Behaviour and its consequences

In this thesis, I have examined the behaviour and some of its neural underpinnings of a ‘model’ animal, the tadpoles and froglets of Xenopus laevis, at different levels of description and detail. At a macroscopic level, I investigated the animals’ movements in a very simple space. Zooming in, I looked at locomotion in freely and fictively swimming animals as well as at some of the sensory and motor consequences of locomotion. For many of these projects, I tested not only one particular developmental stage but a range of stages, allowing me to test for changes in behaviour with development. Methodologically, I employed video tracking to quantify movements in space over a longer period of time, as well as at a higher temporal and spatial resolution for short periods to record head movements during swimming. Semi-intact in vitro preparations of tadpoles were used to examine fictive locomotion and its consequences using electrophysiological recordings of peripheral nerves. Movements in space remained fairly similar over development, from small tadpoles to froglets, with all animals following the walls in a square environment, although the strength of wall following (WF) increased with growth. Tentacles, which are putatively mechanosensory appendages that large tadpoles temporarily possess, did not play any role for the strength of WF. WF was passive at all developmental stages, meaning that the animals never actively turned at a convex curvature to follow the wall, but instead went straight and left the wall. This implies that WF is unlikely to serve a defensive or spatial function. Looking specifically at locomotion in tadpoles showed that these animals commonly swim at 20 - 40 mm/s forward speeds, and move their heads left to right at up to 2500°/s angular velocities. These velocities decrease with development, probably because swimming frequency also decreases, from about 8 to about 5 Hz. Developmentally appropriate swimming frequencies are also seen in fictive swimming when the animals are deprived of normal sensory feedback. The mechanisms behind the developmental decrease in swimming frequency remain to be elucidated; biomechanical factors might well play a role. The left- right head oscillations during swimming also represent vestibular self-stimulation, which reaches amplitudes that are much higher than any of the stimuli used in sensory vestibular experiments. Another consequence of locomotion was observed in large tadpoles with tentacles: These tentacles are retracted during swimming, via a locomotor corollary discharge from the spinal cord. What I have shown in this thesis is first, that navigational behaviour of X. laevis in a simple laboratory setting seems to be mainly driven and constrained by the environment. Second, I have quantified head movements during swimming and therefore vestibular reafference, and found a developmental decrease in the swimming frequency. Finally, I uncovered an unusual effect of locomotion, namely the retraction of the tentacles during swimming. Together, these studies deepen the understanding of behaviour and its consequences in X. laevis

