Optimality principles in spacecraft neural guidance and control.

This Review discusses the main results obtained in training end-to-end neural architectures for guidance and control of interplanetary transfers, planetary landings, and close-proximity operations, highlighting the successful learning of optimality principles by the underlying neural models. Spacecraft and drones aimed at exploring our solar system are designed to operate in conditions where the smart use of onboard resources is vital to the success or failure of the mission. Sensorimotor actions are thus often derived from high-level, quantifiable, optimality principles assigned to each task, using consolidated tools in optimal control theory. The planned actions are derived on the ground and transferred on board, where controllers have the task of tracking the uploaded guidance profile. Here, we review recent trends based on the use of end-to-end networks, called guidance and control networks (G&CNets), which allow spacecraft to depart from such an architecture and to embrace the onboard computation of optimal actions. In this way, the sensor information is transformed in real time into optimal plans, thus increasing mission autonomy and robustness. We then analyze drone racing as an ideal gym environment to test these architectures on real robotic platforms and thus increase confidence in their use in future space exploration missions. Drone racing not only shares with spacecraft missions both limited onboard computational capabilities and similar control structures induced from the optimality principle sought but also entails different levels of uncertainties and unmodeled effects and a very different dynamical timescale.

Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host.

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.

Characterization of the on-board megavoltage imager in a magnetic resonance-guided radiotherapy machine for beam output checks.

We characterized the on-board megavoltage imager (MVI) of a magnetic resonance-guided radiotherapy machine for beam output checks. Linearity and repeatability of its dose response were investigated. Alignment relative to the beam under clinical circumstances was evaluated for a year using daily measurements. Linearity and short-term repeatability were excellent. Long-term repeatability drifted 0.8 % per year, which can be overcome by monthly cross calibrations. Long-term alignment was stable. Thus, the MVI has suitable characteristics for beam output checks.

Multileaf collimator characterization and modeling for a 1.5 T MR-linac using static synchronous and asynchronous sweeping gaps.

Objective.The Elekta unity MR-linac delivers step-and-shoot intensity modulated radiotherapy plans using a multileaf collimator (MLC) based on the Agility MLC used on conventional Elekta linacs. Currently, details of the physical Unity MLC and the computational model within its treatment planning system (TPS)Monacoare lacking in published literature. Recently, a novel approach to characterize the physical properties of MLCs was introduced using dynamic synchronous and asynchronous sweeping gap (aSG) tests. Our objective was to develop a step-and-shoot version of the dynamic aSG test to characterize the Unity MLC and the computational MLC models in theMonacoandRayStationTPSs.Approach.Dynamic aSG were discretized into a step-and-shoot aSG by investigating the number of segments/sweep and the minimal number of monitor units (MU) per segment. The step-and-shoot aSG tests were compared to the dynamic aSG tests on a conventional linac at a source-to-detector distance of 143.5 cm, mimicking the Unity configuration. the step-and-shoot aSG tests were used to characterize the Unity MLC through measurements and dose calculations in both TPSs.Main results.The step-and-shoot aSGs tests with 100 segments and 5 MU/segment gave results very similar to the dynamic aSG experiments. The effective tongue-and-groove width of the Unity gradually increased up to 1.4 cm from the leaf tip end. The MLC models inRayStationandMonacoagreed with experimental data within 2.0% and 10%, respectively. The largest discrepancies inMonacowere found for aSG tests with >10 mm leaf interdigitation, which are non-typical for clinical plans.Significance.The step-and-shoot aSG tests accurately characterize the MLC in step-and-shoot delivery mode. The MLC model inRayStation2023B accurately describes the tongue-and-groove and leaf tip effects whereasMonacooverestimates the tongue-and-groove shadowing further away from the leaf tip end.

Survey on fan-beam computed tomography for radiotherapy: Current implementation and future perspectives of motion management and surface guidance devices.

