Mitochondria are required for pro-ageing features of the senescent phenotype

Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro‐inflammatory and pro‐oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent‐associated changes are dependent on mitochondria, particularly the pro‐inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC‐1β‐dependent mitochondrial biogenesis, contributing to a ROS‐mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC‐1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues

Experimentelle Untersuchungen der Strömung an einem Rotorblattmodell

In dieser Arbeit wurde die Entwicklung der Strömungsablösung an einem Rotorblattmodell mit freier Blattspitze mit linearer Verwindung von 3,3°/m experimentell untersucht. Sowohl die Betrachtung des statischen Strömungsabrisses in einer Anstellwinkelreihe von -5° bis 18° Wurzelanstellwinkel als auch der dynamische Strömungsabriss bei verschiedenen zyklischen Anstellwinkelschwingungen von 11°±6° mit drei unterschiedlichen Frequenzen wurden im Rahmen der Ausarbeitung behandelt. Insbesondere die spannweitigen Differenzen sowie der Einfluss der Nickfrequenz auf die Entwicklung der Strömungsablösung waren dabei von Interesse. Die Betrachtung erfolgte anhand von Stereo-PIV-Messungen an drei Profilschnitten des Rotorblattmodells konstanter Spannweite und Druckmessungen auf der Modelloberfläche

Spanwise Differences in Static and Dynamic Stall on a Pitching Rotor Blade Tip Model

An experimental investigation of static and dynamic stall on a rotor blade tip model with an aspect ratio of 6.2 at a chord Reynolcls number of900 ,000 and a Mach numbcr of0.16 is presented. The spatiotemporal behavior of the flow separation was analyzed using unstcady surface pressurc measurements ancl high-speecl particle image velocimetry. The maximum effective angle of attack prior to stall is shiftecl to approximately two-thirds of the span outboard because of an increasing geometric angle of attack of the model towarcl the tip. Different stages of flow separation for static angles of attack were identified, inclucling the occurrence of two stall cells. Du ring dynamic stall, the leacling edge vortcx formation starts near the spanwise position of thc static stall onset. The subsequent spanwise evolution of the vortex formation results in two vorticcs for deep stall conclitions, covering the samc spanwisc arcas as thc two static stall cclls

Spanwise Differences in Static and Dynamic Stall on a Pitching Rotor Blade Tip Model

An experimental investigation of static and dynamic stall on a rotor blade tip model with a parabolic tip geometry and aspect ratio 6.2 at a chord Reynolds number of 900,000 and a Mach number of 0.16 is presented. The resulting flow is analyzed based on unsteady surface pressure measurements and quantitative flow visualizations by high-speed particle image velocimetry. The flow separation is found to be delayed near the parabolic blade tip for static angles of attack as well as for sinusoidal angle of attack motions. The maximum effective angle of attack prior to stall is shifted to approximately two-thirds of the span outboard from the root because of a positive twist of the model with an increasing geometric angle of attack towards the tip. The stall onset is observed near the section with the maximum effective angle of attack, with a subsequent spanwise spreading of the flow separation. Different stages of flow separation for static angles of attack are identified one of them with the occurrence of two stall cells. During dynamic stall, the leading edge vortex formation starts near the maximum effective angle of attack and the pitching moment peak resulting from the passage of the dynamic stall vortex is higher at this section. Further inboard the maximum aerodynamic loads are of comparable magnitude whereas the outboard section shows reduced peaks due to the influence of the wing tip vortex

Unequal V-H gene rearrangement frequency within the large V(H)7183 gene family is not due to recombination signal sequence variation, and mapping of the genes shows a bias of rearrangement based on chromosomal location

International audienceMuch of the nonrandom usage of V, D, and J genes in the Ab repertoire is due to different frequencies with which gene segments undergo V(D)J rearrangement. The recombination signal sequences flanking each segment are seldom identical with consensus sequences, and this natural variation in recombination signal sequence (RSS) accounts for some differences in rearrangement frequencies in vivo. Here, we have sequenced the RSS of 19 individual VH 7183 genes, revealing that the majority have one of two closely related RSS. One group has a consensus heptamer, and the other has a nonconsensus heptamer. In vitro recombination substrate studies show that the RSS with the nonconsensus heptamer, which include the frequently rearranging 81X, rearrange less well than the RSS with the consensus heptamer. Although 81X differs from the other 7183-I genes at three positions in the spacer, this does not significantly increase its recombination potency in vitro. The rearrangement frequency of all members of the family was determined in mMT mice, and there was no correlation between the in vitro recombination potential and VH gene rearrangement frequency in vivo. Furthermore, genes with identical RSS rearrange at different frequencies in vivo. This demonstrates that other factors can override differences in RSS potency in vivo. We have also determined the gene order of all VH 7183 genes in a bacterial artificial chromosome contig and show that most of the frequently rearranging genes are in the 3* half of the region. This suggests that chromosomal location plays an important role in nonrandom rearrangement of the VH 7183 genes

Genome-wide survey for microdeletions or -duplications in 155 patients with lower urinary tract obstructions (LUTO)

Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw intensity data were collected for CNVs detected in LUTO patients and 4.392 healthy controls using CNVPartition, QuantiSNP and PennCNV. Overlapping CNVs between patients and controls were discarded. Additional filtering implicated CNV frequency in the database of genomic variants, gene content and final visual inspection detecting 37 ultra-rare CNVs. After, prioritization qPCR analysis confirmed 3 microduplications, all detected in PUV patients. One microduplication (5q23.2) occurred de novo in the two remaining microduplications found on chromosome 1p36.21 and 10q23.31. Parental DNA was not available for segregation analysis. All three duplications comprised 11 coding genes: four human specific lncRNA and one microRNA. Three coding genes (FBLIM1, SLC16A12, SNCAIP) and the microRNA MIR107 have previously been shown to be expressed in the developing urinary tract of mouse embryos. We propose that duplications, rare or de novo, contribute to PUV formation, a male-limited phenotype