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This article explores the utility of mindfulness in the field of evaluation. Mindfulness is a translation of the ancient Indian word, Sati, which means awareness, attention, and remembering. While definitions vary, a practical definition of mindfulness is present-moment awareness in an open and nonjudgmental manner. Mindfulness-based interventions have been employed by a wide variety of professions. Although it has received limited attention in the writings of evaluators, we argue that mindfulness can improve the practice of evaluation and support the development of the professional practice and interpersonal domains of American Evaluation Association (AEA) evaluator competencies. We review several mindfulness-based practices and how they can be used by evaluators in their work. Thus, we posit that far from being an esoteric concept, mindfulness practices can serve the pragmatic end of improving our discipline. We also discuss the limits of mindfulness and propose recommendations for future efforts.

Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.

Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel-Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.

We present a reduced-order surrogate model of gravitational waveforms from non-spinning binary black hole systems with comparable to large mass-ratio configurations. This surrogate model, \texttt{BHPTNRSur1dq1e4}, is trained on waveform data generated by point-particle black hole perturbation theory (ppBHPT) with mass ratios varying from 2.5 to 10,000. \texttt{BHPTNRSur1dq1e4} extends an earlier waveform model, \texttt{EMRISur1dq1e4}, by using an updated transition-to-plunge model, covering longer durations up to 30,500 $m_1$ (where $m_1$ is the mass of the primary black hole), includes several more spherical harmonic modes up to $\ell=10$, and calibrates subdominant modes to numerical relativity (NR) data. In the comparable mass-ratio regime, including mass ratios as low as $2.5$, the gravitational waveforms generated through ppBHPT agree surprisingly well with those from NR after this simple calibration step. We also compare our model to recent SXS and RIT NR simulations at mass ratios ranging from $15$ to $32$, and find the dominant quadrupolar modes agree to better than $\approx 10^{-3}$. We expect our model to be useful to study intermediate-mass-ratio binary systems in current and future gravitational-wave detectors., Comment: 20 pages, 15 figures

Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. Based on the structure of the degrader and the neosubstrate, different E3 ligase interfaces are critically involved in this process, thus forming defined “functional hotspots”. Understanding disruptive mutations in functional hotspots informs on the architecture of the underlying assembly, and highlights residues prone to cause drug resistance. Until now, their identification was driven by structural methods with limited scalability. Here, we employ haploid genetics to show that hotspot mutations cluster in the substrate receptors of the hijacked ligases and find that type and frequency of mutations are shaped by the essentiality of the harnessed ligase. Intersection with deep mutational scanning data revealed hotspots that are either conserved, or specific for chemically distinct degraders or recruited neosubstrates. Biophysical and structural validation suggest that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we identified and validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and experimentally widely accessible methodology that empowers the characterization of small-molecule degraders and informs on associated resistance mechanisms.

Very large mass ratio binary black hole systems are of interest both as a clean limit of the two-body problem in general relativity, as well as for their importance as sources of low-frequency gravitational waves. At lowest order, the smaller body moves along a geodesic of the larger black hole's spacetime. Post-geodesic effects include the gravitational self force, which incorporates the backreaction of gravitational-wave emission, and the spin-curvature force, which arises from coupling of the small body's spin to the black hole's spacetime curvature. In this paper, we describe a method for precisely computing bound orbits of spinning bodies about black holes. Our analysis builds off of pioneering work by Witzany which demonstrated how to describe the motion of a spinning body to linear order in the small body's spin. Exploiting the fact that in the large mass-ratio limit spinning-body orbits are close to geodesics and using closed-form results due to van de Meent describing precession of the small body's spin along black hole orbits, we develop a frequency-domain formulation of the motion which can be solved very precisely. We examine a range of orbits with this formulation, focusing in this paper on orbits which are eccentric and nearly equatorial (i.e., the orbit's motion is $\mathcal{O}(S)$ out of the equatorial plane), but for which the small body's spin is arbitrarily oriented. We discuss generic orbits with general small-body spin orientation in a companion paper. We characterize the behavior of these orbits and show how the small body's spin shifts the frequencies $\Omega_r$ and $\Omega_\phi$ which affect orbital motion. These frequency shifts change accumulated phases which are direct gravitational-wave observables, illustrating the importance of precisely characterizing these quantities for gravitational-wave observations. (Abridged), Comment: 38 pages, 5 figures, submitted to Physical Review D; corrected typo in Equation (C6)

