SummaryCircadian clocks in large part rely on transcriptional feedback loops. At the core of the clock machinery, the transcriptional activators CLOCK/BMAL1 (in mammals) and CLOCK/CYCLE (CLK/CYC) (in Drosophila) drive the expression of the period (per) family genes. The PER-containing complexes inhibit the activity of CLOCK/BMAL1 or CLK/CYC, thereby forming a negative feedback loop [1]. In mammals, the ROR and REV-ERB family nuclear receptors add positive and negative transcriptional regulation to this core negative feedback loop to ensure the generation of robust circadian molecular oscillation [2]. Despite the overall similarities between mammalian and Drosophila clocks, whether comparable mechanisms via nuclear receptors are required for the Drosophila clock remains unknown. We show here that the nuclear receptor E75, the fly homolog of REV-ERB α and REV-ERB β, and the NR2E3 subfamily nuclear receptor UNF are components of the molecular clocks in the Drosophila pacemaker neurons. In vivo assays in conjunction with the in vitro experiments demonstrate that E75 and UNF bind to per regulatory sequences and act together to enhance the CLK/CYC-mediated transcription of the per gene, thereby completing the core transcriptional feedback loop necessary for the free-running clockwork. Our results identify a missing link in the Drosophila clock and highlight the significance of the transcriptional regulation via nuclear receptors in metazoan circadian clocks.
Computed ultrasound tomography in echo mode (CUTE) is a promising ultrasound (US) based multi-modal technique that allows to image the spatial distribution of speed of sound (SoS) inside tissue using hand-held pulse-echo US. It is based on measuring the phase shift of echoes when detected under varying steering angles. The SoS is then reconstructed using a regularized inversion of a forward model that describes the relation between the SoS and echo phase shift. Promising results were obtained in phantoms when using a Tikhonovtype regularization of the spatial gradient (SG) of SoS. In-vivo, however, clutter and aberration lead to an increased phase noise. In many subjects, this phase noise causes strong artifacts in the SoS image when using the SG regularization. To solve this shortcoming, we propose to use a Bayesian framework for the inverse calculation, which includes a priori statistical properties of the spatial distribution of the SoS to avoid noise-related artifacts in the SoS images. In this study, the a priori model is based on segmenting the B-Mode image. We show in a simulation and phantom study that this approach leads to SoS images that are much more stable against phase noise compared to the SG regularization. In a preliminary in-vivo study, a reproducibility in the range of 10 ms −1 was achieved when imaging the SoS of a volunteer's liver from different scanning locations. These results demonstrate the diagnostic potential of CUTE for example for the staging of fatty liver disease.
Computed ultrasound tomography in echo mode (CUTE) is a new ultrasound (US)-based medical imaging modality with promise for diagnosing various types of disease based on the tissue’s speed of sound (SoS). It is developed for conventional pulse-echo US using handheld probes and can thus be implemented in state-of-the-art medical US systems. One promising application is the quantification of the liver fat fraction in fatty liver disease. So far, CUTE was using linear array probes where the imaging depth is comparable to the aperture size. For liver imaging, however, convex probes are preferred since they provide a larger penetration depth and a wider view angle allowing to capture a large area of the liver. With the goal of liver imaging in mind, we adapt CUTE to convex probes, with a special focus on discussing strategies that make use of the convex geometry in order to make our implementation computationally efficient. We then demonstrate in an abdominal imaging phantom that accurate quantitative SoS using convex probes is feasible, in spite of the smaller aperture size in relation to the image area compared to linear arrays. A preliminary in vivo result of liver imaging confirms this outcome, but also indicates that deep quantitative imaging in the real liver can be more challenging, probably due to the increased complexity of the tissue compared to phantoms.
Non-alcoholic fatty liver disease is rapidly emerging as the leading global cause of chronic liver disease. Efficient disease management requires low-cost, noninvasive techniques for diagnosing hepatic steatosis accurately. Here we propose quantifying liver speed-of-sound (SoS) with computed US tomography in echo mode (CUTE), a newly developed US imaging modality adapted to clinical pulse-echo systems. CUTE reconstructs the spatial distribution of SoS by measuring local echo phase shifts when probing tissue at different steering angles in transmission and reception. This first-in-human phase II study shows that liver CUTE-SoS estimates correlate strongly (r=-0.84, p=8.27∙10-13) with controlled attenuation parameter values, a commonly used tool for assessing liver steatosis, and have 90.9% (95% confidence interval: 84 - 100%) sensitivity and 95.5% (81 - 100%) specificity for differentiating normal and significantly steatotic livers. Because CUTE offers the same flexibility as conventional US imaging, it can be readily extended to other clinical applications, establishing it as a new quantitative add-on to diagnostic US.
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