Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand

Mitochondrial dysfunction has been implicated for a wide range of human diseases. One of the major biosynthetic processes in human mitochondria is the biogenesis of Iron-Sulfur (Fe-S) clusters which primarily involves in electron transfer reactions during oxidative phosphorylation (OXPHOS). Defects in Fe-S cluster biogenesis process leads to mitochondrial dysfunction and that eventually results in various human mitochondrial disorders. One of the major mitochondrial disorders associated with Fe-S cluster biogenesis impairment is exercise intolerance disorder ISCU myopathy, which is a result of loss of function of Fe-S cluster scaffold protein ISCU. Our biochemical results using yeast model system and HeLa cells lines suggests that ISCU Myopathy results in defective Fe-S cluster biogenesis in mitochondrial compartment. As a result, electron transport chain (ETC) complexes demonstrate significant reduction in their redox properties, leading to loss of cellular respiration. Furthermore, in ISCU Myopathy, mitochondria display enhancement in iron levels and reactive oxygen species, thereby causing oxidative stress leading to impairment in the mitochondrial functions. On the other hand, in mammalian mitochondria, the initial step of Fe-S cluster assembly process is assisted by NFS1-ISD11 complex, which delivers sulfur to the scaffold protein ISCU during Fe-S cluster synthesis. In humans, loss of ISD11 function leads to development of respiratory distress disorder, Combined Oxidative Phosphorylation Deficiency 19 (COXPD19). Our study maps the important ISD11 amino acid residues critical for in vivo Fe-S cluster biogenesis. Importantly, mutation of these critical ISD11 residues to alanine leads to its compromised interaction with NFS1, which results in reduced stability and enhanced aggregation of NFS1 in the mitochondria. Moreover, our findings highlight that, COXPD19 associated R68L ISD11 mutant displays reduced affinity to form a stable sub-complex with NFS1, thereby fails to prevent NFS1 aggregation, resulting impairment of Fe-S cluster biogenesis. The prime affected machinery is the ETC complex which demonstrates compromised redox properties, causing diminished mitochondrial respiration in COXPD19 patients. In summary, our findings provide compelling evidence that respiration defect due to impaired biogenesis of Fe-S clusters in ISCU myopathy patients, leads to manifestation of complex clinical symptoms. Additionally, our study highlights the role of ISD11 protein in Fe-S cluster biogenesis and maps the surface residues of ISD11 protein that are involved in interaction with sulfur donor protein NFS1. Moreover, we have demonstrated the molecular basis of disease progression of COXPD19 as a result of R68L ISD11 mutation.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinikum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinikum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinkum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinikum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinikum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinkum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinkum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.

Das Klinoskop ist die Firmenzeitschrift des Klinikums Chemnitz für Mitarbeiter, Patienten, Angehörige und für unsere Partner. Es erscheint in vier bis fünf Ausgaben pro Jahr in einem Umfang von 40 bis 92 Seiten im Vollfarbdruck. Unsere Firmenzeitschrift wurde seit 2006 von einer qualitativen Mitarbeiterinformation kontinuierlich zu einem relevanten Informationsmedium für unsere Partner wie niedergelassene Ärzte weiterentwickelt. Parallel soll das Klinoskop eine Publikation sein, mit der Patienten und Angehörige einen informativen Zugang zu Ihrem Klinikum Chemnitz erhalten. Damit möchten wir auch unseren Anspruch einer offenen Kommunikation unterlegen. / The Klinoskop is the corporate magazine of the Klinikum Chemnitz for our staff, patients and their family members as well as for our cooperating partners. It is published in full colour, with four or five issues per year, and each issue contains between 40 and 92 pages. Since 2006, our corporate magazine has been continuously refined from a high-quality publication for our staff to the relevant information medium for our partners, in particular physicians in private practice. At the same time, the Klinoskop is intended to be a publication that provides patients and their relatives with more detailed information about their Hospital in Chemnitz. This also helps us to emphasize our intentions of fostering open communication.