In this paper, we continue our study of the motion of spinning test bodies orbiting Kerr black holes. Non-spinning test bodies follow geodesics of the spacetime in which they move. A test body's spin couples to the curvature of that spacetime, introducing a "spin-curvature force" which pushes the body's worldline away from a geodesic trajectory. The spin-curvature force is an important example of a post-geodesic effect which must be modeled carefully in order to accurately characterize the motion of bodies orbiting black holes. One motivation for this work is to understand how to include such effects in models of gravitational waves produced from the inspiral of stellar mass bodies into massive black holes. In this paper's predecessor, we describe a technique for computing bound orbits of spinning bodies around black holes with a frequency-domain description which can be solved very precisely. In that paper, we present an overview of our methods, as well as present results for orbits which are eccentric and nearly equatorial (i.e., the orbit's motion is no more than $\mathcal{O}(S)$ out of the equatorial plane). In this paper, we apply this formulation to the fully generic case -- orbits which are inclined and eccentric, with the small body's spin arbitrarily oriented. We compute the trajectories which such orbits follow, and compute how the small body's spin affects important quantities such as the observable orbital frequencies $\Omega_r$, $\Omega_\theta$ and $\Omega_\phi$., Comment: 24 pages, 8 figures, submitted to Physical Review D; typos in supplementary Mathematica notebook corrected

In recent work, we examined how different modes in the ringdown phase of a binary coalescence are excited as a function of the final plunge geometry. At least in the large mass ratio limit, we found a clean mapping between angles describing the plunge and the amplitude of different quasi-normal modes (QNMs) which constitute the ringdown. In this study, we use that mapping to construct a waveform model expressed as a sum of QNMs where the mode amplitudes and phases are determined by the source plunge parameters. We first generate a large number of calibration waveforms and interpolate between fits of each mode amplitude and phase up to $\ell \leq 8$ and $\ell - |m| \leq 4$. The density of our calibration data allows us to resolve important features such as phase transition discontinuities at large misalignments. Using our ringdown waveform model, we then perform Bayesian parameter estimation with added white Gaussian noise to demonstrate that, in principle, the mode amplitudes can be measured and used to constrain the plunge geometry. We find that inferences are substantially improved by incorporating prior information constraining mode excitation, which motivates work to understand and characterize how the QNM excitation depends on the coalescence geometry. These results are part of a broader effort to map the mode excitation from arbitrary masses and spins, which will be useful for characterizing ringdown waves in upcoming gravitational-wave measurements., Comment: 19 pages, 14 figures, submitted to PRD

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co‐crystal structure of macroPROTAC‐1 bound in a ternary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12‐fold loss of binary binding affinity for Brd4, macroPROTAC‐1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets., Closing the circle: A macrocyclic PROTAC has been designed and synthesized by adding a cyclizing linker to MZ1, a PROTAC targeting the bromodomain of the BET protein, Brd4. A co‐crystal structure of macroPROTAC‐1 bound in a ternary complex with E3 ligase VHL and the second bromodomain of Brd4 validated the rational design. This macrocyclization strategy enhanced the target specificity and cellular activity of the PROTAC.

