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Repetitive subconcussive head impact – Magnetic Resonance Spectroscopy in young athletes
Get PDFWhile sports around the world and its beneficial effects on body and mind and overall health are commonly acknowledged, many sports have faced an increased focus on player’s safety and health over the last few years. Researchers around the world are looking more closely at sports with potential detrimental effects on the body, brain and long-term-trajectories. The United States National Institute of Health (NIH) just recently publicly concluded that repetitive traumatic brain injuries can cause chronic traumatic encephalopathy (CTE) despite the resisting position of many official sport governing bodies of contact sports1.
Soccer, being one of the most played sports, globally and nationally, has also been more closely looked at. Soccer players are not only at risk of unintentional tackles and collisions but face the challenge of heading the ball as intended part of games and practice. Many soccer players start practicing headers at a young age and continue to perform headers throughout their career. While there is some research hinting at increased risk for soccer players and other athletes of contact sports of developing neurodegeneration of the brain, it is important to understand the changes when they begin to be detectable and possibly reversible.
The brain, as a remarkable sensitive, yet robust organ, is the main focus of this thesis. As part of a larger study called RepImpact, its main objective was the study of the effect of headers at a young age (14-16 years old); looking at the brain itself, its structure, pathways and its metabolites, but also at motor and balance skills, cognitive performance as well as blood and saliva markers. In order to detect early effects and minimal changes of repetitive subconcussive head impacts such as headers, Magnetic Resonance Spectroscopy (MRS) as a sequencing part of Magnetic Resonance Imaging (MRI) was used to detect changes in brain metabolites.
This dissertation focused on brain metabolites of young soccer players and controls from Germany and possible changes before, during and after season, as well as in comparison to controls.
Typical developmental changes of the brain – as seen through changes in metabolite levels of total N-acetylaspartate (tNAA) dependent on age and consistent with the limited research available – could be presented. tNAA is shown to be a sensitive marker of age during the age of 14 to 16, indicating ongoing brain development. Further research of the brain metabolite levels during crucial developmental phases is necessary to establish baseline levels of the metabolites during development. This would be an important first step to further investigate possible changes brought on by repetitive subconcussive head impacts (and concussion).
Using the data at hand, differences in metabolite levels between soccer players and controls were not detectable.
A larger data set with longer observation period, more sensitive methods to count headers (and possible other collisions and concussions to evaluate “realistic risks”) and more knowledge about baseline metabolite levels at different ages might further help to understand and see the effects of repetitive subconcussive head impact (and biological compensatory and repair mechanisms). This could provide a basis for guiding and protecting children from detrimental outcomes in their future
Identification and characterization of a protein complex involved in chromatin architecture and the evolution of Drosophila species
Get PDFCentromeres and pericentromeric heterochromatin are involved in a number of essential functions including cell division, silencing of repetitive DNA elements and spatial organization of the genome. The clustering of these regions around chromocenters during interphase is required for their proper function and involves a complex and finely tuned network of protein-protein interactions.
Despite their critical importance, centromeric and pericentromeric chromatin are poorly conserved even among closely related species and are, in fact, often involved in the formation of species.
This apparent paradox is often the result of intrinsically fast-evolving repetitive DNA elements embedded into heterochromatin. The rapid evolution of such repetitive elements poses a threat to cellular fitness thereby exerting a selective pressure on the silencing machinery responsible for their management. Such process typically leads to the rapid coevolution of heterochromatin proteins acting like suppressors of fast-evolving DNA elements. This coevolution can, in turn, lead
two populations once belonging to the same species to diverge by developing species-specific heterochromatin, that can eventually function as a postzygotic barrier between the two newly generated species.
The fruit fly sibling species Drosophila melanogaster (D.mel) and Drosophila simulans (D.sim) have been a privileged model for studying the formation of species since over a century and provide an excellent example of how hybrid incompatibilities can arise within chromatin. Hybrids from D. melanogaster mothers and D. simulans fathers fail to develop because of the detrimental genetic interaction of the three hybrid incompatibility (HI) genes Hmr, Lhr and gfzf.
Genetic studies of the three HI genes have revealed pleiotropic phenotypes, with Hmr and Lhr mutations disrupting oogenesis, female fertility and repetitive elements silencing and gfzf mutants having a broad spectrum of phenotypes including defects in cell cycle regulation.
In addition to their genetic interaction, HMR and LHR proteins interact within a complex network of protein-protein interactions that is important for the architecture and function of centromeric and pericentromeric chromatin. For GFZF, on the other hand, few molecular data are available and there is no evidence of molecular interactions with the other two HI genes.
