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The large-scale dynamics of the heliosphere is driven by solar activity and variable solar wind (SW) conditions. In situ SW observations inform time-dependent heliosphere modeling efforts but are only available up until the present day, thus restricting informed predictions to the very near future. We developed and implemented a method to provide long-term forecasting of SW parameters at 1 au. Such forecasting supports modeling efforts of the time-dependent global heliosphere by providing realistic boundary conditions for heliospheric models at the upwind model-domain boundary ahead of time in order to understand the global dynamic processes in the heliosphere such as the evolution of the termination shock (TS), heliosheath, and heliopause. Such forecasting capabilities are needed to better constrain the timing of New Horizons’ TS encounter and predict energetic neutral atom flux variation for IMAP. We analyzed SW direct measurement time series for periodicities at various timescales using Lomb–Scargle periodogram analysis. Based on identified prominent periodicities, we construct quasiperiodic functions for the SW parameters. By extrapolating these functions forward in time, we obtain a prediction of the SW evolution over the next two solar cycles. Our results indicate that the next pulse in the SW dynamic pressure, which controls the global heliosphere, will occur around 2035.

The heliospheric energetic neutral atoms (ENAs) are products of charge exchange between solar wind and pick-up ions and interstellar neutral atoms. They are created in different regions of the heliosphere and its boundary region with the interstellar medium, constituting different ENA populations, and they carry information about their parent populations and production processes. Thus, ENAs enable mapping of the global structure of the heliosphere and the processes within and at its edge. Three instruments have provided sky maps of the heliospheric ENAs from 200 eV up to 44 keV over the solar activity cycle. The IBEX-Lo and IBEX-Hi instruments on board the Interstellar Boundary Explorer (IBEX) have provided ENA sky maps from 200 eV to 4.3 keV (central energy) from 2009 throughout Solar Cycle 24. The Ion and Neutral Camera (INCA) on board the Cassini–Huygens mission provided sky maps of the ENAs from 8–44 keV (central energy) on the spacecraft route to and in orbit around Saturn through Solar Cycles 23 and 24. We compare large-scale structures of ENA enhancements present across the sky maps in a wide energy range based on IBEX-Lo, IBEX-Hi, and INCA. They include Ribbon, heliotail lobes, and upwind ENA enhancement. We report on similarities and differences observed, including the evolution of the Ribbon from low to higher energies, and the presence of confined north and south heliotail lobes up to 44 keV.

IBEX observes a globally distributed energetic neutral atom (ENA) flux from the heliosheath and very local interstellar medium (VLISM). Over a 14 yr period, Voyager 1 and Voyager 2 traversed the heliosheath from the termination shock to the heliopause. In situ observations from these spacecraft place important constraints on the parent ion populations of the ENAs from the heliosheath in two directions on the upwind side of the heliosphere, i.e., the direction of motion of the Sun in the local interstellar medium. In this study, an MHD model that is constrained by Voyager in situ observations is used to estimate the contribution from the heliosheath to the total ENA fluxes observed by IBEX. At energies greater than about 0.5 keV, the heliosheath provides a significant fraction of the observed ENA flux. However, at energies less than about 0.5 keV, the heliosheath provides an insignificant fraction of the observed ENA flux. These results are the same for both directions, and since the Voyager 1 and 2 directions are not particularly unique, the results are likely to be applicable for much of the upwind hemisphere. Fundamentally, it is the physics of the termination shock and the thickness of the heliosheath that determine the energy-dependent contributions to the observed ENA flux from this region. Because the heliosheath source is insignificant, most ENAs at energies less than about 0.5 keV probably come from the VLISM.

The interactions of our heliosphere with the surrounding local interstellar medium (LISM) lead to a range of observable phenomena such as energetic neutral atoms (ENAs) from the boundary regions of the heliosphere and the influx of interstellar neutrals (ISNs) into the inner solar system. Hydrogen is the dominant neutral species in the LISM, but due to ionization and radiation pressure, only a fraction of the ISN H atoms reach the inner solar system close to Earth. Monitoring this signal therefore provides observational constraints on our assumptions of the LISM and the solar-activity-dependent loss processes inside the heliosphere. The IBEX-Lo instrument on board the Interstellar Boundary Explorer has been the only instrument so far to measure ISN H atoms directly, together with ISN D, He, Ne, O, and ENAs in the energy range from tens of eV to 2 keV. This study covers 15 yr of IBEX-Lo ISN H observations, i.e., more than one solar cycle and includes two solar minima when the ISN H signal in IBEX-Lo is strongest. Despite the very intense ISN He signal, the ISN H signal can be retrieved with appropriate knowledge of the instrument, choice of optimum observation season, and supporting modeling. The retrieved ISN H signal shows a clear anticorrelation with solar activity. The resulting ISN H maps are available in orbit format and in ecliptic coordinates and will be the basis for future more detailed comparison with heliosphere models.

We supply the modelers with a database, SpuBase (doi:10.5281/zenodo.10783295), that is based on the latest approach for obtaining solar wind ion sputter yields in agreement with experimental sputter data outlined in Jäggi et al. We include an overview of sputter results for typical Lunar and Hermean surfaces. To obtain total sputter yields for any given surface, we perform a mass balance of individual mineral sputter yields. For a set of impact angles, the angular and energy distribution data are scaled according to the sputter yield, summed up and fitted to obtain one probability distribution for each chemical element involved. Comparison of the results from different geochemical terranes on the Moon and Mercury has shown that variations in the abundance of silicates result in comparable energy and angular distribution data owing to the underlying model assumptions. The inclusion of sulfides relevant for Mercury, however, significantly affects the energy and angular distributions of sputtered particles. The application of the damage-driven sulfur diffusion rate in FeS in all sulfur-bearing minerals results in 35 times lower sulfur yields on average and a less prominent forward sputtering of sulfur at grazing incidence angles.