Air pollution is becoming increasingly serious along with social and economic development in the southwest of China. The distribution characteristics of particle matter (PM) were studied in Chengdu from 2016 to 2017, and the changes of PM bearing water-soluble ions and heavy metals and the distribution of secondary ions were analyzed during the haze episode. The results showed that at different pollution levels, heavy metals were more likely to be enriched in fine particles and may be used as a tracer of primary pollution sources. The water-soluble ions in PM2.5 were mainly Sulfate-Nitrate-Ammonium (SNA) accounting for 43.02%, 24.23%, 23.50%, respectively. SO42−, NO3−, NH4+ in PM10 accounted for 34.56%, 27.43%, 19.18%, respectively. It was mainly SO42− in PM at Clean levels (PM2.5 = 0~75 μg/m3, PM10 = 0~150 μg/m3), and mainly NH4+ and NO3− at Light-Medium levels (PM2.5 = 75~150 μg/m3, PM10 = 150~350 μg/m3). At Heavy levels (PM2.5 = 150~250 μg/m3, PM10 = 350~420 μg/m3), it is mainly SO42− in PM2.5, and mainly NH4+ and NO3− in PM10. The contribution of mobile sources to the formation of haze in the study area was significant. SNA had significant contributions to the PM during the haze episode, and more attention should be paid to them in order to improve air quality.

Short-term and long-term science plans were developed as part of the strategic planning process used by the Biologic Analog Science Associated with Lava Terrains (BASALT) science team to conduct two Mars-simulation missions investigating basalt habitability at terrestrial volcanic analog sites in 2016. A multidisciplinary team of scientists generated and codified a range of scientific hypotheses distilled into a Science Traceability Matrix (STM) that defined the set of objectives pursued in a series of extravehicular activity (EVA) campaigns performed across multiple field deployments. This STM was used to guide the pre-deployment selection of sampling stations within the selected Mars analog sites on the Earth based on precursor site information such as multispectral imagery. It also informed selection of hand-held instruments and observational data to collect during EVA to aid sample selection through latency-impacted interaction with an Earth-based Science Support Team. A significant portion of the pre-deployment strategic planning activities were devoted to station selection, ultimately the locations used for sample collection and EVA planning. During development of the EVAs, the BASALT science team identified lessons learned that could be used to inform future missions and analog activities, including the critical need for high-resolution precursor imagery that would enable the selection of stations that could meet the scientific objectives outlined in the STM.

Field research target regions within two basaltic geologic provinces are described as Earth analogs to Mars. Regions within the eastern Snake River Plain of Idaho and the Big Island of Hawai‘i, the United States, provinces that represent analogs of present-day and early Mars, respectively, were evaluated on the basis of geologic settings, rock lithology and geochemistry, rock alteration, and climate. Each of these factors provides rationale for the selection of specific targets for field research in five analog target regions: (1) Big Craters and (2) Highway lava flows at Craters of the Moon National Monument and Preserve, Idaho, and (3) Mauna Ulu low shield, (4) Kīlauea Iki lava lake, and (5) Kīlauea caldera in the Kīlauea Volcano summit region and the East Rift Zone of Hawai‘i. Our evaluation of compositional and textural attributes, as well as the effects of syn- and posteruptive rock alteration, shows that basaltic terrains in Idaho and Hawai‘i provide a way to characterize the geology and major geologic substrates that host biological activity of relevance to Mars exploration. This work provides the foundation to better understand the scientific questions related to the habitability of basaltic terrains, the rationale behind selecting analog field targets, and their applicability as analogs to Mars.

Biologic Analog Science Associated with Lava Terrains (BASALT) is a science-driven exploration program seeking to determine the best tools, techniques, training requirements, and execution strategies for conducting Mars-relevant field science under spaceflight mission conditions. BASALT encompasses Science, Science Operations, and Technology objectives. This article outlines the BASALT Science Operations background, strategic research questions, study design, and a portion of the results from the second field test. BASALT field tests are used to iteratively develop, integrate, test, evaluate, and refine new concepts of operations (ConOps) and capabilities that enable efficient and productive science. This article highlights the ConOps investigated during BASALT in light of future planetary extravehicular activity (EVA), which will focus on scientific exploration and discovery, and serves as an introduction to integrating exploration flexibility with operational rigor, the value of tactical and strategic science planning and execution, and capabilities that enable and enhance future science EVA operations.

