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We study a mid-order wavefront sensor (MOWFS) to address fine cophasing errors in exoplanet imaging with future large segmented aperture space telescopes. Observing Earth analogs around Sun-like stars requires contrasts down to \\(10^-10\\) in visible light. One promising solution consists of producing a high-contrast dark zone in the image of an observed star. In a space observatory, this dark region will be altered by several effects, and among them, the small misalignments of the telescope mirror segments due to fine thermo-mechanical drifts. To correct for these errors in real time, we investigate a wavefront control loop based on a MOWFS with a Zernike sensor. Such a MOWFS was installed on the high-contrast imager for complex aperture telescopes (HiCAT) testbed in Baltimore in June 2023. The bench uses a 37-segment Iris-AO deformable mirror to mimic telescope segmentation and some wavefront control strategies to produce a dark zone with such an aperture. In this contribution, we first use the MOWFS to characterize the Iris-AO segment discretization steps. For the central segment, we find a minimal step of 125 \\(\\) 31 pm. This result will help us to assess the contribution of the Iris-AO DM on the contrast in HiCAT. We then determine the detection limits of the MOWFS, estimating wavefront error amplitudes of 119 and 102 pm for 10 s and 1 min exposure time with a SNR of 3. These values inform us about the measurement capabilities of our wavefront sensor on the testbed. These preliminary results will be useful to provide insights on metrology and stability for exo-Earth observations with the Habitable Worlds Observatory.

Wavefront sensing and control (WFSC) will play a key role in improving the stability of future large segmented space telescopes while relaxing the thermo-mechanical constraints on the observatory structure. Coupled with a coronagraph to reject the light of an observed bright star, WFSC enables the generation and stabilisation of a dark hole (DH) in the star image to perform planet observations. While WFSC traditionally relies on a single wavefront sensor (WFS) input to measure wavefront errors, the next generation of instruments will require several WFSs to address aberrations with different sets of spatial and temporal frequency contents. The multiple measurements produced in such a way will then have to be combined and converted to commands for deformable mirrors (DMs) to modify the wavefront subsequently. We asynchronously operate a loop controlling the high-order modes digging a DH and a control loop that uses the rejected light by a Lyot coronagraph with a Zernike wavefront sensor to stabilize the low-order aberrations. Using the HiCAT testbed with a segmented telescope aperture, we implement concurrent operations and quantify the expected cross-talk between the two controllers. We then present experiments that alternate high-order and low-order control loops to identify and estimate their respective contributions. We show an efficient combination of the high-order and low-order control loops, keeping a DH contrast better than 5 x 10-8 over a 30 min experiment and stability improvement by a factor of 1.5. In particular, we show a contrast gain of 1.5 at separations close to the DH inner working angle, thanks to the low-order controller contribution. Concurrently digging a DH and using the light rejected by a Lyot coronagraph to stabilize the wavefront is a promising path towards exoplanet imaging and spectroscopy with future large space observatories.

Combining large segmented space telescopes, coronagraphy and wavefront control methods is a promising solution to produce a dark hole (DH) region in the coronagraphic image of an observed star and study planetary companions. The thermal and mechanical evolution of such a high-contrast facility leads to wavefront drifts that degrade the DH contrast during the observing time, thus limiting the ability to retrieve planetary signals. Lyot-style coronagraphs are starlight suppression systems that remove the central part of the image for an unresolved observed star, the point spread function, with an opaque focal plane mask (FPM). When implemented with a flat mirror containing an etched pinhole, the mask rejects part of the starlight through the pinhole which can be used to retrieve information about low-order aberrations. We propose an active control scheme using a Zernike wavefront sensor (ZWFS) to analyze the light rejected by the FPM, control low-order aberrations, and stabilize the DH contrast. The concept formalism is first presented before characterizing the sensor behavior in simulations and in laboratory. We then perform experimental tests to validate a wavefront control loop using a ZWFS on the HiCAT testbed. By controlling the first 11 Zernike modes, we show a decrease in wavefront error standard deviation by a factor of up to 9 between open- and closed-loop operations using the ZWFS. In the presence of wavefront perturbations, we show the ability of this control loop to stabilize a DH contrast around 7x10^-8 with a standard deviation of 7x10^-9. Active control with a ZWFS proves a promising solution in Lyot coronagraphs with an FPM-filtered beam to control and stabilize low-order wavefront aberrations and DH contrast for exoplanet imaging with future space missions.

The discovery of an Earth-mass exoplanet around the nearby star Proxima Centauri provides a prime target for the search for life on planets outside our solar system. Atmospheric characterization of these planets has been proposed by blocking the starlight with a stellar coronagraph and using a high-resolution spectrograph to search for reflected starlight off the planet. Due to the large flux ratio and small angular separation between Proxima b and its host star (\\(\\lesssim10^{-7}\\) and \\(\\lesssim2.2\\lambda/D\\) respectively; at 750nm for an 8m-class telescope) the coronagraph needs to have a high starlight suppression at low inner-working angles. We aim to find the global optimum of an integrated coronagraphic integral-field spectrograph. We present the Single-mode Complex Amplitude Refinement (SCAR) coronagraph that uses a microlens-fed single-mode fiber array in the focal plane downstream from a pupil-plane phase plate. The mode-filtering property of the single-mode fibers allows for the nulling of starlight on the fibers. The phase pattern in the pupil plane is specifically designed to take advantage of this mode-filtering capability. Second-order nulling on the fibers expands the spectral bandwidth and decreases the tip-tilt sensitivity of the coronagraph. The SCAR coronagraph has a low inner-working angle (\\(\\sim1\\lambda/D\\)) at a contrast of \\(<3\\times10^{-5}\\) for the 6 fibers surrounding the star using a sufficiently-good adaptive optics system. It can operate over broad spectral bandwidths (\\(\\sim20\\%\\)) and delivers high throughput (\\(>50\\%\\) including fiber injection losses). Additionally, it is robust against tip-tilt errors (\\(\\sim0.1\\lambda/D\\) rms). We present SCAR designs for both an unobstructed and a VLT-like pupil. The SCAR coronagraph is a promising candidate for exoplanet detection and characterization around nearby stars using current high-resolution imaging instruments.