The Analyzers for Cusp Ions (ACIs) on the TRACERS mission measure ion velocity distribution functions in the magnetospheric cusp from two closely spaced spacecraft in low Earth orbit. The precipitating and upflowing ion measurements contribute to the overarching goal of the TRACERS mission and are key to all three science objectives of the mission. ACI is a toroidal top-hat electrostatic analyzer on a spinning platform that provides full angular coverage with instantaneous 22.5° × ∼6° angular resolution for a single energy step. ACI has an ion energy range from ∼8 eV/e to 20,000 eV/e covered in 47 logarithmic-spaced energy steps with fractional energy resolution of ∼10%. It provides reasonably high cadence (312 ms) measurements of the ion energy-pitch angle distribution with good sensitivity and energy resolution, enabling detection of cusp boundaries and characterization of cusp ion steps.

Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets 1 – 3 , but a substantial subset of proteins are resistant to targeted degradation using existing approaches 4 , 5 . Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL6 6 . We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand–protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology. Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

Objective The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm (AAA) rupture or repair (defined as AAA events) among participants with small AAAs. Methods PWS and PWRI were estimated from computed tomography angiography (CTA) scans of 210 participants with small AAAs (≥ 30 and  ≤ 50 mm) prospectively recruited between 2002 and 2016 from two existing databases. Participants were followed for a median of 2.0 (inter-quartile range 1.9, 2.8) years to record the incidence of AAA events. The associations between PWS and PWRI with AAA events were assessed using Cox proportional hazard analyses. The ability of PWS and PWRI to reclassify the risk of AAA events compared to the initial AAA diameter was examined using net reclassification index (NRI) and classification and regression tree (CART) analysis. Results After adjusting for other risk factors, one standard deviation increase in PWS (hazard ratio, HR, 1.56, 95% confidence intervals, CI 1.19, 2.06; p  = 0.001) and PWRI (HR 1.74, 95% CI 1.29, 2.34; p  < 0.001) were associated with significantly higher risks of AAA events. In the CART analysis, PWRI was identified as the best single predictor of AAA events at a cut-off value of  > 0.562. PWRI, but not PWS, significantly improved the classification of risk of AAA events compared to the initial AAA diameter alone. Conclusion PWS and PWRI predicted the risk of AAA events but only PWRI significantly improved the risk stratification compared to aortic diameter alone. Key Points • Aortic diameter is an imperfect measure of abdominal aortic aneurysm (AAA) rupture risk. • This observational study of 210 participants found that peak wall stress (PWS) and peak wall rupture index (PWRI) predicted the risk of aortic rupture or AAA repair. • PWRI, but not PWS, significantly improved the risk stratification for AAA events compared to aortic diameter alone.

While waiting for an efficient vaccine to protect against SARS-CoV-2 infection, alternative approaches to treat or prevent acute COVID-19 are urgently needed. Transfusion of convalescent plasma to treat COVID-19 patients is currently being explored; neutralizing activity in convalescent plasma is thought to play a central role in the efficacy of this treatment. Here, we observed that plasma neutralization activity decreased a few weeks after the onset of the symptoms. If neutralizing activity is required for the efficacy of convalescent plasma transfer, our results suggest that convalescent plasma should be recovered rapidly after the donor recovers from active infection. In the absence of effective vaccines and with limited therapeutic options, convalescent plasma is being collected across the globe for potential transfusion to coronavirus disease 2019 (COVID-19) patients. The therapy has been deemed safe, and several clinical trials assessing its efficacy are ongoing. While it remains to be formally proven, the presence of neutralizing antibodies is thought to play a positive role in the efficacy of this treatment. Indeed, neutralizing titers of ≥1:160 have been recommended in some convalescent plasma trials for inclusion. Here, we performed repeated analyses at 1-month intervals on 31 convalescent individuals to evaluate how the humoral responses against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein, including neutralization, evolve over time. We observed that the levels of receptor-binding-domain (RBD)-specific IgG and IgA slightly decreased between 6 and 10 weeks after the onset of symptoms but that RBD-specific IgM levels decreased much more abruptly. Similarly, we observed a significant decrease in the capacity of convalescent plasma to neutralize pseudoparticles bearing wild-type SARS-CoV-2 S or its D614G variant. If neutralization activity proves to be an important factor in the clinical efficacy of convalescent plasma transfer, our results suggest that plasma from convalescent donors should be recovered rapidly after resolution of symptoms. IMPORTANCE While waiting for an efficient vaccine to protect against SARS-CoV-2 infection, alternative approaches to treat or prevent acute COVID-19 are urgently needed. Transfusion of convalescent plasma to treat COVID-19 patients is currently being explored; neutralizing activity in convalescent plasma is thought to play a central role in the efficacy of this treatment. Here, we observed that plasma neutralization activity decreased a few weeks after the onset of the symptoms. If neutralizing activity is required for the efficacy of convalescent plasma transfer, our results suggest that convalescent plasma should be recovered rapidly after the donor recovers from active infection.

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”—CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy. The identification of new drug targets is highly challenging, particularly for diseases of the brain. This study describes a general computational gene regulatory framework called CRAFT for drug target discovery, and the authors use CRAFT to identify the microglial membrane receptor Csf1R as a potential therapeutic target for epilepsy.