Science-driven, human spaceflight missions of the future will rely on regular and interactive communication between Earth- and space-based teams during activity in which astronauts work directly on Mars or other planetary surfaces (extravehicular activity, EVA). The Biologic Analog Science Associated with Lava Terrains (BASALT) project conducted simulated human missions to Mars, complete with realistic one-way light time (OWLT) communication latency. We discuss the modes of communication used by the Mars- and Earth-based teams, including text, audio, video, and still imagery. Real-time communication between astronauts in the field (extravehicular, EV) and astronauts in a communication relay station (intravehicular, IV) was broadcast over OWLT, providing important contextual information to the Science Backroom Team (SBT) in Mission Control. Collaborative communication between the Earth- and Mars-based teams, however, requires active communication across latency via the Mission Log. We provide descriptive statistics of text communication between IV and SBT in a high-fidelity, scientifically driven analog for human space exploration. Over an EVA, the SBT sent an average of ∼23 text messages containing recommendations, requests, and answers to questions, while the science-focused IV crew member (IV2) sent an average of ∼38 text messages. Though patterns varied, communication between the IV and SBT teams tended to be highest during ∼50–150 min into the EVA, corresponding to the candidate sample search and presampling instrument survey phases, and then decreased dramatically after minute ∼200 during the sample collection phase. Generally, the IV2 and SBT used ∼4.6 min to craft a reply to a direct question or comment, regardless of message length or OWLT, offering a valuable glimpse into actual time-to-reply. We discuss IV2-SBT communication within the context of case examples from an EVA during which communication failures affected operations in the field. Finally, we offer recommendations for communication practices for use in future analogs and, perhaps, science-driven human spaceflight.

Human explorers on the surface of Mars will have access to a far wider array of scientific tools than previous crewed planetary exploration missions, but not every tool will be compatible with the restrictions of this exploration. Spectrometers on flyby, orbital, and landed missions are currently used to determine the composition and mineralogy of geological materials of various types and sizes, from small fragments to celestial bodies in the solar system. Handheld spectrometers that are capable of in situ analyses are already used for geological exploration on Earth; however, their usefulness for human exploration missions and how data from multiple handheld instruments could be combined to enhance scientific return must be further evaluated. As part of the Biologic Analog Science Associated with Lava Terrains (BASALT) research project, we incorporated two handheld instruments, a visible-near infrared spectrometer and an X-Ray Fluorescence spectrometer, into simulated Mars exploration missions conducted on basaltic terrains in Idaho and Hawai'i. To understand the data quality provided by these handheld spectrometers, we evaluated their performance under varying conditions of measurement time, distance, angle, atmosphere, and sample matrix, and we compared data quality between handheld instruments and laboratory techniques. Here, we summarize these findings, provide guidelines and requirements on how to effectively incorporate these instruments into human exploration missions to Mars, and posit that future iterations of these instruments will be beneficial for enhancing science returned from human exploration missions.

The articles associated with this Special Collection focus on the NASA BASALT (Biologic Analog Science Associated with Lava Terrains) Research Program, which aims at answering the question, “How do we support and enable scientific exploration during human Mars missions?” To answer this the BASALT team conducted scientific field studies under simulated Mars mission conditions to both broaden our understanding of the habitability potential of basalt-rich terrains on Mars and examine the effects of science on current Mars mission concepts of operations. This article provides an overview of the BASALT research project, from the science, to the operational concepts that were tested and developed, to the technical capabilities that supported all elements of the team's research. Further, this article introduces the 12 articles that are included in this Special Collection.

