Analysis of neuronal transcripts of PGC-1α transgenic mice

Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator involved in mitochondrial biogenesis, oxidative stress response, and energy metabolism. PGC-1α is part of an energy sensing network that translates environmental influences into alterations in gene expression of mainly mitochondrial molecular pathways. A role in neuroprotection has been implicated for PGC-1α in the context of mitochondrial expression networks. Our research group has previously established a transgenic mouse line with stable overexpression of PGC-1α in brain neurons. Transgenic overexpression of PGC-1α is associated with an enhanced functional state of mitochondrial energy production. In the context of neurodegenerative processes, brain neurons of PGC-1α transgenic mice are protected against oxidative stressors in the MPTP mouse model of Parkinson's Disease. To further characterize the transcriptional activity of PGC-1α regulated gene networks in brains of transgenic mice, a quantitative real-time PCR based system was established. Gene expression was measured for a subset of genes found to be differentially regulated in a microarray based screening of RNA obtained from hippocampus and cortex of PGC-1α transgenic mice. Increased PGC-1α gene expression was found in hippocampus and cortex of PGC-1α transgenic mice, and their translation into protein was confirmed immunohistochemically. Expression analysis revealed significant changes in mRNA levels of PGC-1α controlled molecular pathways involved in mitochondrial energy production and antioxidant responses. Furthermore, alterations in the expression of some non-mitochondrial genes with established links to neurodegeneration were observed. Furthermore, a change in GABAA receptor subunit expression was detected. In accordance with previous studies on the PGC-1α transgenic mouse line, these findings suggest that differential gene expression associated with PGC-1α overexpression contributes to an enhanced functional state of neurons in hippocampus and cortex of PGC-1α transgenic mice. Increased knowledge about the transcriptional modulation of neuronal genes regulated by PGC-1α can lead to better insights into mechanisms governing neurodegeneration and neuroprotective pathways. Pharmacological modulation of PGC-1α activity may be a feasible approach for neuroprotective treatments in neurodegenerative diseases, such as Parkinson's Disease

Cognitive Profiles of Developmental Dysgraphia

Developmental dysgraphia is a disorder of writing/spelling skills, closely related to developmental dyslexia. For developmental dyslexia, profiles with a focus on phonological, attentional, visual or auditory deficits have recently been established. Unlike for developmental dyslexia, however, there are only few studies about dysgraphia, in particular about the variability of its causes. Research has demonstrated high similarity between developmental dyslexia and dysgraphia. Thus, the aim of the study was to investigate cognitive deficits as potential predictors of dysgraphia, analogously to those for dyslexia, in order to identify dysgraphia profiles, depending on the particular underlying disorder. Different tests were carried out with 3rd and 4th grade school children to assess their spelling abilities, tapping into phonological processing, auditory sound discrimination, visual attention and visual magnocellular functions as well as reading. A group of 45 children with developmental dysgraphia was compared to a control group. The results showed that besides phonological processing abilities, auditory skills and visual magnocellular functions affected spelling ability, too. Consequently, by means of a two-step cluster analysis, the group of dysgraphic children could be split into two distinct clusters, one with auditory deficits and the other with deficits in visual magnocellular functions. Visual attention was also related to spelling disabilities, but had no characteristic distinguishing effect for the two clusters. Together, these findings demonstrate that a more fine-grained diagnostic view on developmental dysgraphia, which takes the underlying cognitive profiles into account, might be advantageous for optimizing the outcome of individuum-centered intervention programs

Infinitival complements of causative/perception verbs in a diachronic perspective.

This paper traces the diachrony of three alternative configurations of infinitival complementation with causative and perception verbs in Portuguese, namely the faire-infinitive, the Exceptional Case Marking and the inflected infinitive constructions. It is shown that the faire-infinitive construction is the earlier pattern of infinitival complementation with causative and perception verbs. The ECM construction is the subsequent innovation and creates the conditions for the appearance of the inflected infinitive. Hence the diachronic development of the structures analyzed in the paper defines a clear path of functional enrichment of the infinitival complements of causative and perception verbs, which gradually acquire greater syntactic autonomy. The structurally ambiguous configurations that lie behind each step of the change are identified in the paper.info:eu-repo/semantics/publishedVersio

Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

Hutchinson-Gilford progeria syndrome (HGPS) is the result of a defective form of the lamin A protein called progerin. While progerin is known to disrupt the properties of the nuclear lamina, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Previous studies in our laboratory have shown that progerin expression in murine epidermal basal cells results in impaired stratification and halted development of the skin. Stratification and differentiation of the epidermis is regulated by asymmetric stem cell division. Here, we show that expression of progerin impairs the ability of stem cells to maintain tissue homeostasis as a result of altered cell division. Quantification of basal skin cells showed an increase in symmetric cell division that correlated with progerin accumulation in HGPS mice. Investigation of the mechanisms underlying this phenomenon revealed a putative role of Wnt/beta-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of beta-catenin involving the inner and outer nuclear membrane proteins, emerin and nesprin-2. Taken together, our results suggest a direct involvement of progerin in the transmission of Wnt signaling and normal stem cell division. These insights into the molecular mechanisms of progerin may help develop new treatment strategies for HGPS.Peer reviewe

Developmental dyslexia and dysgraphia: What can we learn from the one about the other?