Background and purpose: This work reports on the results of a survey performed on the use of computed tomography (CT) imaging for motion management, surface guidance devices, and their quality assurance (QA). Additionally, it details the collected user insights regarding professional needs in CT for radiotherapy. The purpose of the survey is to understand current practice, professional needs and future directions in the field of fan-beam CT in radiation therapy (RT). Materials and methods: An online institutional survey was conducted between 1-Sep-2022 and 10-Oct-2022 among medical physics experts at Belgian and Dutch radiotherapy institutions, to assess the current status, challenges, and future directions of motion management and surface image-guided radiotherapy. The survey consisted of a maximum of 143 questions, with the exact number depending on participants' responses. Results: The response rate was 66 % (31/47). Respiratory management was reported as standard practice in all but one institution; surface imaging during CT-simulation was reported in ten institutions. QA procedures are applied with varying frequencies and methodologies, primarily with commercial anatomy-like phantoms. Surface guidance users report employing commercial static and dynamic phantoms. Four main subjects are considered clinically important by the respondents: surface guidance, CT protocol optimisation, implementing gated imaging (4DCT, breath-hold), and a tattoo-less workflow. Conclusions: The survey highlights the scattered pattern of QA procedures for respiratory motion management, indicating the need for well-defined, unambiguous, and practicable guidelines. Surface guidance is considered one of the most important techniques that should be implemented in the clinical radiotherapy simulation workflow.

Survey on fan-beam computed tomography for radiotherapy: Imaging for dose calculation and delineation.

Background and purpose: To obtain an understanding of current practice, professional needs and future directions in the field of fan-beam CT in RT, a survey was conducted. This work presents the collected information regarding the use of CT imaging for dose calculation and structure delineation. Materials and methods: An online institutional survey was distributed to medical physics experts employed at Belgian and Dutch radiotherapy institutions to assess the status, challenges, and future directions of QA practices for fan-beam CT. A maximum of 143 questions covered topics such as CT scanner availability, CT scanner specifications, QA protocols, treatment simulation workflow, and radiotherapy dose calculation. Answer forms were collected between 1-Sep-2022 and 10-Oct-2022. Results: A 66 % response rate was achieved, yielding data on a total of 58 CT scanners. For MV photon therapy, all single-energy CT scans are reconstructed in Hounsfield Units for delineation or dose calculation, and a direct- or stoichiometric method was used to convert CT numbers for dose calculation. Limited use of dual-energy CT is reported for photon (N = 3) and proton dose calculations (N = 1). For brachytherapy, most institutions adopt water-based dose calculation, while approximately 26 % of the institutions take tissue heterogeneity into account. Commissioning and regular QA include eleven tasks, which are performed by two or more professions (29/31) with varying frequencies. Conclusions: Dual usage of a planning CT limits protocol optimization for both tissue characterization and delineation. DECT has been implemented only gradually. A variation of QA testing frequencies and tests are reported.

Effects of chronic caffeine on patterns of brain blood flow and behavior throughout the sleep-wake cycle in freely behaving mice.

Caffeine has significant effects on neurovascular activity and behavior throughout the sleep-wake cycle. We used a minimally invasive microchip/video system to continuously record effects of caffeine in the drinking water of freely behaving mice. Chronic caffeine shifted both rest and active phases by up to 2 h relative to the light-dark cycle in a dose-dependent fashion. There was a particular delay in the onset of rapid eye movement (REM) sleep as compared with non-REM sleep during the rest phase. Chronic caffeine increased wakefulness during the active phase and consolidated sleep during the rest phase; overall, there was no net change in the amount of time spent in the wake, sleep, or REM sleep states during caffeine administration. Despite these effects on wakefulness and sleep, chronic caffeine decreased mean cerebral blood volume (CBV) during the active phase and increased mean CBV during the rest phase. Chronic caffeine also increased heart rate variability in both the sleep and wake states. These results provide new insight into the effects of caffeine on the biology of the sleep-wake cycle. Increased blood flow during sleep caused by chronic caffeine may have implications for its potential neuroprotective effects through vascular mechanisms of brain waste clearance.

Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses.

The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.

The crucial role of titin in fetal development: recurrent miscarriages and bone, heart and muscle anomalies characterise the severe end of titinopathies spectrum.

BACKGROUND: Titin truncating variants (TTNtvs) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity, they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. Often karyotype or chromosomal microarray analyses are the only tests performed when prenatal anomalies are identified. Thereby, many cases caused by TTN defects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum. METHODS: We performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv. RESULTS: We identified recurrent clinical features showing a significant correlation with the genotype, including fetal akinesia (up to 62%), arthrogryposis (up to 85%), facial dysmorphisms (up to 73%), joint (up to 17%), bone (up to 22%) and heart anomalies (up to 27%) resembling complex, syndromic phenotypes. CONCLUSION: We suggest TTN to be carefully evaluated in any diagnostic process involving patients with these prenatal signs. This step will be essential to improve diagnostic performance, expand our knowledge and optimise prenatal genetic counselling.