A major objective in the exploration of Mars is to test the hypothesis that the planet hosted life. Even in the absence of life, the mapping of habitable and uninhabitable environments is an essential task in developing a complete understanding of the geological and aqueous history of Mars and, as a consequence, understanding what factors caused Earth to take a different trajectory of biological potential. We carried out the aseptic collection of samples and comparison of the bacterial and archaeal communities associated with basaltic fumaroles and rocks of varying weathering states in Hawai'i to test four hypotheses concerning the diversity of life in these environments. Using high-throughput sequencing, we found that all these materials are inhabited by a low-diversity biota. Multivariate analyses of bacterial community data showed a clear separation between sites that have active fumaroles and other sites that comprised relict fumaroles, unaltered, and syn-emplacement basalts. Contrary to our hypothesis that high water flow environments, such as fumaroles with active mineral leaching, would be sites of high biological diversity, alpha diversity was lower in active fumaroles compared to relict or nonfumarolic sites, potentially due to high-temperature constraints on microbial diversity in fumarolic sites. A comparison of these data with communities inhabiting unaltered and weathered basaltic rocks in Idaho suggests that bacterial taxon composition of basaltic materials varies between sites, although the archaeal communities were similar in Hawai'i and Idaho. The taxa present in both sites suggest that most of them obtain organic carbon compounds from the atmosphere and from phototrophs and that some of them, including archaeal taxa, cycle fixed nitrogen. The low diversity shows that, on Earth, extreme basaltic terrains are environments on the edge of sustaining life with implications for the biological potential of similar environments on Mars and their exploration by robots and humans.

Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target:PROTAC:ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation in vitro using purified proteins. We benchmark our assay using four PROTACs that target the bromodomains (BDs) of BET proteins Brd2, Brd3 and Brd4 to the E3 ligase VHL. We reveal marked differences in ternary complex off-rates for different PROTACs that exhibit either positive or negative cooperativity for ternary complex formation relative to binary binding. The positively cooperative degrader MZ1 forms comparatively stable and long-lived ternary complexes with either Brd4BD2 or Brd2BD2 and VHL. Equivalent complexes with Brd3BD2 are destabilised due to a single amino acid difference (Glu/Gly swap) present in the bromodomain. We observe that this difference in ternary complex dissociative half-life correlates to a greater initial rate of intracellular degradation of Brd2 and Brd4 relative to Brd3. These findings establish a novel assay to measure the kinetics of PROTAC ternary complexes and elucidate the important kinetic parameters that drive effective target degradation.

The gravitational waves accompanying the merger of two massive compact objects encode the distance to the merger without the usual appeal to a hierarchy of length scales.

Vanadium (V) can have toxic effects on human organs and physiological systems, yet tracing V sources remains challenging. Here, two methods were used for V source tracing in soil based on speciation characteristics and isotope compositions. According to the sequential extraction method of the European Communities Bureau of Reference (BCR), the analysis of speciation distributions offers a possible means of distinguishing V sources. Here, the isotope compositions of polluted soils around a coal-fired power plant and smelter in China were used to identify the sources of V. Significant V isotope variation (δ51V range = -0.74 ± 0.07; mean ± 2SD = -0.52 ± 0.05‰) was observed in the soil samples, attributed to coal-burning (Δ51VCoal-Fly ash 1 = -0.31 ± 0.05‰; mean ± 2SD; n = 1) and smelting processes (Δ51VSlag-Fly ash 2 = -0.31 ± 0.07‰; mean ± 2SD; n = 1). All of the soil V isotope ratios plotted within the range of end-member components corresponding to potential V contributors in the environment. Among these, δ51V ranged from -0.74 ± 0.07 to -0.55 ± 0.02‰ in topsoil, the average δ51V was -0.52 ± 0.05‰ in the deep soils, and the δ51V of the end-member components ranged from -0.52 ± 0.05 to -0.94 ± 0.11‰. The primary anthropogenic source of V in the topsoil was fly ash from coal-burning that was consistent with the BCR method results. Furthermore, the downward migration of V was identified in the soil profile adjacent to the smelting plant, and V in the deep soils was dominated by natural sources relative to anthropogenic sources in the surface soils.

