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Additional file 12: Figure S10. Regulation of genes of TGF-beta signaling pathway during senescence induction in MRC-5 strains. Genes of the “TGF-beta signaling” pathway which are significantly up- (green) and down- (red) regulated (log2 fold change >1) during irradiation induced senescence (120 h after 20 Gy irradiation) in MRC-5 fibroblast strains. Blue color signifies genes which are commonly down-regulated during both, irradiation induced and replicative senescence.

Growth curve and percentage of SA β-Gal positive cells in WI-38 fibroblasts +/− rotenone treatment. (A) Growth curve of WI-38 fibroblasts supplemented with 0.1 μM rotenone (green), compared to DMSO-treated controls (black). (B) Percentage of SA β-Gal positive cells in 0.1 μM rotenone-treated WI-38 fibroblasts (green), compared to DMSO-treated controls (black). The bars indicate the mean ± S.D. n = 3. (DOCX 26 kb)

Up-regulated pathways in human foreskin fibroblasts on low dose rotenone treatment. Pathways significantly (p

Down-regulated pathways in human foreskin fibroblasts on low dose rotenone treatment. Pathways significantly (p

The most significant commonly up- and down-regulated genes in primary human fibroblast strains independent of their cell origin. The common genes most significantly differentially regulated at transcript levels in low dose rotenone treated MRC-5 (PDs 42, 48) and HFFs (PDs 26, 30, 34) compared to untreated controls. These genes were selected according to the statistical stringency criteria of p

Common significantly up- and down-regulated pathways in primary human fibroblast strains independent of their cell origin. Pathways significantly (p

Apoptosis induction by higher concentrations of rotenone treatment in MRC-5 fibroblasts. Numbers of days MRC-5 fibroblasts were maintained in culture before induction of apoptosis (as detected by phosphorylation of p38) in response to different concentrations of rotenone. (DOCX 15 kb)

D-Glucosamine (GlcN) is a freely available and commonly used dietary supplement potentially promoting cartilage health in humans, which also acts as an inhibitor of glycolysis. Here we show that GlcN, independent of the hexosamine pathway, extends Caenorhabditis elegans life span by impairing glucose metabolism that activates AMP-activated protein kinase (AMPK/AAK-2) and increases mitochondrial biogenesis. Consistent with the concept of mitohormesis, GlcN promotes increased formation of mitochondrial reactive oxygen species (ROS) culminating in increased expression of the nematodal amino acid-transporter 1 (aat-1) gene. Ameliorating mitochondrial ROS formation or impairment of aat-1-expression abolishes GlcN-mediated life span extension in an NRF2/SKN-1-dependent fashion. Unlike other calorie restriction mimetics, such as 2-deoxyglucose, GlcN extends life span of ageing C57BL/6 mice, which show an induction of mitochondrial biogenesis, lowered blood glucose levels, enhanced expression of several murine amino-acid transporters, as well as increased amino-acid catabolism. Taken together, we provide evidence that GlcN extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet., Nature Communications, 5, ISSN:2041-1723

Background: Carnitine has attracted scientific interest due to several health-related effects, like protection against neurodegeneration, mitochondrial decay, and oxidative stress as well as improvement of glucose tolerance and insulin sensitivity. The mechanisms underlying most of the health-related effects of carnitine are largely unknown.Methods: To gain insight into mechanisms through which carnitine exerts its beneficial metabolic effects, we fed piglets either a control or a carnitine supplemented diet, and analysed the transcriptome in the liver.Results: Transcript profiling revealed 563 genes to be differentially expressed in liver by carnitine supplementation. Clustering analysis of the identified genes revealed that most of the top-ranked annotation term clusters were dealing with metabolic processes. Representative genes of these clusters which were significantly up-regulated by carnitine were involved in cellular fatty acid uptake, fatty acid activation, fatty acid β-oxidation, glucose uptake, and glycolysis. In contrast, genes involved in gluconeogenesis were down-regulated by carnitine. Moreover, clustering analysis identified genes involved in the insulin signaling cascade to be significantly associated with carnitine supplementation. Furthermore, clustering analysis revealed that biological processes dealing with posttranscriptional RNA processing were significantly associated with carnitine supplementation.Conclusion: The data suggest that carnitine supplementation has beneficial effects on lipid and glucose homeostasis by inducing genes involved in fatty acid catabolism and glycolysis and repressing genes involved in gluconeogenesis.