Although the last decade has brought enormous progress in the field, the molecular details underlying both the divergent evolution of these hybrid incompatibility factors in the respective pure species and their genetic interactions in interspecific hybrids are still poorly understood.
A major twist in the field has been the finding that the expression of HMR and LHR proteins has diverged during the evolution in D.mel and D.sim species and that the two proteins are both overrepresented in hybrids. However, while these findings revealed the importance of a proper quantitative balance of HMR and LHR, the HMR/LHR protein-protein interaction network could only be studied in overexpressing conditions so far.
Characterizing the HMR/LHR protein complex in native conditions could therefore pave the way, on the one hand for understanding how these two proteins interact to mediate normal pericentromeric and centromeric functions in pure species, and, on the other hand, how their interaction network is altered in hybrids where they are overexpressed.
To address these questions, in the first publication, we used affinity purification coupled with Mass Spectrometry (AP-MS) and revealed for the first time the existence of a stable six-subunit HMR/LHR protein complex in native conditions. In addition to HMR and LHR, the complex contains the two nucleolar proteins nucleoplasmin (NLP) and nucleophosmin (NPH), as well as the two non-characterized proteins, CG33213 and CG4788. For these last two proteins our publication provided the first molecular characterization and we named them Buddy Of HMR 1 (BOH1) and Buddy Of HMR 2 (BOH2), respectively. In addition, as a resource for the field, we published a detailed description of the intricate network of interactions (interactome) involving each complex component.
After identifying the complex we went further and generated two different mutants targeting two different Hmr domains, to dissect how HMR interacts with other complex components and how disrupting such interactions affects HMR localization and function. Our results suggest that the integrity of the HMR/LHR complex is necessary for both HMR physiological function in pure species and its toxic function in hybrids.
Next, we started from the HMR/LHR native complex and induced HMR/LHR overexpression to mimic a hybrid background in a cell culture system and asked how the HMR protein-protein interaction network is altered upon their overexpression. A range of new chromatin interactors, from architectural proteins like insulators to zinc-finger DNA binding proteins, appear to specifically interact when HMR is in excess, suggesting that these may be binding with low affinity and therefore only observed when HMR amount is not limiting, such as in hybrids.
Finally, we set out to study HMR subnuclear localization with respect to CENP-A and HP1a, a centromeric and a pericentromeric marker, respectively. Our findings allow us to build a model that reconciles previous controversies and suggests that HMR is neither centromeric nor pericentromeric but it is rather sitting in the middle, bridging these two types of chromatin by forming a complex that interacts with both.
In the second publication, we focused on the third and less known HI factor and asked how GFZF localizes in D.mel, D.sim and hybrids and how it molecularly interacts with HMR to cause hybrid incompatibility. We used in situ hybridization in polytene chromosomes to describe for the first time GFZF localization in D.mel, D.sim and hybrids. In addition, here we show the first evidence of a molecular interaction between GFZF and HMR by looking at their respective localization in
both polytene chromosomes and cell lines where HMR was present in physiological amounts or overexpressed with LHR (hybrid-mimicking condition). Strikingly, while the two HI proteins HMR and GFZF occupy distinct and non-overlapping territories in pure species, their localization merges in the hybrid background
Substitution im Maßregelvollzug
Get PDFBackground: There are no universal treatment standards for patients within opioid maintenance treatment programs in forensic psychiatric hospitals. Currently, the maintenance treatment in forensic psychiatries is composed of various different cri-teria. Additionally, the offered therapeutic interventions, such as sanctions for drug relapses and rule violations, are individualized for each patient. However, the goal should be to implement a standardized treatment approach in order to treat opioid addicts more efficiently. For this reason, this paper will investigate the effects of maintenance therapy on the therapeutic process of patients placed in forensic psy-chiatric hospitals according to bavarian Criminal Code § 64 StGB. The aim is to aid the advancement of addiction medicine, accompanied by an improvement of the therapeutic approaches within a forensic psychiatric setting.
Methods: A total of 144 participants from 11 psychiatric prisons in Bavaria were in-cluded in this study. For this purpose, existing data of the clinic documentation sys-tems were used. The non-substituted participants at the time of data collection were compared as a control group with the substituted participants of the experimental group with regard to baseline characteristics, duration of placement, dropout rate, number of lock-up levels reached, downgrades, as well as willingness to participate in therapy and number of rule violations.
