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Doctor of Philosophy / Department of Biology / Susan J. Brown / How animals polarize and establish the main axis during embryogenesis has been one of the most attractive questions in Biology. Increasing body of work in various model organisms implicates that most metazoans utilize the canonical Wnt signaling pathway to pattern the anterior-posterior (AP) axis, despite the limited evidence from arthropods. In Drosophila, a highly derived insect, canonical Wnt activity is not required for global AP patterning, but in typical insects including Tribolium castaneum, loss of canonical Wnt activity results in posterior truncation. To determine the eff ects of increased canonical Wnt levels, I analyzed the function of axin, encoding a highly conserved negative regulator of the pathway. Tc-axin transcripts are maternally localized to the anterior pole in freshly laid eggs. Parental RNAi for Tc-axin produced progeny phenotypes that ranged from mildly a ffected embryos with cuticles displaying a graded loss of anterior structures, to severely a ffected embryos lacking cuticles and condensing to the posterior pole of the egg without any de finable structures. Altered expression patterns of several blastodermal markers indicated anterior expansion of posterior fates. Epistasis analysis of other canonical Wnt pathway components and the expansion of Tc-caudal expression, a Wnt target, suggest that the eff ects of Tc-axin depletion are mediated through this pathway and that canonical Wnt activity must be repressed for proper anterior development in Tribolium. These studies provide unique evidence that canonical Wnt activity must be carefully regulated along the AP axis in an arthropod, and support an ancestral role for Wnt signaling in de fining AP polarity and patterning in metazoan development. Additionally, as an anterior structure, the extraembryonic serosa is reduced in Tc-axin RNAi progeny. However, in Tc-pangolin (Tc-pan, a homolog of Wnt downstream component) RNAi progeny, an interesting phenotype was produced that serosa was not only reduced but also separated into distinct anterior and dorsal domains. I carefully recorded this phenomenon with live imaging using a Tribolium transgenic line that expresses GFP in each nucleus. Through careful examination with embryonic fate-map markers, I found that the tissue between separated serosa domains is dorsally extended head lobe. And I also found that in severe phenotype, dorsal serosa was completely gone while anterior serosa not, suggesting independent regulation mechanisms for anterior and dorsal serosa formation. This descriptive data will complement future study in the genetic mechanism underlying serosa formation by providing more details in morphogenesis.

O ácido retinóico (AR) é sintetizado a partir de oxidações sucessivas do retinol. A última etapa de oxidação é catalisada pelas enzimas RALDHs. O estabelecimento da polaridade ântero-posterior (AP) do coração é crítico para a demarcação das regiões de efluxo (ventrículos) e de influxo (átrios). Nosso grupo propõe que uma onda caudo-rostral (CR) de RALDH2 seja o mecanismo responsável por esta padronização em vertebrados. Para testar o papel da sinalização pelo AR na padronização AP do peixe zebra, manipulamos sua via com o inibidor das enzimas RALDHs, DEAB, com AR e com um inibidor da enzima CYP26 (IC), que cataboliza o AR. Os tratamentos com DEAB durante o período da onda de RALDH2 produziram átrios reduzidos, enquanto que os tratados com AR e com IC apresentam o domínio atrial expandido. Animais tratados com DEAB e AR em um estágio posterior a onda não mostraram diferença significativa ao controle. Estes dados sugerem uma forte correlação entre o evento da onda e a padronização das câmaras cardíacas, semelhante ao que ocorre nos demais amniotos. / The retinoic acid (RA) is synthetized by successive oxidations of retinol. The last oxidation step is catalyzed by the RALDHs enzymes. The establishment of the anteroposterior (AP) polarity is critical for the demarcation of outflow (ventricle) and inflow (atrium) regions. Our group proposes that a caudorostral (CR) wave of RALDH2 is the mechanism responsible for this patterning in vertebrates. In order to test the role of the RA signaling in zebrafish AP patterning, we manipulated its pathway with a RALDH enzymatic inhibitor, DEAB, with RA and with a CYP26 (IC) enzymatic inhibitor, that catabolises the RA. The DEAB treatments during the manifestation of the RALDH wave produced reduced atriums; meanwhile, the treatments with RA and IC presented an atrium expansion. Animals treated with DEAB and RA during a stage posterior to the wave did not present any significant difference. These data suggest a strong correlation between the wave event and the cardiac chamber patterning, similar to the mechanism observed in others amniotes.