Die Ausnutzung von Parallelität ist schon immer eine für den Benutzer unsichtbare, aber große Quelle zur Verbesserung der Prozessorleistung gewesen. Da aber die Menge an implizit nutzbarer Parallelität auf Befehlsebene begrenzt ist und gleichzeitig immer größere Rechenleistungen benötigt werden, erleben wir gegenwärtig eine Renaissance expliziter paralleler Techniken sowohl auf Hardware- als auch auf Softwareebene. Aufgrund ihrer Komplexität sind parallele Systeme mit traditionellen Programmiersprachen schwer zu handhaben. Deshalb werden zunehmend abstraktere Programmiersprachen betrachtet. Eden ist eine solche Sprache, die Programmkonstrukte zur gleichzeitigen Auswertung von Ausdrücken in die funktionale Programmiersprache Haskell integriert. Eden ist ein Kompromiss zwischen vollständiger und fehlender Parallelitätskontrolle durch den Programmierer: Es wird genügend Kontrolle zur Erreichung guter Beschleunigungen bereitgestellt, gleichzeitig wird aber auch ein abstrakter Programmierstil durch die Übernahme weniger wichtiger Vorgänge durch das Laufzeitsystem gewahrt. In dieser Arbeit stellen wir Eden drei Sprachkonzepte zur Seite, um eine noch weitergehende Abstraktion zu erreichen: 1) Unter Meta-Programmierung versteht man die Definition von Programmen, die andere Programme erzeugen oder verändern. Diese Technik wird benutzt, um in Haskell programmierte statische Präprozessorphasen zur Verbesserung von Eden-Programmen zu konstruieren. Dadurch wird die Portabilität des Eden-Compilers verbessert, da diese Phasen nun nicht mehr in den zugrundeliegenden Haskell-Compiler integriert werden müssen. 2) Generische Programmierung erweitert parametrische zur strukturellen Polymorphie und ermöglicht daher die Definition von Funktionen, die mit beliebigen Argumentdatenstrukturen arbeiten. Wir beschreiben einen reduzierten strukturorientierten Ansatz zur generischen Programmierung, der für den Einsatz in Eden konzipiert wurde. Mit diesem Ansatz definieren wir allgemeine parallele Verarbeitungsschemata. 3) Möglichkeiten zur Auswertungskontrolle müssen vorhanden sein, wenn in einer funktionalen Sprache Bedarfssteuerung auf Parallelität trifft. Deren Ziele sind gegensätzlich: Auf der einen Seite werden Auswertungen zeitlich nach hinten geschoben, während auf der anderen Seite frühe Auswertung die Gleichzeitigkeit und damit die Parallelität fördert. Wir zeigen Wege auf, um die Auswertung zu Gunsten der Parallelität zu steuern. In funktionalen Sprachen wird der Auswertungsverlauf durch Datenabhängigkeiten sowie durch Kontrollkonstrukte bestimmt. Analog kann man bei parallelen funktionalen Programmen zwischen datenorientierten und kontrollorientierten unterscheiden. Entsprechend zeigen wir zunächst generische Methoden zur Partitionierung von Datenstrukturen sowie generische Versionen der parallelen map-Funktion. Dann stellen wir kontrollparallele Methoden vor, mit denen die in Eden oft vorkommenden Datenströme behandelt werden können; zusätzlich zeigen wir parallele Schemata zur effizienten Verarbeitung irregulärer Strukturen und langer Kommunikationswege. Letztendlich vereinigen wir die gezeigten Techniken in einer Programmentwicklungsmethodik für Eden., Parallelism has always been a main, yet hidden, source of processor power. As a result of the limited amount of implicitly exploitable small-scale parallelism (for example on the instruction-level) and ever-growing needs for more computational power, parallel techniques break their way from a minor matter to a major feature in both hardware and software. Due to their complexity, such parallel systems are getting increasingly difficult to control with conventional programming languages. Therefore, more abstract high-level approaches move into focus. Eden is a representative of these approaches which integrates constructs for remote evaluation into the standard functional language Haskell. It strikes a balance between full and no parallelism control and delivers good speedups while providing a high-level style of programming. In this thesis we equip Eden with three language features to raise the abstraction level even more: 1) Meta-programming, which means that programs manipulate other programs, will be used to define static preprocessing steps coded in Haskell for enhancing Eden programs. This supports portability of the Eden compiler, as some transformations can be pulled out of the foreign Haskell implementation. 2) Generic programming raises parametric to structural polymorphism and allows to write functions which are valid for all data structures. We will present a reduced, structure-oriented approach to generic programming tailored for Eden's needs. Using this approach, very general parallel schemes are defined. 3) Demand control is a basic requirement if a lazy functional language is faced with parallelism. The contradictory aims of postponing evaluations and simultaneity of evaluations enforces demand control in favour of parallelism. We present a set of means to do that. In functional programs, evaluation progress is determined by a mix of control structures and data dependencies. Accordingly, parallel functional programs can roughly be classified into data-oriented and control-oriented ones. Firstly, we will present generic methods for partitioning data structures as well as generic versions of the parallel map function. Secondly, we will show methods to manage the omnipresent streams as well as parallel schemes for dealing with irregular task sizes and long communication distances. To conclude, we will summarise all methods shown in a program developing guide for Eden.