The role of Memo in premature aging and FGFR signaling

Memo was recently identified in a screen for proteins required for ErbB receptor induced cell migration. Encoded by a single-copy gene present in all branches of life, it is ubiquitously expressed during all stages of embryogenesis and in adult tissues. This study aimed to investigate the physiological role of Memo. Initially, we generated a conventional knock out of Memo, which was embryonic lethal between E12.5 to E14.5. We subsequently generated a mouse strain to allow temporal control of Memo deletion by crossing a mouse strain harboring a homozygous floxed Memo allele (Memofl/fl) with pCX-CreERTM transgenics, where the ubiquitous actin promoter drives the Cre recombinase. Following tamoxifen treatment, Memo was deleted in all organs (Memo null mice). Knock out of Memo in mice at the age of 2 to 14 weeks revealed a severe premature aging phenotype accompanied by alterations in insulin and glucose metabolism. The phenotype of the Memo null mice, especially the metabolic phenotype, revealed an interesting similarity to the Klotho and FGF23 mutant mice. In particular, insulin and glucose metabolism was very similar to the phenotype shown by both Klotho mutant and FGF23 knock-out mice. To investigate this phenotype further, and as Klotho is mainly expressed in the renal tubular cells, we generated a mouse model, which lacked Memo specifically in the kidney. We chose a Pax8 promoter system to delete Memo in the renal tubular cells (1). Kidney specific Memo knock-out mice were generated by crossing Memo floxed (Memofl/fl) mice with a mouse line expressing the tetracycline-sensitive transactivator rtTA under control of the Pax8 promoter, and a mouse line harboring Cre recombinase under a promoter that contains a tetracycline-responsive promoter element. In these mice doxycycline treatment induced loss of Memo in renal tubular epithelial cells. By investigation of the Memo null and kidney-specific Memo KO mice we found that only the Memo null mice showed premature aging symptoms. However, both KO models showed deregulation of the FGF23-Klotho axis measuring expression of enzymes involved in vitamin D metabolism and phosphate reabsorption. Moreover, blood analysis of both models showed renal insufficiency and hypercalcemia. For the kidney-specific Memo KO animals we also performed analysis of the urine and found hypercaliuria. Surprisingly, for both models there was no difference in serum phosphate levels, which has earlier been shown by others to be causative for the premature aging syndrome. In conclusion, we found that deletion of Memo in the full body or specifically in the kidney induces renal insufficiency and hypercalcemia. Furthermore, Memo deletion in the full body results in severe premature aging symptoms that cannot be explained by elevated serum phosphate levels. To date, it is not clear how hypercalcemia and hypercalciuria affects Memo mice and what specifically induces the premature aging in Memo null animals. To investigate the function of Memo in vitro we isolated and immortalized mouse embryonic fibroblasts (MEFs) from Memofl/fl embryos. These cells were then infected with a Cre recombinase containing vector, which following 4-hydroxytamoxifen treatment ablated Memo expression (KO MEFs). Our studies showed that signaling downstream of FGF2 was reduced in activity and duration in Memo KO MEFs and furthermore that Memo was associated with the FGFR signaling complex (FGFR-FRS2-GRB2-GAB1). In addition, we tested mammary carcinoma cells (4T1) for sensitivity to FGFR inhibition and revealed lower sensitivity to FGFR inhibition in Memo downregulated cells. To investigate the role of Memo in the metabolic signaling we used HEK293 cells that are stably transfected with Klotho or ßKlotho and therefore responsive to FGF19, 21 and 23. We found that in Memo downregulated HEK293-Klotho and –ßKlotho cells, FGFR signaling activity after stimulation with FGF23 and FGF19 was affected. In summary, this study provides evidence for a physiological role of Memo downstream of the FGFR pathway. We show that Memo is part of the FGFR signaling complex. Loss of Memo affects the intensity and duration of the FGFR signaling and modulates sensitivity to FGFR inhibition and to oxidative stress. Furthermore, we uncovered an important role of Memo in renal physiology that contributed to a premature aging phenotype, which is similar to that observed in Klotho mutant or FGF23 knock out animals

Das wirklich Neue wird im Keim erstickt : Interview

Ulrich Oevermann, Begründer der Objektiven Hermeneutik, ist Professor für Soziologie an der Johann Wolfgang Goethe-Universität in Frankfurt am Main. Am Rande seines traditionellen Blockseminars am Berner Institut für Soziologie bot sich für soz:mag die Gelegenheit, den Professionalisierungs- und Sozialisationstheoretiker zu treffen. Bei einer Portion Fisch mit feinen Salzkartoffeln und Salat im Restaurant "Mappamondo" kam es zum Gespräch über die Hochschulreform, die Logik der Forschung, das Problem von Uni-Rankings, die Konkurrenz um den guten Studenten und die Vorteile der Zwiebel

Allgegenwärtige Potentialität. Zukunftsträchtigkeit als gesellschaftliche Formgeberin unserer Zeit

Es ist dies eine eigentümliche Einmütigkeit, die da im frühen 21. Jahrhundert zwischen Astrologie und Soziologie, zwischen Bodybuilding-Experten und Schweinezüchtern, Bildungseinrichtungen und Arbeitgebern, ja selbst zwischen der sozialdemokratischen Bundessozialministerin und einer Großbank herrscht: Allesamt besingen sie unserer Tage – als hätten sie gemeinsam dafür geprobt – den hohen Stellenwert zukunftsträchtiger ›Potenziale‹. Der Beitrag rekonstruiert die gleichsam allgegenwärtige Beschwörung von Potentialitäten als Kennzeichen eines neuen Modus der gesellschaftlichen Zeitbearbeitung, der nicht mehr – wie noch jener des 20. Jahrhunderts – auf unbegrenzte Möglichkeiten setzt, sondern auf Wesenheiten, die eine bestimmte Zukunft zugleich verheißen und vorwegnehmen. Anhand der Betrachtung exemplarischer Felder, in denen die Orientierung an vermeintlich wesenhaften ›Potenzialen‹ aktuell Konjunktur hat, wird diese Leitfigur als eine zeitlich-sachliche Überbrückungsformel erhellt. Wie sich zeigt, stellt sich diese Formel gerade in solchen gesellschaftlichen Zusammenhängen als problemlösend dar, in denen althergebrachte Glaubensfundamente an sozialer Tragfähigkeit eingebüßt haben. Als für die Zukunft gewappnet erscheint unter dem Regime der Potentialität nurmehr, wer dem ureigensten ›Potenzial‹ nach heute schon als ein zukunftsträchtig strukturiertes Wesen – gewissermaßen als ein ›future‹ – gelten kann. Ein Abriss der verworrenen Genealogie potentialistischen Denkens lässt schließlich erkennen, dass auch unsere Disziplin an der gesellschaftlichen Verdichtung dieses spezifisch-unspezifischen Glaubens ihren Anteil hat. Ein Grund mehr, sich der Frage nach dem ›kritischen Potenzial‹ der Soziologie anzunehmen

