Cellular mechano-environment regulates the mammary circadian clock

Circadian clocks drive B24 h rhythms in tissue physiology. They rely on transcriptional/ translational feedback loops driven by interacting networks of clock complexes. However, little is known about how cell-intrinsic circadian clocks sense and respond to their microenvironment. Here, we reveal that the breast epithelial clock is regulated by the mechano-chemical stiffness of the cellular microenvironment in primary cell culture. Moreover, the mammary clock is controlled by the periductal extracellular matrix in vivo, which contributes to a dampened circadian rhythm during ageing. Mechanistically, the tension sensing cell-matrix adhesion molecule, vinculin, and the Rho/ROCK pathway, which transduces signals provided by extracellular stiffness into cells, regulate the activity of the core circadian clock complex. We also show that genetic perturbation, or age-associated disruption of self-sustained clocks, compromises the self-renewal capacity of mammary epithelia. Thus, circadian clocks are mechano-sensitive, providing a potential mechanism to explain how ageing influences their amplitude and function

Astrophysical science metrics for next-generation gravitational-wave detectors

The second generation of gravitational-wave (GW) detectors are being built and tuned all over the world. The detection of signals from binary black holes is beginning to fulfil the promise of GW astronomy. In this work, we examine several possible configurations for third-generation laser interferometers in existing km-scale facilities. We propose a set of astrophysically motivated metrics to evaluate detector performance. We measure the impact of detector design choices against these metrics, providing a quantitative cost-benefit analyses of the resulting scientific payoffs

The scientific potential of space-based gravitational wave detectors

The millihertz gravitational wave band can only be accessed with a space-based interferometer, but it is one of the richest in potential sources. Observations in this band have amazing scientific potential. The mergers between massive black holes with mass in the range 10 thousand to 10 million solar masses, which are expected to occur following the mergers of their host galaxies, produce strong millihertz gravitational radiation. Observations of these systems will trace the hierarchical assembly of structure in the Universe in a mass range that is very difficult to probe electromagnetically. Stellar mass compact objects falling into such black holes in the centres of galaxies generate detectable gravitational radiation for several years prior to the final plunge and merger with the central black hole. Measurements of these systems offer an unprecedented opportunity to probe the predictions of general relativity in the strong-field and dynamical regime. Millihertz gravitational waves are also generated by millions of ultra-compact binaries in the Milky Way, providing a new way to probe galactic stellar populations. ESA has recognised this great scientific potential by selecting The Gravitational Universe as its theme for the L3 large satellite mission, scheduled for launch in ~2034. In this article we will review the likely sources for millihertz gravitational wave detectors and describe the wide applications that observations of these sources could have for astrophysics, cosmology and fundamental physics.Comment: 18 pages, 2 figures, contribution to Gravitational Wave Astrophysics, the proceedings of the 2014 Sant Cugat Forum on Astrophysics; v2 includes one additional referenc

Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses

Scientific Objectives of Einstein Telescope

The advanced interferometer network will herald a new era in observational astronomy. There is a very strong science case to go beyond the advanced detector network and build detectors that operate in a frequency range from 1 Hz-10 kHz, with sensitivity a factor ten better in amplitude. Such detectors will be able to probe a range of topics in nuclear physics, astronomy, cosmology and fundamental physics, providing insights into many unsolved problems in these areas.Comment: 18 pages, 4 figures, Plenary talk given at Amaldi Meeting, July 201

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

The basic physics of the binary black hole merger GW150914

The first direct gravitational-wave detection was made by the Advanced Laser Interferometer Gravitational Wave Observatory on September 14, 2015. The GW150914 signal was strong enough to be apparent, without using any waveform model, in the filtered detector strain data. Here, features of the signal visible in the data are analyzed using concepts from Newtonian physics and general relativity, accessible to anyone with a general physics background. The simple analysis presented here is consistent with the fully general-relativistic analyses published elsewhere, in showing that the signal was produced by the inspiral and subsequent merger of two black holes. The black holes were each of approximately 35 M⊙, still orbited each other as close as ∼350 km apart and subsequently merged to form a single black hole. Similar reasoning, directly from the data, is used to roughly estimate how far these black holes were from the Earth, and the energy that they radiated in gravitational waves