prevalence rates of stress-related disorders, knowledge on sex differences regarding stress regulation in the brain is scarce.Therefore, we performed an in-depth analysis of data from 67 healthy participants (31 women, taking oral contraceptives), who were exposed to the ScanSTRESS paradigm in an fMRI study. Changes in cortisol, affect, heart rate, and neural activation in response to psychosocial stress were examined in women and men as well as potential sex-specific interactions between stress response domains.Stress exposure led to significant cortisol increases with men exhibiting higher levels than women. Dependent on sex, cortisol elevations were differently associated with stress-related responses in striato-limbic structures: Higher increases were associated with activations in men but with deactivations in women. Regarding affect or heart rate responses, no sex differences emerged.Although women and men differ in their overall stress reactivity, our findings do not support the idea of distinct neural networks as base of this difference. Instead, we found differential stress reactions for women and men in identical structures. We propose considering quantitative predictors like sex-specific cortisol increases when exploring neural response differences of women and men