Over the last decade, the vector-apodizing phase plate (vAPP) coronagraph has been developed from concept to on-sky application in many high-contrast imaging systems on 8-m class telescopes. The vAPP is an geometric-phase patterned coronagraph that is inherently broadband, and its manufacturing is enabled only by direct-write technology for liquid-crystal patterns. The vAPP generates two coronagraphic PSFs that cancel starlight on opposite sides of the point spread function (PSF) and have opposite circular polarization states. The efficiency, that is the amount of light in these PSFs, depends on the retardance offset from half-wave of the liquid-crystal retarder. Using different liquid-crystal recipes to tune the retardance, different vAPPs operate with high efficiencies (\\(>96\\%\\)) in the visible and thermal infrared (0.55 \\(\\mu\\)m to 5 \\(\\mu\\)m). Since 2015, seven vAPPs have been installed in a total of six different instruments, including Magellan/MagAO, Magellan/MagAO-X, Subaru/SCExAO, and LBT/LMIRcam. Using two integral field spectrographs installed on the latter two instruments, these vAPPs can provide low-resolution spectra (R\\(\\sim\\)30) between 1 \\(\\mu\\)m and 5 \\(\\mu\\)m. We review the design process, development, commissioning, on-sky performance, and first scientific results of all commissioned vAPPs. We report on the lessons learned and conclude with perspectives for future developments and applications.

The Optimal Optical Coronagraph (OOC) Workshop at the Lorentz Center in September 2017 in Leiden, the Netherlands gathered a diverse group of 25 researchers working on exoplanet instrumentation to stimulate the emergence and sharing of new ideas. In this first installment of a series of three papers summarizing the outcomes of the OOC workshop, we present an overview of design methods and optical performance metrics developed for coronagraph instruments. The design and optimization of coronagraphs for future telescopes has progressed rapidly over the past several years in the context of space mission studies for Exo-C, WFIRST, HabEx, and LUVOIR as well as ground-based telescopes. Design tools have been developed at several institutions to optimize a variety of coronagraph mask types. We aim to give a broad overview of the approaches used, examples of their utility, and provide the optimization tools to the community. Though it is clear that the basic function of coronagraphs is to suppress starlight while maintaining light from off-axis sources, our community lacks a general set of standard performance metrics that apply to both detecting and characterizing exoplanets. The attendees of the OOC workshop agreed that it would benefit our community to clearly define quantities for comparing the performance of coronagraph designs and systems. Therefore, we also present a set of metrics that may be applied to theoretical designs, testbeds, and deployed instruments. We show how these quantities may be used to easily relate the basic properties of the optical instrument to the detection significance of the given point source in the presence of realistic noise.

We present the monochromatic lab verification of the newly developed SCAR coronagraph that combines a phase plate (PP) in the pupil with a microlens-fed single-mode fiber array in the focal plane. The two SCAR designs that have been measured, create respectively a 360 degree and 180 degree dark region from 0.8-2.4 \\lambda/D around the star. The 360 SCAR has been designed for a clear aperture and the 180 SCAR has been designed for a realistic aperture with central obscuration and spiders. The 360 SCAR creates a measured stellar null of \\(2-3 \\times 10^{-4}\\) , and the 180 SCAR reaches a null of \\(1 \\times 10^{-4}\\) . Their monochromatic contrast is maintained within a range of \\(\\pm\\) 0.16 \\lambda/D peak-to-valley tip-tilt, which shows the robustness against tip-tilt errors. The small inner working angle and tip-tilt stability makes the SCAR coronagraph a very promising technique for an upgrade of current high-contrast instruments to characterize and detect exoplanets in the solar neighborhood.

Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods for protein structure predictions have reached the accuracy of experimentally determined models. Although this has been independently verified, the implementation of these methods across structural-biology applications remains to be tested. Here, we evaluate the use of AlphaFold2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modeling of interactions; and modeling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modeled when compared with homology modeling, identifying structural features rarely seen in the Protein Data Bank. AF2-based predictions of protein disorder and complexes surpass dedicated tools, and AF2 models can be used across diverse applications equally well compared with experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life-science research. Here, the authors evaluate the performance of AlphaFold2 and its predicted structures on common structural biological applications, including missense variants, function and ligand binding site prediction, modeling of interactions and modeling of experimental structural data.

IntroductionThe evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant.MethodsThe EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed.ResultsAt 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group.ConclusionThis long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS.Trial registration number NCT02924129.

Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m −2 , to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P  =  0.039 ). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90–100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P  =  0.016 ). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449 . Preclinical evidence suggests that a fasting mimicking diet (FMD) can make cancer cells more vulnerable to chemotherapy, while protecting normal cells. In this randomized phase II clinical trial of 131 patients with HER2 negative early stage breast cancer, the authors demonstrate that FMD is safe and enhances the effects of neoadjuvant chemotherapy on radiological and pathological tumor response.