<p>Because of the difficulties in concluding whether a person has drowned or not, information that could be relevant for postmortal diagnosis of drowning was studied. With postmortal CT images lung volume, mean attenuation, anterior-posterior difference, lung density profile and amount of water within the lungs were investigated.</p><p>The report also evaluates three examples of software that calculates lung volume from postmortal CT images: Siemens’ Syngo Pulmo CT, Siemens‘ Volume Evaluation and GE Medical Systems’ Volume Viewer. The method used at autopsy was also studied. The repeatability and validity were tested and sources of errors identified.</p><p>Repeatability and validity for the three tested types of software were acceptable, while the method used at autopsy had to be improved. The study also showed that lung volume related to length, anterior-posterior difference and lung density profile seemed to vary between drowned and other deceased. These measures might conclude whether a person has drowned.</p>

Because of the difficulties in concluding whether a person has drowned or not, information that could be relevant for postmortal diagnosis of drowning was studied. With postmortal CT images lung volume, mean attenuation, anterior-posterior difference, lung density profile and amount of water within the lungs were investigated. The report also evaluates three examples of software that calculates lung volume from postmortal CT images: Siemens’ Syngo Pulmo CT, Siemens‘ Volume Evaluation and GE Medical Systems’ Volume Viewer. The method used at autopsy was also studied. The repeatability and validity were tested and sources of errors identified. Repeatability and validity for the three tested types of software were acceptable, while the method used at autopsy had to be improved. The study also showed that lung volume related to length, anterior-posterior difference and lung density profile seemed to vary between drowned and other deceased. These measures might conclude whether a person has drowned.

Το φυλοσύνδετο γονίδιο wiser (CG32711) είναι απαραίτητο για την ανάπτυξη της Drosophila melanogaster. Η μελέτη μιας θερμοευαίσθητης, θανατογόνου μετάλλαξης που ονομάζεται wisertsl αποκάλυψε ότι το γονίδιο wiser εμπλέκεται μεταξύ άλλων στην ανάπτυξη των φτερών. Η μετάλλαξη wisertsl οφείλεται σε ένα P στοιχείο (7E P) που βρίσκεται 490 bp ανοδικά του σημείου έναρξης της μεταγραφής του γονιδίου wiser. 95 bp καθοδικά του 7E P στοιχείου υπάρχει μια P{lacW} ένθεση υπεύθυνη για τη θανατογόνο μετάλλαξη PL26. Οι μεταλλάξεις wisertsl και PL26 είναι αλληλόμορφα του ίδιου γονιδίου ενώ 12000 περίπου βάσεις ανοδικά του γονιδίου wiser και 490 bp ανοδικά του γονιδίου trf2 υπάρχει μια άλλη P{lacW} ένθεση που είναι υπεύθυνη για τη θανατογόνο μετάλλαξη PL28. Οι PL26 και PL28 δεν δείχνουν συμπληρωματικότητα με τη μετάλλαξη wisertsl όσον αφορά το θανατογόνο φαινότυπο στους 29ºC. Όμως το διαγονίδιο UAS-wiser δε διασώζει το θανατογόνο φαινότυπο του PL28. Τα αποτελέσματα της παρούσας εργασίας αποκάλυψαν ότι: 1) Το γονίδιο wiser αλληλεπιδρά με το γονίδιο dpp. Εκτοπική έκφραση του διαγονιδίου (UAS wiser) υπό τον έλεγχο του οδηγού στελέχους apGAL4, μειώνει την έκφραση του dpp στην περιοχή του εμβρυικού δίσκου που θα δώσει τμήμα του θώρακα (notum). 2) Σε ομόζυγα wisertsl άτομα η έκφραση των γονιδίων dpp, dad, omb και salm (όπως αποκαλύπτεται από την έκφραση των αντίστοιχων –lacZ διαγονιδίων) μειώνεται στον εμβρυικό δίσκο του φτερού. Τα παραπάνω γονίδια είναι απαραίτητα για την ανάπτυξη του προσθοπίσθιου άξονα του εμβρυικού δίσκου του φτερού που σημαίνει ότι και το γονίδιο wiser εμπλέκεται στο σχηματισμό του. 3) Το γονίδιο wiser αλληλεπιδρά με το γονίδιο Notch (N) καθώς N wisertsl /wisertsl θηλυκά έχουν εντονότερα φαγωμένα φτερά. 4) Οι μεταλλάξεις wisertsl και PL28 είτε αφορούν και οι δύο το γονίδιο wiser ή η PL28 αφορά το γονίδιο trf2 που σημαίνει ότι και αυτό εμπλέκεται στο σχηματισμό του φτερού. / The X- linked wiser (CG32711) gene is a vital gene for the development of Drosophila melanogaster. The study of a temperature sensitive lethal mutation, named wisertsl, revealed that the wiser gene is implicated among others in the development of wings. The wisertsl mutation is due to a wild P element (7E P) located 490 bp upstream of the presumed transcription start site of the gene wiser at the region 7Ε. 95 bp downstream of the 7E P element is located a P{lacW} responsible for the lethal mutation PL26 and ~ 12000 bp upstream of the gene wiser and 490 bp upstream of the gene trf2 exists another P{lacW} insertion which is responsible of the lethal mutation PL28. The mutations PL26 and PL28 do not show complementation with the wisertsl mutation as regards the lethal phenotype at 29°C. However, while the transgene UAS-wiser saves the lethal phenotypes of wisertsl and PL26 it does not save the lethal phenotype of the mutation PL28. The present data study revealed that: 1) The wiser gene interacts with the dpp gene. Ectoping expression of the UAS wiserCDS construct under the control of apGAL4 driver, reduced the dpp expression (revealed by dpp-lacZ) in the notum territory of the wing imaginal disc. 2) In the homozygous wisertsl individuals the expression of dpp, dad, salm and omb genes (revealed by the corresponding -lacZ strains) is reduced in the wing imaginal disc. The above genes are implicated in the development of the anterior-posterior (A/P) axis of the wing imaginal disc. 3) The wiser gene interacts with the Notch (N) gene. N wisertsl/wisertsl females have stronger notching phenotype. 4) The induction of mitotic clones revealed that the mutation PL28 either concerns an enhancer of the wiser gene or the gene trf2. At the late case the gene trf2 must affect the development of the wings as well.