Extensive industrial activities have led to an increase of the content of chromium in the environment, which causes serious pollution to the surrounding water, soil and atmosphere. The enrichment of chromium in the environment through the food chain ultimately affects human health. Therefore, the remediation of chromium pollution is crucial to development of human society. A lot of scholars have paid attention to bioremediation technology owing to its environmentally friendly and low-cost. Previous reviews mostly involved pure culture of microorganisms and rarely discussed the optimization of bioreduction conditions. To make up for these shortcomings, we not only introduced in detail the conditions that affect microbial reduction but also innovatively introduced consortium which may be the cornerstone for future treatment of complex field environments. The aim of this study is to summary chromium toxicity, factors affecting microbial remediation, and methods for enhancing bioremediation. However, the actual application of bioremediation technology is still facing a major challenge. This study also put forward the current research problems and proposed future research directions, providing theoretical guidance and scientific basis for the application of bioremediation technology.

Proteolysis targeting chimeras (PROTACs) are complex molecules to design and optimize as degraders, primarily because the linker that bridges the two binding ligands is a highly variable element of design, yet critical for simultaneous engagement of target and E3 ligase into a ternary complex, target ubiquitination and ultimately degradation. These chemical and mechanistic complexities mean that the PROTAC design process can be a daunting endeavour, and it remains unpredictable how to best optimize them into high-quality degraders. To understand how medicinal chemistry decisions could translate into functional outcomes, here we present a retrospective and holistic mechanistic study of a two-part sequential medicinal chemistry program, termed Series 1 and 2, which previously led to the discovery of VZ185, a potent VHL-based dual BRD7 and BRD9 degrader. Analysis of the initial Series 1 compounds across three different cell lines containing endogenously tagged CRISPR HiBiT BRD7 or BRD9 revealed only partial degradation of BRD9, and no degradation of BRD7. Analysis of Series 2 PROTACs, which was designed based on the degradation outcomes of Series 1 and in the absence of ternary complex structural information, showed the emergence of three lead compounds improved in BRD9 degradation and with additional specificity for BRD7. Biochemical analysis to interrogate ternary complex affinity and cooperativity demonstrated how subtle chemistry alterations impacted these parameters both positively and negatively, though on average, achieving only minor improvements in Series 2. In contrast, the greatest change between Series 1 and 2 was an improvement in cellular permeability, with the three lead degradation compounds showing high permeability. Lastly, cellular ubiquitination studies were performed and demonstrated the most potent degrader, VZ185, was the most robust for ubiquitination despite neither being the most permeable nor the best at forming ternary complex within the entire set. VZ185 and similarly active compounds were found to be efficacious degraders across all cell lines tested. Our mechanistic characterization provides insights that, while our structurally unguided medicinal chemistry campaign improved most notably cell permeability, increased degradation outcomes also required retaining productive ternary complex formation and target ubiquitination.

A powerful technique to calculate gravitational radiation from binary systems involves a perturbative expansion: if the masses of the two bodies are very different, the "small" body is treated as a point particle of mass $m_p$ moving in the gravitational field generated by the large mass $M$, and one keeps only linear terms in the small mass ratio $m_p/M$. This technique usually yields finite answers, which are often in good agreement with fully nonlinear numerical relativity results, even when extrapolated to nearly comparable mass ratios. Here we study two situations in which the point-particle approximation yields a divergent result: the instantaneous flux emitted by a small body as it orbits the light ring of a black hole, and the total energy absorbed by the horizon when a small body plunges into a black hole. By integrating the Teukolsky (or Zerilli/Regge-Wheeler) equations in the frequency and time domains we show that both of these quantities diverge. We find that these divergences are an artifact of the point-particle idealization, and are able to interpret and regularize this behavior by introducing a finite size for the point particle. These divergences do not play a role in black-hole imaging, e.g. by the Event Horizon Telescope., 11 pages, 6 figures, matches version published in Physical Review D