Fördern und Auslesen: Deutungsmuster von Lehrpersonen zu einem beruflichen Handlungsproblem

"Der Lehrberuf ist von einer Spannung zwischen 'Fördern' und 'Auslesen' geprägt: Lehrpersonen vermitteln nicht nur Wissen und tragen zur Sozialisation von Schülern und Schülerinnen bei, sie finden sich auch in Selektionsprozesse eingebunden, die das Wohl des Schülers und der Schülerin beeinträchtigen können. Aus professionalisierungstheoretischer Sicht erschweren es die selektionsbezogenen Aufgaben, dass zwischen der Lehrperson und dem Schüler bzw. der Schülerin ein Arbeitsbündnis entsteht, in dessen Rahmen sich neugieriges Lernen und Autonomieentwicklung entfalten können. Das Interesse gilt der Frage, auf welche Deutungsmuster Lehrpersonen rekurrieren, um die Spannung zwischen Fördern und Auslesen lebbar zu machen und handlungsfähig zu bleiben. Dabei gehen die Verfasser davon aus, dass die Deutungsmuster sich auf die soziale Herkunft der interessierenden Akteure, auf das Geschlecht sowie auf den absolvierten Ausbildungsgang (Real- versus Sekundarlehrausbildung) strukturell rückbeziehen lassen und in den Zusammenhang pädagogischer Denktraditionen gestellt werden können. Eine Grundvermutung lautet, dass Lehrpersonen ihre selektionsrelevanten Aufgaben in fördernde Aufgaben umdefinieren, sobald Selektion dem Schüler Unannehmlichkeiten bringt. Wer einem solchen Verständnis anhängt, bezieht sich als Lehrperson auf ein Berufskonzept, das historisch vor der Einführung eines selektionierenden Volksschulwesens zu verorten ist. Ausgehend von theoretischen Erörterungen zum Lehrberuf wird im geplanten Referat eine konkrete, sequenzanalytisch erarbeitete Fallanalyse präsentiert und vor dem Hintergrund der Grundvermutung kommentiert. Der vorzustellende Fall stammt aus einem laufenden Forschungsprojekt, in dem Lehrkräfte befragt werden, die in der Stadt Bern auf der Sekundarstufe I tätig sind." (Autorenreferat

Noise Fingerprints of Fiber Supercontinuum Sources

We present a novel technique for measuring unique ”noise fingerprints” of fiber supercontinuum (SC) sources, revealing a strong dependence of SC relative intensity noise not only on the dispersion of the fiber, but also on its cross-sectional geometry

Application of the Theory of the Critical Distances based methodology for the analysis of Environmentally Assisted Cracking processes in biomaterials

ABSTRACT: The complex interaction between physiological stresses and corrosive human fluids can lead to the premature failure of metallic biomaterials due to the development of Environmental Assisted Cracking (EAC) processes. In this paper, the EAC phenomenon is analysed through a Theory of Critical Distances based methodology, which has been validated in other materials and aggressive environments, and the apparent crack propagation threshold in notched conditions is estimated. Notch-like defects, which are frequently found in aggressive environments, may present higher values of crack propagation thresholds than those exhibited in cracked components. The knowledge of this higher material performance makes it possible to address the problem avoiding oversizing or unnecessary replacements in biomaterials, which leads to an improvement in the quality of life of the people carrying these materials. In this study, the susceptibility of AZ31 magnesium alloy to EAC and the evolution of the apparent crack propagation threshold have been analysed. The aggressive environment used was Simulated Body Fluid (SBF). The main conclusion is that the Theory of Critical Distances predicts the behaviour of this biomaterial in notched conditions and subjected to the aggressive environment being studied

Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity.