Results: The samples differed clinically only in the frequency of failed detoxification attempts, which was significantly higher in the substitution group (median 1 vs. 3, p = 0.008). No significant differences were found with regard to the duration of ac-commodation, the dropout rate, the number of detoxification levels reached, the number of downgradings, the number of extensions of individual detoxification lev-els, and general therapy participation (occupational therapy, sports therapy, occupa-tional therapy, etc.). In the group of relapsed participants, significantly more relapses were recorded among the non-substituted participants (median 3 [1; 4–5] vs. 1 [1; 2–3] relapses, p = 0.008). In addition, nonsubstituted participants had more rule viola-tions than substituted participants (median 1 [1; 2]) vs. 2 [1; 3], p = 0.026, r = 0.298).
Discussion: Although substituted participants in this study did not differ from the control group with regard to clinical parameters, such as length of stay, positive ef-fects of substitution therapy on the course of therapy in the correctional facility can still be derived. The subgroup studies of participants with rule violations and recidi-vism indicate that substitution therapy could have a positive effect on the course of therapy, especially with regard to the number of recidivism and rule violations. How-ever, further investigations are necessary here
Asymmetric infall beyond natal cores to protoplanetary disks
Get PDFDie Masse eines Sterns wird während des protostellaren Stadiums festgelegt, in dem ein Protostern und die ihn begleitende Scheibe in ihren Geburtskern eingebettet sind. Die Mechanismen, die die Anhäufung von Masse innerhalb des Stern und Scheibensystems vorantreiben, sind jedoch nicht gut verstanden. Das klassische Bild der Sternentstehung geht davon aus, dass ein Protostern und seine planetenbildende Scheibe im Zentrum eines sphärisch symmetrischen Kerns akkretieren, der von äußeren Einflüssen isoliert ist. In Wirklichkeit ist die Verteilung des molekularen Gases auf allen Skalen asymmetrisch, von den parsec-großen Filamenten bis hin zu Asymmetrien in protoplanetaren Scheiben. Numerische Simulationen, die realistische Bedingungen in Sternentstehungsgebieten berücksichtigen, zeigen, dass der Einfall von Kernen in protostellare Scheiben durch lange und dünne Kanäle, sogenannte Streamer, erfolgt. Dank der Entwicklung leistungsfähiger Interferometer wie ALMA und NOEMA können wir nun diese Einfallkanäle in der Emission von molekularem Gas untersuchen. In dieser Dissertation untersuche ich die Eigenschaften von Streamers mit Hilfe von Submillimeter-Beobachtungen, wie zum Beispiel ihr Vorkommen und den Ursprung ihrer Massen.
Das erste Projekt zielt darauf ab, die Massenzufuhr zu einer protostellaren Scheibe durch einen Streamer zu verfolgen. Mit interferometrischen Daten des PRODIGE NOEMA Großprogramms habe ich die Hülle von Per-emb 50, einem eingebetteten Protostern im Perseus, untersucht. Ich finde einen Streamer, der mehr als genug Masse liefert, um die aktuelle Akkretionsrate von der Scheibe zum Protostern aufrechtzuerhalten, und so sammelt sich in der Scheibe selbst gas an, was in der Zukunft einen Akkretionsausbruch auslösen kann. Ich finde auch molekulare Emission, die mit einem Akkretionsschock in der Nähe des voraussichtlichen Landeplatzes des Streamers übereinstimmen, was auf eine chemische Veränderung aufgrund des Masseneinfalls hinweist.
Die Länge der beobachteten Streamer zeigt, dass sie Masse von außerhalb des Geburtskerns transportieren können, aber es ist nicht klar, woher die Masse kommt. Im zweiten Projekt verfolge ich den Massentransport von der größeren filamentären Struktur, die die Molekülwolken dominiert, hin zu einem einzelnen eingebetteten Protostern. Zu diesem Zweck untersuche ich die Gaskinematik in zwei verschiedenen physikalischen Größenordnungen, dem Gasfluss auf filamentärer Ebene (∼ 10000 au) und der Hülle eines eingebetteten Protosterns (100 au). Dank dichtebasierter Clustering-Algorithmen, die auf die Molekülliniendaten angewandt werden, finde ich einen Streamer in Richtung eines eingebetteten Protosterns, den isolierten und dichten Barnard 5-Kern. Ich entdecke auch einen Zufluss aus der größeren umgebendenWolke in Richtung der Filamentstrukturen, in die der Protostern eingebettet ist. Meine Analyse der Gaseigenschaften auf beiden Ebenen deutet darauf hin, dass der Zufluss aus der Wolke mit dem Streamer verbunden ist, was bedeutet, dass die protostellare Scheibe Zugang zu frischem Gas aus der umgebenden Wolke hat.