We compute adiabatic waveforms for extreme mass-ratio inspirals (EMRIs) by "stitching" together a long inspiral waveform from a sequence of waveform snapshots, each of which corresponds to a particular geodesic orbit. We show that the complicated total waveform can be regarded as a sum of "voices." Each voice evolves in a simple way on long timescales, a property which can be exploited to efficiently produce waveform models that faithfully encode the properties of EMRI systems. We look at examples for a range of different orbital geometries: spherical orbits, equatorial eccentric orbits, and one example of generic (inclined and eccentric) orbits. To our knowledge, this is the first calculation of a generic EMRI waveform that uses strong-field radiation reaction. We examine waveforms in both the time and frequency domains. Although EMRIs evolve slowly enough that the stationary phase approximation (SPA) to the Fourier transform is valid, the SPA calculation must be done to higher order for some voices, since their instantaneous frequency can change from chirping forward ($\dot f > 0$) to chirping backward ($\dot f < 0$). The approach we develop can eventually be extended to more complete EMRI waveform models, for example to include effects neglected by the adiabatic approximation such as the conservative self force and spin-curvature coupling., 31 pages, 17 figures. Update: corrected a sign error in a term in Eq. (B5). This factor was correct in the related code, it was purely a typo in the manuscript. An erratum to PRD has been submitted. Many thanks to Angelica Albertini for bringing this error to our attention

Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided by intra-complex interactions. We hypothesized these molecular recognition features could be enhanced by increasing binding valency. Here we present trivalent PROTACs as a strategy to boost protein degradation. Our design for a trivalent PROTAC consisted of two BET bromodomain inhibitors and an E3 ligase ligand, each separately tethered via a branched linker. In screening, we identified SIM1, a VHL-based PROTAC, as a highly potent BET degrader, capable of low picomolar degradation for all family members, with preference for BRD2. In functional comparison studies to bivalent PROTACs or inhibitors, SIM1 showed more sustained anti-cancer activity across numerous therapeutically relevant cell lines. Biophysical, biochemical, and cellular mechanistic studies showed SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. The resulting 1:1:1 complex showed positive cooperativity, high stability and prolonged cellular residence time. We provide proof-of-concept for augmenting the binding valency of proximity-induced modalities as a strategy to leverage both cooperativity and avidity within the ternary complex to advance functional outcomes.

The surface morphology and roughness of a lava flow provides insight on its lava properties and emplacement processes. This is essential information for understanding the eruption history of lava fields, and magmatic processes beneath the surface of Earth and other planetary bodies such as the Moon. The surface morphology is influenced by lava properties such as viscosity, temperature, composition, and rate of shear. In this work, we seek to understand how we can interpret the emplacement processes and lava properties of lava flows using remote sensing data. Craters of the Moon (COTM) National Monument and Preserve in Idaho hosts a suite of compositionally diverse lava flows with a wide range of surface roughness making it the ideal case study. Lava flows there have surface morphologies consistent with smooth pāhoehoe, slabby pāhoehoe, hummocky pāhoehoe, rubbly pāhoehoe, ‘a’ā, block-`a’ā, and blocky textures. The variation in surface roughness across the lava field reflects changes in lava properties and/or emplacement processes over space and time. We investigate geochemical and petrographic variations of the different lava flow morphologies and analyse how they relate to airborne radar data. Results show L-Band (24 ​cm) radar circular polarization ratios (CPR) distinguish the contrasting surface roughness at COTM, separating the smoother (primitive; low SiO2 and alkali) and rougher (evolved; high SiO2 and alkali) lava flows. However, ambiguities are present when comparing the CPR values for rubbly pāhoehoe and block-`a’ā flow. Even though their CPR values appear similar at the decimetre scale, they have distinct morphologies that formed under different emplacement processes. Without ground-truth information, the rubbly pāhoehoe and block-`a’ā lava flows could therefore be misinterpreted to be the same type of flow morphology, which would lead to false interpretations about their lava properties and emplacement processes. This is important when comparing these flows to lava flows on other planetary bodies that share similar CPR values, such as the Moon. Thus, using terrestrial analogues such as those at COTM can provide an improved understanding of the surface morphology and emplacement processes of lunar lava flows. This will lead to more refined interpretations about past volcanic processes on the Moon.