The epigenetic EZH2/H3K27me3 axis modulates lactotroph tumor cell proliferation.

Interest in epigenetics has gained substantial momentum as a result of their identified role in the regulation of tumor progression as well as their ability to pharmacologically target genes. Pituitary neuroendocrine tumors (PitNETs) tend to be inactivated via epigenetic modification, and although emerging evidence has suggested a role for epigenetic factors in PitNET tumorigenesis, the degree to which these factors may be targeted by new therapeutic strategies still remains poorly understood. The objective of the present study was to examine the participation of the EZH2/H3K27me3 axis in the proliferation of lactotroph tumor cells. We demonstrated that the levels of EZH2 and H3K27me3 were increased in murine experimental prolactin (PRL) tumors with respect to a control pituitary, in contrast with the low p21 mRNA levels encountered, with an H3K27me3 enrichment being observed in its promoter region in a GH3 tumor cell. Furthermore, specific EZH2/H3K27me3 axis inhibition blocked the proliferation of primary tumor cell culture and GH3 cells, thereby making it an attractive therapeutic target for PRL PitNETs.

Beam output checks of a commercial high-field magnetic resonance-guided radiotherapy machine with its on-board megavoltage imager.

Beam output checks of a commercial high-field magnetic resonance-guided radiotherapy machine can be performed with its on-board megavoltage imager (MVI). This is a fast and efficient method, but only recommended for daily checks. The aim of our study was to show its suitability for weekly checks by investigating its long-term agreement with the golden standard: ionization chamber measurements in a water tank. For one year, the output deviations obtained with both methods were compared. The difference was 0.1 ± 0.3 (1SD) percentage point. This indicated an excellent agreement, and translated into a tolerance level of ± 2 %.

VelcroVax: a "Bolt-On" Vaccine Platform for Glycoprotein Display.

Having varied approaches to the design and manufacture of vaccines is critical in being able to respond to worldwide needs and newly emerging pathogens. Virus-like particles (VLPs) form the basis of two of the most successful licensed vaccines (against hepatitis B virus [HBV] and human papillomavirus). They are produced by recombinant expression of viral structural proteins, which assemble into immunogenic nanoparticles. VLPs can be modified to present unrelated antigens, and here we describe a universal "bolt-on" platform (termed VelcroVax) where the capturing VLP and the target antigen are produced separately. We utilize a modified HBV core (HBcAg) VLP with surface expression of a high-affinity binding sequence (Affimer) directed against a SUMO tag and use this to capture SUMO-tagged gp1 glycoprotein from the arenavirus Junín virus (JUNV). Using this model system, we have solved the first high-resolution structures of VelcroVax VLPs and shown that the VelcroVax-JUNV gp1 complex induces superior humoral immune responses compared to the noncomplexed viral protein. We propose that this system could be modified to present a range of antigens and therefore form the foundation of future rapid-response vaccination strategies. IMPORTANCE The hepatitis B core protein (HBc) forms noninfectious virus-like particles, which can be modified to present a capturing molecule, allowing suitably tagged antigens to be bound on their surface. This system can be adapted and provides the foundation for a universal "bolt-on" vaccine platform (termed VelcroVax) that can be easily and rapidly modified to generate nanoparticle vaccine candidates.

Vapor Swelling of Polymer Brushes Compared to Nongrafted Films.

Polymer brushes, coatings of polymers covalently end-grafted to a surface, have been proposed as a more stable alternative to traditional physisorbed coatings. However, when such coatings are applied in settings such as vapor sensing and gas separation technologies, their responsiveness to solvent vapors becomes an important consideration. It can be anticipated that the end-anchoring in polymer brushes reduces the translational entropy of the polymers and instead introduces an entropic penalty against stretching when vapor is absorbed. Therefore, swelling can be expected to be diminished in brushes compared to nongrafted films. Here, we study the effect of the anchoring-constraint on vapor sorption in polymer coatings using coarse-grained molecular dynamics simulations as well as humidity-controlled ellipsometry on chemically identical polymer brushes and nongrafted films. We find a qualitative agreement between simulations and experiments, with both indicating that brushes certainly swell less than physisorbed films, although this effect is minor for common grafting densities. Our results imply that polymer brushes indeed hold great potential for the intended applications.

