Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Models of muscle relevant to the study of the active state have been reviewed. Some of the implications of the existing force-velocity equations have been examined preliminary to the presentation of a new method for determining the active state curve and the formulation of a general active state equation. It has been demonstrated, both theoretically and experimentally, that the intensity of the active state at any instant can be determined from a set of isometric myograms recorded rapidly but with different external compliances. The length of the muscle must be kept constant while these myograms are being recorded. From such sets of isometric myograms taken at 25uC and at different resting tensions, regression lines of developed tension against compliance were calculated at 10 msec intervals after the stimulus. The tension, independent of external compliance, was calculated from such regression lines. The extension of the series elastic component at any instant was determined according to the method of MacPherson (1953) while the compliance of the series elastic component was determined by dividing this extension by P t' the intensity of the active state at that instant. Substituting this compliance in the corresponding regression equation, a general equation Pt - Ptpt - a Lt = 0 (where P t is the intensity of the active state, pt is the isometric tension at zero external compliance, a is the regression coefficient and Lt is the extension of the series elastic component at time t after the stimulus) was developed. Pt was obtained by solving this equation. The active state curves determined according to this method rise much more gradually than those previously proposed. / 2031-01-01

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Abstract not available

Amendments inserted at back. "May 2002" Includes bibliographical references (leaves 237-290) Experiments described in this thesis address the potential role of inducible nitric oxide synthase (iNOS) in hibernating myocardium. Specifically it was sought to establish a cellular model of hibernating myocardium and investigate the expression, regulation and effects of iNOS in this model. Experiments were performed using primary cultures of neonatal rat ventricular myocytes.

Amendments inserted at back. / "May 2002" / Includes bibliographical references (leaves 237-290) / xvii, 290 leaves : ill., plates (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Experiments described in this thesis address the potential role of inducible nitric oxide synthase (iNOS) in hibernating myocardium. Specifically it was sought to establish a cellular model of hibernating myocardium and investigate the expression, regulation and effects of iNOS in this model. Experiments were performed using primary cultures of neonatal rat ventricular myocytes. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2002

LKB1 est un gène suppresseur de tumeur qui code une kinase « maitre » dont l’activité contrôle la polarité et la prolifération cellulaire en les coordonnant avec l’état métabolique de la cellule. Ce travail a abouti à l’identification d’une nouvelle isoforme LKB1 appelée ∆N-LKB1 qui est générée par transcription alternative et initiation interne de la traduction de l'ARNm LKB1. La protéine ∆N-LKB1 est délétée de sa partie N-terminale incluant une partie de son domaine kinase. Bien que la protéine N-LKB1 soit catalytiquement inactive, elle potentialise l'effet activateur de la protéine LKB1 sur sa cible principale l’APMK, senseur énergétique de la cellule, via une interaction directe avec le domaine d'auto-inhibition de l’AMPK. En revanche, ∆N-LKB1 interfère négativement avec la capacité de LKB1 à induire la polarité cellulaire. Enfin, en utilisant des approches in vitro et in vivo, nous avons montré que N-LKB1 possède une propriété oncogénique intrinsèque. N-LKB1 est exprimée seule dans la lignée NCI-H460 issue du cancer du poumon. L’inhibition de l’expression de N-LKB1 dans les cellules NCI-H460 induit une diminution de la survie de ces cellules et inhibe leur pouvoir oncogénique quand elles sont greffées dans la souris nude. Nous avons donc identifié une nouvelle isoforme LKB1 qui stimule l’adaptation métabolique LKB1-dépendante, mais qui inhibe la polarité cellulaire contrôlée par LKB1. Le suppresseur de tumeur LKB1 ainsi que l’oncogène N-LKB1 sont codé par le même gène, ce qui peut expliquer certains des effets paradoxaux de LKB1 durant la tumorigenèse. / The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism, cell growth and cell polarity. We now report the identification of a novel isoform of LKB1 named N-LKB1 that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The N-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although N-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory auto-inhibitory domain of AMPK. Contrasting, N-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showedthat N-LKB1 has an intrinsic oncogenic property. N-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of N-LKB1 decreased survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both, the LKB1 tumor suppressor and the oncogene, N-LKB1, are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.