The future space mission LISA will observe a wealth of gravitational-wave sources at millihertz frequencies. Of these, the extreme-mass-ratio inspirals of compact objects into massive black holes are the only sources that combine the challenges of strong-field complexity with that of long-lived signals. Such signals are found and characterized by comparing them against a large number of accurate waveform templates during data analysis, but the rapid generation of such templates is hindered by computing the $\sim10^3$-$10^5$ harmonic modes in a fully relativistic waveform. We use order-reduction and deep-learning techniques to derive a global fit for these modes, and implement it in a complete waveform framework with hardware acceleration. Our high-fidelity waveforms can be generated in under $1\,\mathrm{s}$, and achieve a mismatch of $\lesssim 5\times 10^{-4}$ against reference waveforms that take $\gtrsim 10^4$ times longer. This marks the first time that analysis-length waveforms with full harmonic content can be produced on timescales useful for direct implementation in LISA analysis algorithms., 6 pages, 3 figures

Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the proteasome. Most degraders lie outside the chemical space associated with most membrane-permeable drugs. Although many PROTACs have been described with potent activity in cells, our understanding of the relationship between structure and permeability in these compounds remains limited. Here, we describe a label-free method for assessing the permeability of several VH032-based PROTACs and their components by combining a parallel artificial membrane permeability assay (PAMPA) and a lipophilic permeability efficiency (LPE) metric. Our results show that the combination of these two cell-free membrane permeability assays provides new insight into PROTAC structure-permeability relationships and offers a conceptual framework for predicting the physicochemical properties of PROTACs in order to better inform the design of more permeable and more effective degraders.

Physical and compositional measurements are made at the ~ 7 km-long (~ 2200 years B.P.) Kings Bowl basaltic fissure system and surrounding lava field in order to further understand the interaction of fissure-fed lavas with phreatic explosive events. These assessments are intended to elucidate the cause and potential for hazards associated with phreatic phases that occur during basaltic fissure eruptions. In the present paper we focus on a general understanding of the geological history of the site. We utilize geospatial analysis of lava surfaces, lithologic and geochemical signatures of lava flows and explosively ejected blocks, and surveys via ground observation and remote sensing. Lithologic and geochemical signatures readily distinguish between Kings Bowl and underlying pre-Kings Bowl lava flows, both of which comprise phreatic ejecta from the Kings Bowl fissure. These basalt types, as well as neighboring lava flows from the contemporaneous Wapi lava field and the older Inferno Chasm vent and outflow channel, fall compositionally within the framework of eastern Snake River Plain olivine tholeiites. Total volume of lava in the Kings Bowl field is estimated to be ~ 0.0125 km3, compared to a previous estimate of 0.005 km3. The main (central) lava lake lost a total of ~ 0.0018 km3 of magma by either drain-back into the fissure system or breakout flows from breached levees. Phreatic explosions along the Kings Bowl fissure system occurred after magma supply was cut off, leading to fissure evacuation, and were triggered by magma withdrawal. The fissure system produced multiple phreatic explosions and the main pit is accompanied by others that occur as subordinate pits and linear blast corridors along the fissure. The drop in magma supply and the concomitant influx of groundwater were necessary processes that led to the formation of Kings Bowl and other pits along the fissure. A conceptual model is presented that has relevance to the broader range of low-volume, monogenetic basaltic fissure eruptions on Earth, the Moon and other planetary bodies.

We have measured the induced thermoluminescence (TL) properties of fifteen samples of basalts collected from the Big Island of Hawaii in order to continue our investigation into the possible utility of this technique as a chronometer. Previous studies of basalts from Idaho have suggested the induced TL of basalts increases with age. Meteorite data suggest two possible explanations for this observation which are that (1) the initial glassy or amorphous phases crystalize with time to produce feldspar, the mineral producing the TL signal, and (2) feldspars lose Fe as they equilibrate and since Fe is a quencher of TL this would cause an increase in TL. The old basalts from Kohala (> 100 ka), which are mostly alkali basalts, have TL sensitivities 10–100 times higher than the much younger tholeiites from Kilauea and Mauna Loa (