Memo1 deletion in mice causes premature aging and an unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. We report a role for Memo's redox function in renal FGF23-Klotho signaling using mice with postnatally induced Memo deficiency in the whole body (cKO). Memo cKO mice showed impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involved activation of oxidation-sensitive protein phosphotyrosyl phosphatases in the kidney. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1) in Memo cKO, and we detected a functional interaction between Memo's redox function and oxidation at Rho-GDI1 Cys79. In isolated cellular systems, Rho-GDI1 did not directly affect FGF23-driven cell signaling, but we detected disturbed Rho-GDI1 dependent small Rho-GTPase protein abundance and activity in the kidney of Memo cKO mice. Collectively, this study reveals previously unknown layers in the regulation of renal FGF23 signaling and connects Memo with the network of small Rho-GTPases

Expression of Developmentally Important Axon Guidance Cues in the Adult Optic Chiasm.

Funder: Wellcome TrustPURPOSE: Regeneration of optic nerve axons after injury can be facilitated by several approaches, but misguidance at the optic chiasm is often observed. We characterized guidance cues in the embryonic visual system and adult optic chiasm before and after optic nerve crush (ONC) injury to better understand barriers to optic nerve regeneration in adults. METHODS: Radial glial (RC2/BLBP/Slit1), developmental (Pax2) and extracellular markers (CSPG: H2B/CS-56) were assessed in C57BL/6J mice by immunohistochemistry. RC2, BLBP, Slit1, and CSPG are known inhibitory guidance cues while Pax2 is a permissive guidance cue. RESULTS: At embryonic day 15.5 (E.15.5), RC2 and BLBP were identified superior to, and extending through, the optic chiasm. The optic chiasm was BLBP-ve in adult uninjured mice but BLBP+ve in adult mice 10 days after ONC injury. The reverse was true for RC2. Both BLBP and RC2 were absent in adult mice 6 weeks post-ONC. Slit1 was present in the optic chiasm midline and optic tracts in embryonic samples but was absent in uninjured adult tissue. Slit1 was observed superior to and at the midline of the optic chiasm 10 days post-ONC but absent 6 weeks after injury. Pax2 was expressed at the junction between the optic nerve and optic chiasm in embryonic brain tissue. In embryonic sections, CS-56 was observed at the junction between the optic chiasm and optic tract, and immediately superior to the optic chiasm. Both 2H6 and CS-56 staining was absent in uninjured and ONC-injured adult brains. CONCLUSION: Differences in guidance cue expression during development, in adulthood and after injury may contribute to misguidance of regenerating RGC axons in the adult optic chiasm

Grain refinement of magnesium alloys: a review of recent research, theoretical developments and their application

This paper builds on the ‘‘Grain Refinement of Mg Alloys’’ published in 2005 and reviews the grain refinement research onMg alloys that has been undertaken since then with an emphasis on the theoretical and analytical methods that have been developed. Consideration of recent research results and current theoretical knowledge has highlighted two important factors that affect an alloy’s as-cast grain size. The first factor applies to commercial Mg-Al alloys where it is concluded that impurity and minor elements such as Fe and Mn have a substantially negative impact on grain size because, in combination with Al, intermetallic phases can be formed that tend to poison the more potent native or deliberately added nucleant particles present in the melt. This factor appears to explain the contradictory experimental outcomes reported in the literature and suggests that the search for a more potent and reliable grain refining technology may need to take a different approach. The second factor applies to all alloys and is related to the role of constitutional supercooling which, on the one hand, promotes grain nucleation and, on the other hand, forms a nucleation-free zone preventing further nucleation within this zone, consequently limiting the grain refinement achievable, particularly in low solute-containing alloys. Strategies to reduce the negative impact of these two factors are discussed. Further, the Interdependence model has been shown to apply to a broad range of casting methods from slow cooling gravity die casting to fast cooling high pressure die casting and dynamic methods such as ultrasonic treatment