Enhanced vapor sorption in block and random copolymer brushes.

Polymer brushes in gaseous environments absorb and adsorb vapors of favorable solvents, which makes them potentially relevant for sensing applications and separation technologies. Though significant amounts of vapor are sorbed in homopolymer brushes at high vapor pressures, at low vapor pressures sorption remains limited. In this work, we vary the structure of two-component polymer brushes and investigate the enhancement in vapor sorption at different relative vapor pressures compared to homopolymer brushes. We perform molecular dynamics simulations on two-component block and random copolymer brushes and investigate the influence of monomer miscibility and formation of high-energy interfaces between immiscible monomers on vapor sorption. Additionally, we present absorption isotherms of pure homopolymer, mixed binary brush and 2-block, 4-block, and random copolymer brushes. Based on these isotherms, we finally show that random copolymer brushes absorb more vapor than any other architecture investigated thus far. Random brushes display enhanced sorption at both high and low vapor pressures, with the largest enhancement in sorption at low vapor pressures.

Accommodating unobservability to control flight attitude with optic flow.

Attitude control is an essential flight capability. Whereas flying robots commonly rely on accelerometers1 for estimating attitude, flying insects lack an unambiguous sense of gravity2,3. Despite the established role of several sense organs in attitude stabilization3-5, the dependence of flying insects on an internal gravity direction estimate remains unclear. Here we show how attitude can be extracted from optic flow when combined with a motion model that relates attitude to acceleration direction. Although there are conditions such as hover in which the attitude is unobservable, we prove that the ensuing control system is still stable, continuously moving into and out of these conditions. Flying robot experiments confirm that accommodating unobservability in this manner leads to stable, but slightly oscillatory, attitude control. Moreover, experiments with a bio-inspired flapping-wing robot show that residual, high-frequency attitude oscillations from flapping motion improve observability. The presented approach holds a promise for robotics, with accelerometer-less autopilots paving the road for insect-scale autonomous flying robots6. Finally, it forms a hypothesis on insect attitude estimation and control, with the potential to provide further insight into known biological phenomena5,7,8 and to generate new predictions such as reduced head and body attitude variance at higher flight speeds9.

Fundamentals and Applications of Polymer Brushes in Air.

For several decades, high-density, end-tethered polymers, forming so-called polymer brushes, have inspired scientists to understand their properties and to translate them to applications. While earlier research focused on polymer brushes in liquids, it was recently recognized that these brushes can find application in air as well. In this review, we report on recent progress in unraveling fundamental concepts of brushes in air, such as their vapor-swelling and solvent partitioning. Moreover, we provide an overview of the plethora of applications in air (e.g., in sensing, separations or smart adhesives) where brushes can be key components. To conclude, we provide an outlook by identifying open questions and issues that, when solved, will pave the way for the large scale application of brushes in air.

Different characteristics of cortical spreading depression in the sleep and wake states.

OBJECTIVE: The objective of this study is to characterize the effects of the sleep-wake cycle on neurovascular and behavioral characteristics of cortical spreading depression (CSD). BACKGROUND: There is an important bi-directional relationship between migraine and the sleep-wake cycle, but the basic mechanisms of this relationship are poorly understood. METHODS: We have developed a minimally invasive microchip system to continuously monitor cerebral blood volume (CBV) with optical intrinsic signal (OIS), head movement, and multiple other physiological and behavioral parameters in freely behaving mice over weeks. Behavior is also monitored with simultaneous video recording. This system can also be used to intermittently trigger and record CSD and accompanying neurovascular and behavioral responses. CSD was triggered optically in different stages of the sleep-wake cycle. RESULTS: The optical stimulus threshold to trigger CSD was significantly higher in the wake state compared to sleep (stimulation duration = 16.4 ± 9.7 s vs. 10.8 ± 5.8 s, p = 0.037, n = 6 mice). CSD evoked in the wake versus sleep state produced changes in CBV that were smaller (largest relative change -4.5 ± 5.0% ∆OIS vs. -14.3 ± 8.5% ∆OIS, p = 0.001) and shorter in duration (33:22 ± 6:37 vs. 49:42 ± 8:05 min:s, p = 0.012, n = 6 mice). The threshold for CSD and kinetics of associated CBV changes were correlated with the time since falling asleep or awakening (n = 47 CSDs in 6 mice). CSD triggered in the wake state was associated with a transient freezing behavior. CSD triggered during sleep typically caused a transient awakening and behavioral response. This was followed by a return to sleep until recovery from the sustained phase of decreased CBV that occurred 30-60 min later, at which time there was consistent awakening with behaviors similar to those that occurred at CSD onset. CSD triggered in the wake state evoked a transient decrease in heart rate (from 11.9 ± 0.8 to 9.6 ± 0.8 Hz, p = 0.002, n = 5), whereas when triggered in the sleep state there was a transient increase in HR (from 7.5 ± 0.4 Hz to 9.3 ± 1.1 Hz, p = 0.016, n = 5). CONCLUSIONS: The sleep-wake cycle has significant effects on CSD that may have relevance to the clinical presentations of migraine and brain injury.