Up to 17% of German school children suffer from reading and writing disabilities. Unlike developmental dyslexia, only few studies have addressed dysgraphia. Presenting a comprehensive overview of the current state of the art in developmental dyslexia and dysgraphia, this paper aims to determine how far existing knowledge about the causes of developmental dyslexia also apply to developmental dysgraphia. To promote understanding of developmental dysgraphia, the paper discusses relevant aspects such as predictors, causes and comorbidities, models of acquisition as well as existing deficit models. A comparison of definitions in the DSM-V and ICD-10 complemented by an overview of the most recent German guideline ought to give the reader deeper insight into this topic. The current issue of growing up bilingually and the connection between reading and writing deficits are also discussed. In conclusion, this paper presents a critical survey of theoretical and practical implications for the diagnostics and treatment of developmental dysgraphia

Afferent sensory mechanisms involved in jaw gape related activation ofmasticatory muscles in unilateral biting.

Problemstellung Die Aktivierung der Kaumuskeln folgt bei einseitigen Kraftapplikationen wie z.B. Kauen oder Beißen einer neuromuskulären Strategie, die darauf abzielt, die Zähne auf der Balanceseite vor Überlastung durch direkte Zahnkontakte zu schützen. Diese Strategie besteht darin, bei Annäherung des Unterkiefers an den Oberkiefer in einem Abstandsbereich von weniger als 3 mm bei ansteigender Bisskraft die Muskelaktivität des balanceseitigen M. masseter gegenüber derjenigen des arbeitsseitigen Muskels zu reduzieren. Dies bewirkt nachweislich eine verminderte Kippung des Unterkiefers um die transversale Achse und damit eine geringere und "vorsichtigere" Annäherung der balanceseitigen Zahnreihen. Diese, als "bisssperrungsabhängige relative Aktivierung" bezeichnete Schutzstrategie erfordert, dass die zentralnervöse Steuerung den momentanen Interokklusalabstand jederzeit erkennt, wofür primär Muskelrezeptoren als afferente Signalquellen in Frage kommen. Jedoch ist bisher nicht bekannt, wie Muskelspindeln bei einer Kontraktion die Lage von Gliedmaßen differenzieren können. Es wird vermutet, dass hierzu geringe Restbewegungen notwendig sind. Wenn dies zutrifft, so müsste die bisssperrungsabhängige Aktivierung beim Beißen auf ein unnachgiebiges Objekt ausbleiben. In der vorliegenden Arbeit sollte daher untersucht werden, ob die Verhinderung von Restbewegungen des Unterkiefers beim isometrischen Beißen die bisssperrungsabhängige Aktivierung der Massetermuskeln unterbindet. Material und Methoden Bei 20 vollbezahnten, funktionsgesunden Testpersonen wurden die Muskelaktivitäten der rechten und linken Mm. masseteres und anterioren Mm. temporales mit Hilfe von Oberflächenelektroden bei einseitig ausgeführten Kauund Beißaktionen abgeleitet. Diese Aktionen umfassten i) Kauen von Gummibären, ii) isometrisches Beißen auf geringfügig nachgiebige Silikongummis der Stärken 8, 5, 3, 2, 1 und 0.5 mm, iii) isometrisches Beißen auf unnachgiebige, zahnfassende Aufbissschienen aus dem zahnärztlichen Bissregistriermaterial Futar®D mit Dicken von 5 und 1 mm sowie iv)isometrisches Beißen auf unnachgiebige, nicht-zahnfassende Kunststoffplatten mit Dicken von 5 und 1 mm. Die isometrischen Aktionen wurden intermittierend, im gleichen Rhythmus und mit der gleichen Kraft wie beim Kauen ausgeführt. Jede Aktion wurde 20 Sekunden lang aufgezeichnet. Aus den Aktivitätsverläufen wurden die Aktivitätsamplituden bestimmt und daraus Arbeits/Balanceseiten-Verhältnisse (A/B-Verhältnisse) der Masseter - bzw. Temporalismuskeln gebildet. Ergebnisse Beim Beißen auf Silikon mit abnehmender Bisssperrung stieg das A/BVerhältnis der Mm. masseteres von 1.2 ± 0.2 bei 8 mm auf 2.3 ± 0.2 bei 0.5 mm signifikant an. Bei den "kauähnlichen" Bisssperrungen 1 mm und 0.5 mm war das A/B-Verhältnis beim Beißen nicht signifikant unterschiedlich vom A/BVerhältnis des Kauens, welches bei 1.9 ± 0.4 mm lag. Beim Beißen auf die unnachgiebigen, zahnfassenden Schienen stieg das A/B-Verhältnis der Mm. masseteres von 1.2 ± 0.2 bei 5 mm lediglich auf 1.3 ± 0.2 bei 1 mm an. Der Wert bei 1 mm war signifikant niedriger als beim Kauen sowie beim Beißen auf Silikon der gleichen Dicke. Das A/B-Verhältnis der Mm. temporales zeigte nur eine schwache Abhängigkeit von der Bisssperrung, so dass daraus keine Aussage bezüglich einer Veränderung des A/B-Verhältnisses beim Beißen auf die unnachgiebige Schiene festgestellt werden konnte. Die Ergebnisse des Beißens auf unnachgiebige, nicht-zahnfassende Platten waren analog zu den Ergebnissen des Beißens auf die zahnfassenden Schienen. Schlussfolgerungen Die Ergebnisse zeigen, dass bei Verhinderung von Unterkieferrestbewegungen beim isometrischen Beißen die bisssperrungsabhängige