Rupture of the anterior cruciate ligament (ACL) increases anterior-posterior (AP) laxity. The treatment aims to reduce or teach the patient to control this instability. Altered kinematics due to absent ligament function may result in knee arthrosis. This study evaluated the clinical and functional results of reconstructive surgery. Roentgen stereophotogrammetry (RSA) was used to analyse the stabilising effect of knee braces, reconstructive surgery and the kinematics of the knee with and without weight-bearing. The stability of the knees were assessed in 86 patients with ACL injuries before and/or after reconstructive surgery with the RSA technique and with the KT-1000 arthrometer The KT- 1000 (89 N) recorded smaller side to side differences than the RSA set-up without any correlation between the methods. The effect of three different braces on the AP and rotatory laxity was studied on patients with ACL injuries. The ECKO and the modified Lenox Hill reduced the instability with about one third. The SKB had no significant effect. None of the braces decreased the internal rotatory laxity but the Lenox Hill reduced the external rotatory laxity. Thirty-two patients with old ACL tears were treated with surgical reconstruction using the over the top technique (OTT) with or without augmentation. A small reduction in AP laxity was observed at the 6 month follow-up, The AP laxity was almost the same two years after as before surgery. No correlation was observed between the stability and knee function. Fifty-four patients with old unilateral anterior cruciate ligament injuries were randomised either to the over the top (OTT) or the isometric femoral tunnel position (ISO) at ACL reconstructive surgery. Seven of 24 (ISO) and 9 of 25 (OTT) had "normal" laxity two years after surgery. The patients operated with the ISO technique did not have better subjective knee function, muscle strength, functional performance or knee stability than patients operated with the OTT technique. The knee kinematics in patients with chronic unilateral ACL ruptures were examined during active extension in the supine position (13 patients) and during extension and weight-bearing (13 patients). The tibia displaced at an average 1.9 mm more anteriorly and 0.8 mm distally in the injured than in the intact knees during active extension. During extension and weightbearing the tibia was about 2 mm more posteriorly positioned than in the intact knee. The ACL rupture did not affect tibial rotations. Conclusions: The RSA recorded larger side to side differences in ACL injured and reconstructed patients than the KT-1000 arthrometer. Some knee braces are able to reduce AP laxity in ACL injured knees. No correlation was observed after surgery between knee laxity and functional scoring or tests. ACL reconstructions with isometric graft position on the femoral side did not offer any advantages compared to the over the top placement. Altered knee kinematics in the ACL injured knees were observed during knee extension with and without weight-bearing. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 6 uppsatser</p> / digitalisering@umu

O ácido retinóico (AR) é sintetizado a partir de oxidações sucessivas do retinol. A última etapa de oxidação é catalisada pelas enzimas RALDHs. O estabelecimento da polaridade ântero-posterior (AP) do coração é crítico para a demarcação das regiões de efluxo (ventrículos) e de influxo (átrios). Nosso grupo propõe que uma onda caudo-rostral (CR) de RALDH2 seja o mecanismo responsável por esta padronização em vertebrados. Para testar o papel da sinalização pelo AR na padronização AP do peixe zebra, manipulamos sua via com o inibidor das enzimas RALDHs, DEAB, com AR e com um inibidor da enzima CYP26 (IC), que cataboliza o AR. Os tratamentos com DEAB durante o período da onda de RALDH2 produziram átrios reduzidos, enquanto que os tratados com AR e com IC apresentam o domínio atrial expandido. Animais tratados com DEAB e AR em um estágio posterior a onda não mostraram diferença significativa ao controle. Estes dados sugerem uma forte correlação entre o evento da onda e a padronização das câmaras cardíacas, semelhante ao que ocorre nos demais amniotos. / The retinoic acid (RA) is synthetized by successive oxidations of retinol. The last oxidation step is catalyzed by the RALDHs enzymes. The establishment of the anteroposterior (AP) polarity is critical for the demarcation of outflow (ventricle) and inflow (atrium) regions. Our group proposes that a caudorostral (CR) wave of RALDH2 is the mechanism responsible for this patterning in vertebrates. In order to test the role of the RA signaling in zebrafish AP patterning, we manipulated its pathway with a RALDH enzymatic inhibitor, DEAB, with RA and with a CYP26 (IC) enzymatic inhibitor, that catabolises the RA. The DEAB treatments during the manifestation of the RALDH wave produced reduced atriums; meanwhile, the treatments with RA and IC presented an atrium expansion. Animals treated with DEAB and RA during a stage posterior to the wave did not present any significant difference. These data suggest a strong correlation between the wave event and the cardiac chamber patterning, similar to the mechanism observed in others amniotes.