Ultrasound stimulation of the motor cortex during tonic muscle contraction.

Transcranial ultrasound stimulation (tUS) shows potential as a noninvasive brain stimulation (NIBS) technique, offering increased spatial precision compared to other NIBS techniques. However, its reported effects on primary motor cortex (M1) are limited. We aimed to better understand tUS effects in human M1 by performing tUS of the hand area of M1 (M1hand) during tonic muscle contraction of the index finger. Stimulation during muscle contraction was chosen because of the transcranial magnetic stimulation-induced phenomenon known as cortical silent period (cSP), in which transcranial magnetic stimulation (TMS) of M1hand involuntarily suppresses voluntary motor activity. Since cSP is widely considered an inhibitory phenomenon, it presents an ideal parallel for tUS, which has often been proposed to preferentially influence inhibitory interneurons. Recording electromyography (EMG) of the first dorsal interosseous (FDI) muscle, we investigated effects on muscle activity both during and after tUS. We found no change in FDI EMG activity concurrent with tUS stimulation. Using single-pulse TMS, we found no difference in M1 excitability before versus after sparsely repetitive tUS exposure. Using acoustic simulations in models made from structural MRI of the participants that matched the experimental setups, we estimated in-brain pressures and generated an estimate of cumulative tUS exposure experienced by M1hand for each subject. We were unable to find any correlation between cumulative M1hand exposure and M1 excitability change. We also present data that suggest a TMS-induced MEP always preceded a near-threshold cSP.

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies.

Transmission of the New World hemorrhagic fever arenaviruses Junín virus (JUNV) and Machupo virus (MACV) to humans is facilitated, in part, by the interaction between the arenavirus GP1 glycoprotein and the human transferrin receptor 1 (hTfR1). We utilize a mouse model of live-attenuated immunization with envelope exchange viruses to isolate neutralizing monoclonal antibodies (NAbs) specific to JUNV GP1 and MACV GP1. Structures of two NAbs, termed JUN1 and MAC1, demonstrate that they neutralize through disruption of hTfR1 recognition. JUN1 utilizes a binding mode common to all characterized infection- and vaccine-elicited JUNV-specific NAbs, which involves mimicking hTfR1 binding through the insertion of a tyrosine into the receptor-binding site. In contrast, MAC1 undergoes a tyrosine-mediated mode of antigen recognition distinct from that used by the reported anti-JUNV NAbs and the only other characterized anti-MACV NAb. These data reveal the varied modes of GP1-specific recognition among New World arenaviruses by the antibody-mediated immune response. IMPORTANCE The GP1 subcomponent of the New World arenavirus GP is a primary target of the neutralizing antibody response, which has been shown to be effective in the prevention and treatment of infection. Here, we characterize the structural basis of the antibody-mediated immune response that arises from immunization of mice against Junín virus and Machupo virus, two rodent-borne zoonotic New World arenaviruses. We isolate a panel of GP1-specific monoclonal antibodies that recognize overlapping epitopes and exhibit neutralizing behavior, in vitro. Structural characterization of two of these antibodies indicates that antibody recognition likely interferes with GP1-mediated recognition of the transferrin receptor 1. These data provide molecular-level detail for a key region of vulnerability on the New World arenavirus surface and a blueprint for therapeutic antibody development.