relative Aktivierung weitgehend ausbleibt. Der afferente sensorische Informationsfluss ist in diesem Fall demjenigen des Kauens weniger ähnlich als beim Beißen auf Silikon. Zur sensorischen Wahrnehmung solcher Veränderungen sind sowohl Muskelspindeln als auch Periodontal-, Haut- und Schleimhautrezeptoren geeignet, welche die ausbleibende Bewegung in Form von veränderten Berührungsreizen erfassen können. Sollten primär die Muskelspindeln für die sensorische Wahrnehmung der sehr kleinen Bisssperrungen verantwortlich sein, so würden die Ergebnisse bedeuten, dass zur Wahrnehmung der Muskellängen geringe Längenänderungen notwendig sind. Um diese Schlussfolgerung zu erhärten wäre es nötig, in einem Nachfolgeexperiment durch Deaktivierung von Periodontal-, Haut- und Schleimhautrezeptoren deren mögliche Beteiligung an der Wahrnehmung der Unterkieferlage abzuklären.Problem The activation of masticatory muscles in unilateral force applications like chewing or biting is controlled by a neuromuscular strategy which aims to prevent overloading of balancing side teeth due to possible direct tooth contacts.This strategy consists in reducing the activity of the balancing side masseter relative to that of the working side muscle when the jaw approaches the maxilla to less than 3 mm. The reduction of balancing side activity results in less tilt of the jaw around the sagittal axis and thus to a less and more cautious approach of lower to upper balancing side teeth. This socalled "jaw-gape-related activation" requires, that central nervous control has information on the jaw gape at any instant of time, for which primarily muscle spindles could account as afferent signalling sources. So far, however it is not known how muscle spindles in a contraction could encode the position of a limb and thus the jaw gape. It is supposed that minor movements of a limb are necessary for encoding position. If this applies, then jaw gape related activation should fail to appear if biting is performed on a completely rigid object. The aim of this study therefore was to clarify whether impedence of minor jaw movements in isometric biting would result in non-appearance of jaw gape related activation. Materials and methods In 20 dentate and functionally healthy subjects, electric activities of masseter and anterior temporalis muscles were recorded by means of surface electromyography during various unilateral chewing and biting tasks. These comprised i) chewing of winegum, ii) isometric biting on slightly yielding pads of silicone with thicknesses of 8, 5, 3, 2, 1 and 0.5 mm, iii) isometric biting on rigid 8 (non-yielding), teeth-embedding splints made of Futar®D impression material with thicknesses of 5 and 1 mm and iv) isometric biting on rigid, non-teethembedding plastic plates. The isometric actions were performed intermittently with a rhythm and bite force like in chewing. Each task was recorded for 20 seconds. From the electromyographic signals, activity amplitudes were determined and transformed into working/balancing-side ratios (W/B-ratios) of masseter and temporalis muscles. Results In biting on silicone with decreasing jaw gape, the W/B-ratio of the masseter muscle increased significantly from 1.2 ± 0.2 at 8 mm to 2.3 ± 0.2 at 0.5 mm jaw gape. With the "chewing-like" jaw gapes of 1 and 5 mm the W/B-ratio in biting did not differ significantly from the W/B-ratio of chewing which amounted to 1.9 ± 0.4. In biting on the rigid, embedding splint the masseter W/B-ratio increased just slightly form 1.2 ± 0.2 at 5 mm to 1.3 ± 0.2 at 1 mm. With 1 mm, the W/Bratio in splint biting was significantly smaller than in chewing or in biting on silicone with the same jaw gape. The W/B-ratio of the temporalis muscles showed just a weak respons to the jaw gape so that no statements could be inferred with respect to a changed W/B-ratio in biting on the splints. Biting on the rigid, non-teeth-embedding plates yielded results analogous to biting on the teeth-embedding splints. Conclusions The results show, that with impedence of minor jaw movements in isometric biting, the jaw gape related activation was widely suppressed. In this case the afferent flow of sensory information is less similar to that of chewing than in biting on yielding silicone. Sensory perception of such changes could be achieved by muscle spindles or by periodontal-, mucosal- or skin receptors that could perceive the lacking of minor movements via altered touch stimulations. If muscle spindles are primarily responsible for the perception of the very small jaw gapes, the results would mean that perception of muscle length requires minor length changes. To corroborate this conclusion, it would be necessary to test the possible involvement of periodontal-, mucosal- and skin receptors by deactivating these receptors in a modified follow-up experiment