Die Physik der Lauterzeugung (Phonation) wurde mit Hilfe der Theorie der Nichtlinearen Dynamik untersucht. Digitale Hochgeschwindigkeitsaufnamen von Schwingungen in menschlichen und nichtmenschlichen Kehlkoepfen, digitale Bildanalyse, Signalanalyse und Modenanalyse wurden zur quantitativen Beschreibung nichtlinearer Phaenomene eingesetzt. Es wurden nichtlineare Phaenomene bei stimmkranker (pathologischer) menschlicher Lauterzeugung untersucht, wie auch in stimmgesunden Singstimmen und in Kehlkoepfen von nichtmenschlichen Saeugetieren mit Stimmlippen-Membranen. Durch Bifurkationsanalyse eines einfachen mathematischen Modells fuer Stimmlippen mit Membranen konnten beobachtete Lautmuster nichtmenschlicher Saeugetiere qualitativ "nichtlinear gefittet" werden. Die Schwerpunkte dieser Arbeit waren: 1. die Klassifikation von Lautmustern in zeitgenoessischer Vokalmusik, um Erzeugungsmechanismen fuer komplexe Stimmklaenge zu erklaeren, die im kuenstlerischen Kontext vorkommen. Im besonderen war die Rolle der Quelle-Trakt-Kopplung von Interesse; 2. Instabilitaeten in Stimmpatienten, die durch Asymmetrien in einzelnen Stimmlippen wie auch zwischen den Stimmlippen verursacht wurden; 3. dynamische Effekte von duennen, leichten und schwingenden Stimmlippen-Membranen, vertikalen Fortsaetzen der Stimmlippen bei Saeugetieren. Stimmlippen-Membrane finden sich in Kehlkoepfen von Fledermaeusen und Primaten, wo sie einerseits zur Ultraschallerzeugung verwendet werden und andererseits fuer eine grosse Lautvielfalt sorgen. Ein Stimmlippen-Membran-Modell wurde entwickelt, um dieses diverse Lautrepertoire zu reproduzieren. Dieses Modell zeigte zwei Stimmregister. Ueber die Geometry der Stimmlippen-Membrane konnte der subglottale Einsatzdruck minimiert werden und der Druckbereich fuer Phonationen vergroessert werden. Numerische Simulationen demonstrierten, dass das phaenomenologische Stimm-Membran-Modell das Lautrepertoire von Fledermaeusen und Primaten qualitativ reproduzieren konnte. / In this thesis, the physics of phonation was discussed using the theory of nonlinear dynamics. Digital high speed recordings of human and nonhuman laryneal oscillations, image processing, signal analysis, and modal analysis have been used to quantitatively describe nonlinear phenomena in pathological human phonation, healthy voices in singing, and nonhuman mammalian larynges with vocal membranes. Bifurcation analysis of a simple mathematical model for vocal folds with vocal membranes allowed a qualitative ''nonlinear fit'' of observed vocalization patterns in nonhuman mammals. The main focus of the present work was on: 1. the classification of vocalizations of contemporary vocal music to provide insight to production mechanisms of complex sonorities in artistic contexts, especially to nonlinear source-tract coupling; 2. pathological voice instabilities induced by asymmetries within single vocal folds and between vocal folds; 3. the dynamic effects of thin, lightweight, and vibrating vocal membranes as upward extensions of vocal folds in nonhuman mammals. In nonhuman mammals, vocal membranes are one widespread morphological variation of vocal folds. In bats they are responsible to produce ultrasonic echolocation calls. In nonhuman primates they facilitate the production of highly diverse vocalizations. A vocal membrane model was developed to understand the production of these complex calls. Two voice registers were found in the vocal membrane model. The vocal membrane geometry could minimize phonation onset pressure and enlarge the phonatory pressure range of the model. Numerical simulations of the model revealed instabilities that qualitatively resembled observed vocalization patterns in bats and primates.