Fast alle Streamer wurden zufällig gefunden, und es ist unklar, ob sie in der Nähe von Protosternen häufig vorkommen oder nicht. Im Rahmen des Abschlussprojekts führe ich die erste systematische Suche nach Streamers unter Verwendung von NOEMA- und 30-m-Teleskopbeobachtungen. Ich stelle fest, dass im Süden von NGC 1333, der aktivsten Sternentstehungsregion in der Perseus-Molekülwolke, etwa 40 % der Protosterne Anzeichen für einen asymmetrischen Einfall in Richtung ihrer Scheiben aufweisen. Ich stelle auch fest, dass das Gas aus der größeren umgebenden Molekülwolke stammt. Streamers sind also nicht nur häufig, sondern vergrößern auch das Massenreservoir, das nach dem klassischen Bild erwartet wird.
Ich schließe diese Arbeit mit einem Ausblick darauf, wie wir einige der offenen Fragen zu den Auswirkungen von Streamern bei der Stern- und Planetenentstehung klären können. Jetzt, da wir wissen, dass Streamer ein häufiges Merkmal sind, ist es unerlässlich, die Auswirkungen des asymmetrischen Einfalls auf die Struktur der protoplanetaren Scheiben zu erforschen. Hochauflösende Beobachtungen von Molekülen innerhalb der protostellaren Scheiben in frühen Entwicklungsstadien werden es Astronomen ermöglichen, die Streamers in das Rätsel der Sternentstehung einzuordnen.The mass of a star is set during the protostellar stage, where a protostar and its accompanying disk are embedded in their natal core. However, the mechanisms that drive the accumulation of mass within the star and disk system are not well understood. The classical picture of star formation assumes a protostar and its planet-forming disk are accreting at the center of a spherically symmetric core, isolated from external influences. In reality, molecular gas distribution is asymmetric at all scales, from the parsec-sized filaments to asymmetries in protoplanetary disks. Numerical simulations that take into account realistic conditions within star forming regions find that infall from cores to disks proceeds through long and thin channels called streamers. Thanks to the development of powerful interferometers, such as ALMA and NOEMA, we can now study these infall channels in molecular gas emission. In this thesis, I investigate the properties of streamers using sub-millimeter observations, such as their occurrence and the origin of their masses.
The first project aims to follow the mass delivery to a protostellar disk through a streamer. Using interferometric data from the PRODIGE NOEMA large program, I investigated the envelope of Per-emb 50, an embedded protostar in Perseus. I find a streamer that delivers more than enough mass to sustain the current accretion rate from disk to protostar, and thus gas accumulates in the disk itself, which can produce an accretion outburst in the future. I also find molecular emission consistent with an accretion shock near the predicted landing site of the streamer, suggesting a chemical change due to the mass infall.
The length of observed streamers suggests that they can transport mass from outside the natal core, but it is not clear from where the mass comes from. In the second project, I follow the mass delivery from the larger filamentary structure that dominates molecular clouds toward an individual embedded protostar. For this, I study the gas kinematics in two different physical scales, the gas flow at filamentary scales (∼ 10000 au) and the envelope of an embedded protostar (∼ 100 au). Thanks to density-based clustering algorithms applied to the molecular line data, I find a streamer toward an embedded protostar in the isolated Barnard 5 dense core. I also detect inflow from the larger ambient cloud toward the filament spines where the protostar is embedded. My analysis of the gas properties at both scales suggests that the inflow from the cloud is connected to the streamer, implying the protostellar disk can access fresh gas from the ambient cloud.
Almost all streamers have been found serendipitously, and it is unclear if they are a frequent feature around protostars or not. In the final project, I lead the first systematic search for streamers, using NOEMA and 30-m telescope observations. I find that in the south of NGC 1333, the most active star-forming region in the Perseus Molecular Cloud, around 40% of the protostars show signs of asymmetric infall toward their disks. I also determine that the gas feeding the streamers comes from the larger ambient molecular cloud. Therefore, streamers are not only frequent, but also expand the mass reservoir expected from the classical picture.
I close this thesis with an outlook on how to resolve some of the open questions regarding the effects of streamers in star and planet formation. Now that we know streamers are a frequent feature, it is imperative to observe the effect of the asymmetric infall in the structure of protoplanetary disks. High resolution observations of molecules within the protostellar disks in early stages will allow astronomers to place streamers neatly in the puzzle of star formation
Mittelfristige klinische und radiologische Ergebnisse nach Implantation einer zementfreien Schultertotalprothese mit konvertierbarer Metal-Back-Pfanne
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