Regression of atherosclerosis : the clinical and metabolic response to cholesterol-lowering

A large number of studies have established that raised cholesterol levels increase the probability of the development of atherosclerotic vascular disease, and that reducing serum cholesterol will result in fewer cardiac events in the treated population, both in those with and without evidence of pre-existing coronary disease. More direct evidence that this is due to alteration of the progression of the atheromatous plaques has resulted from angiographic studies demonstrating the halting of progression or even regression of the stenotic lesions. Some workers have found a relationship between the extent of lowering of the serum lipoproteins and the likelihood of regression, although it has not been clear whether this continues to hold true at the lower extremes, nor whether there may be a threshold level which requires to be achieved before regression may take place. The principal purpose of these studies was to investigate the effects of applying very intensive lipid-lowering therapy, including LDL-apheresis, in a group of patients with coronary artery disease and moderately severe hypercholesterolaemia to achieve subnormal lipoprotein levels, and comparing the effects of such treatment with those achieved in another group of subjects treated with drug therapy to the currently recommended therapeutic targets for such patients. The studies involved the measurement of lipids and lipoproteins before and after apheresis and at regular intervals throughout the two-year study period. ApoB metabolism was assessed at baseline and following completion of the treatment period, and the data analysed using a multicompartmental mathematical model. The patients were assessed non-invasively by exercise electrocardiography at regular intervals, and by thallium scintigraphy at baseline and at annual intervals. The principal end-point was the proportion of arterial segments undergoing regression or progression in each group assessed by computer-assisted analysis of coronary angiograms performed at baseline and on completion of the intervention. The results from these studies demonstrated radical differences in lipoprotein concentration and composition during treatment. There was increased catabolism of LDL precursors with diminished flux of apoB which may reflect up-regulation of the LDL-receptor, but a rapid return to pre-treatment lipid levels indicated the effects on lipoprotein metabolism were transient. There was a reduction in the progression of coronary disease in the majority of lesions, with a small number in each group undergoing definite regression. There were significant differences in the changes in exercise tolerance with treatment, and the likely mechanisms for this are discussed. The thallium scans demonstrated no difference between the groups in the number of segments with improved perfusion, but were shown to have some value in the non-invasive assessment of predicting angiographic changes in the proximal segments, particularly in the right coronary artery. The findings are put into the context of the recent publications on cholesterol reduction in coronary disease; implications for clinical management are drawn, and areas of potential future research are highlighted

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

Optical properties of germania and titania at 1064 nm and at 1550 nm

One of the main noise sources in current gravitational wave detectors is the thermal noise of the high-reflectivity coatings on the main interferometer optics.
Coating thermal noise is dominated by the mechanical loss of the high-refractive index material within the coating stacks, Ta2O5 mixed with TiO2. For upgrades to room-temperature detectors, a mixture of GeO2 and TiO2 is an interesting alternative candidate coating material. While the rather low refractive index of GeO2 increases with increasing TiO2 content, a higher TiO2 content results in a lower threshold temperature before heat treatment leads to crystallisation, and potentially to a degradation of optical properties. For future cryogenic detectors, on the other hand, a higher TiO2 content is beneficial as the TiO2 suppresses the low-temperature mechanical loss peak of GeO2. In this paper, we present the optical properties of coatings -- produced by plasma-assisted ion-beam evaporation -- with high TiO2 content at 1550nm, a laser wavelength considered for cryogenic gravitational-wave detectors, as a function of heat-treatment temperature. For comparison, the absorption was also measured of pure GeO2. Furthermore, results at the currently-used wavelength of 1064nm are presented

Titania mixed with silica: a low thermal-noise coating material for gravitational-wave detectors

Coating thermal noise is one of the dominant noise sources in current gravitational wave detectors and ultimately limits their ability to observe weaker or more distant astronomical sources. This Letter presents investigations of TiO2 mixed with SiO2 (TiO2:SiO2) as a coating material. We find that, after heat treatment for 100 h at 850 °C, thermal noise of a highly reflective coating comprising of TiO2:SiO2 and SiO2 reduces to 76% of the current levels in the Advanced LIGO and Advanced Virgo detectors—with potential for reaching 45%, if we assume the mechanical loss of state-of-the-art SiO2 layers. Furthermore, those coatings show low optical absorption of <1  ppm and optical scattering of ≲5  ppm. Notably, we still observe excellent optical and thermal noise performance following crystallization in the coatings. These results show the potential to meet the parameters required for the next upgrades of the Advanced LIGO and Advanced Virgo detectors

A Cryogenic Silicon Interferometer for Gravitational-wave Detection

The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument able to detect gravitational waves at distances 5 times further away than possible with Advanced LIGO, or at greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby Universe, as well as observing the Universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects