Oncometabolites: tailoring our genes

Increased glucose metabolism in cancer cells is a phenomenon that has been known for over 90 years, allowing maximal cell growth through faster ATP production and redistribution of carbons towards nucleotide, protein and fatty acid synthesis. Recently, metabolites that can promote tumorigeneis by altering the epigenome have been identified. These ‘oncometabolites’ include the tricarboxylic acid cycle metabolites succinate and fumarate, whose levels are elevated in rare tumours with succinate dehydrogenase and fumarate hydratase mutations, respectively. 2-Hydroxyglutarate is another oncometabolite; it is produced de novo as a result of the mutation of isocitrate dehydrogenase, and is commonly found in gliomas and acute myeloid leukaemia. Interestingly, the structural similarity of these oncometabolites to their precursor metabolite, α-ketoglutarate, explains the tumorigenic potential of these metabolites, by competitive inhibition of a superfamily of enzymes called the α-ketoglutarate-dependent dioxygenases. These enzymes utilize α-ketoglutarate as a cosubstrate, and are involved in fatty acid metabolism, oxygen sensing, collagen biosynthesis, and modulation of the epigenome. They include enzymes that are involved in regulating gene expression via DNA and histone tail demethylation. In this review, we will focus on the link between metabolism and epigenetics, and how we may target oncometabolite-induced tumorigenesis in the future

Comparison of acoustic and strain gauge techniques for crack closure measurements

A quantitative study on the systems performances of the COD gauge and the acoustic transmission techniques to elastic deformation of part-through crack and compact tension specimens has been conducted. It is shown that the two instruments measure two completely different quantities: The COD gauge yields information on the length change of the specimen whereas the acoustic technique is sensitive directly to the amount of contract area between two surfaces, interfering with the acoustic signal. In another series of experiments, compression tests on parts with specifically prepared surfaces were performed so that the surface contact area could be correlated with the transmitted acoustic signal, as well as the acoustic with the COD gauge signal. A linear relation between contact area and COD gauge signal was obtained until full contact had been established

On the interaction of ultrasound with cracks: Applications to fatigue crack growth

Partial contact of two rough fatigue crack surfaces leads to transmission and diffraction of an acoustic signal at those contacts. Recent experimental and theoretical efforts to understand and quantify such contact in greater detail are discussed. The objective is to develop an understanding of the closure phenomenon and its application to the interpretation of fatigue data, in particular the R-ratio, spike overload/underload and threshold effects on crack propagation

Membrane Stored Curvature Elastic Stress Modulates Recruitment of Maintenance Proteins PspA and Vipp1

Phage shock protein A (PspA), which is responsible for maintaining inner membrane integrity under stress in enterobacteria, and vesicle-inducting protein in plastids 1 (Vipp1), which functions for membrane maintenance and thylakoid biogenesis in cyanobacteria and plants, are similar peripheral membrane-binding proteins. Their homologous N-terminal amphipathic helices are required for membrane binding; however, the membrane features recognized and required for expressing their functionalities have remained largely uncharacterized. Rigorously controlled, in vitro methodologies with lipid vesicles and purified proteins were used in this study and provided the first biochemical and biophysical characterizations of membrane binding by PspA and Vipp1. Both proteins are found to sense stored curvature elastic (SCE) stress and anionic lipids within the membrane. PspA has an enhanced sensitivity for SCE stress and a higher affinity for the membrane than Vipp1. These variations in binding may be crucial for some of the proteins’ differing roles in vivo. Assays probing the transcriptional regulatory function of PspA in the presence of vesicles showed that a relief of transcription inhibition occurs in an SCE stress-specific manner. This in vitro recapitulation of membrane stress-dependent transcription control suggests that the Psp response may be mounted in vivo when a cell’s inner membrane experiences increased SCE stress

Tensile Overload and Stress Intensity Shielding Investigations by Ultrasound

Growth of a fatigue crack is modified according to the development of contacts between the crack faces [1,2] creating shielding, thus canceling a portion of the crack driving force. These contacts develop through a number of mechanisms, including plastic deformation, sliding of the faces with respect to each other and the collection of debris such as oxide particles [3]. Compressive stresses are created on either side of the partially contacting crack faces resulting in opening loads that must be overcome in order to apply a driving force at the crack tip. In this way, the crack tip is shielded from a portion of the applied load, thus creating the need for modification [1] of the applied stress intensity range from ΔK = KImax − KImin to ΔKeff = KImax − KIsh. Determination of the contact size and density in the region of closure from ultrasonic transmission and diffraction experiments [4] has allowed estimation of the magnitude of Kish on a crack grown under constant ΔK conditions. The calculation has since [5] been extended to fatigue cracks grown with a tensile overload block. The calculation was also successful in predicting the growth rate of the crack after reinitiation had occurred. This paper reports the further extension to the effects of a variable ΔK on fatigue crack growth. In addition, this paper presents preliminary results on detection of the tightly closed crack extension present during the growth retardation period after application of a tensile overload as well as an observation of the crack surface during reinitiation of growth that presents some interesting questions

Surface Wave Techniques for Predicting the Remaining Life of Fatigue Damaged Metals

In our continuing efforts to investigate methods to characterize the state of fatigue nondestructively and to apply these observations to lifetime predictions, we have initiated acoustic surface wave studies using Al 2024-T351. A smooth bar specimen was designed which can be tested in tension-compression fatigue. Acoustic wedge transducers were mounted on the specimen to sample fatigue induced changes within the gauge section. Data on acoustic harmonic generation were taken as a function of applied external load at any point of the sample\u27s fatigue life. An optical microscope was attached to the load frame to monitor microcrack formation in the gauge section. Significant changes of the second harmonic have been observed as a function of stress and fatigue. First results indicate a decrease of the second harmonic as a function of stress. At about 50% of the fatigue life microcracks initiated at surface intermetallics and a substantial increase of the second harmonic amplitude in the vicinity of zero external applied load was observed

Crack Length Determination by Ultrasonic Methods

Accurate calculation of the stress intensity factor on a given component under load relies on an accurate size determination of the flaws present in the component. The challenge to the NDE community has been development of reliable techniques to provide that accurate size determination. Many research groups have investigated this problem using ultrasonic methods with summaries of their techniques and results provided by various authors [1–3]. In general, the techniques developed fall into three general categories; (1) determination of crack length from signal amplitude measurements, (2) determination of crack length from time-of-flight measurements, and (3) determination of crack length using diffracted waves. Sketches of representative techniques in each category are shown in Figure 1

Isomorphic classical molecular dynamics model for an excess electron in a supercritical fluid

Ring polymer molecular dynamics (RPMD) is used to directly simulate the dynamics of an excess electron in a supercritical fluid over a broad range of densities. The accuracy of the RPMD model is tested against numerically exact path integral statistics through the use of analytical continuation techniques. At low fluid densities, the RPMD model substantially underestimates the contribution of delocalized states to the dynamics of the excess electron. However, with increasing solvent density, the RPMD model improves, nearly satisfying analytical continuation constraints at densities approaching those of typical liquids. In the high density regime, quantum dispersion substantially decreases the self-diffusion of the solvated electron. In this regime where the dynamics of the electron is strongly coupled to the dynamics of the atoms in the fluid, trajectories that can reveal diffusive motion of the electron are long in comparison to $\beta\hbar$.Comment: 24 pages, 4 figure