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We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
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Antivirales , Antivirales/farmacología , Antivirales/química , Humanos , Animales , Proteínas 14-3-3/metabolismo , Complejos Multiproteicos/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Línea CelularRESUMEN
Plastic scintillators, a class of solid-state materials used for radiation detection, were additively manufactured with vat photopolymerization. The photopolymer resins consisted of a primary dopant and a secondary dopant dissolved in a bisphenol A ethoxylate diacrylate-based matrix. The absorptive dopants significantly influence important print parameters, for example, secondary dopants decrease the light penetration depth by a factor > 12 ×. The primary dopant 2,5-diphenyloxazole had minimal impact on the printing process even when loaded at 25 % by mass of the resin. Working curve measurements, which relate energy dose to cure depth, were performed as a function of feature size to further assess the influence of dopants. Photopatterns smaller than 150 µm width had apparent increases in critical energy dose compared to larger photopatterns, while all resins maintained printed features in line gratings with 50 µm of separation. Printed scintillator monoliths were compared to scintillators cast by traditional molding, demonstrating that the layer-by-layer printing process does not decrease scintillation response. A maximum light output of 31 % of a benchmark plastic scintillator (EJ-200) and successful pulse shape discrimination were achieved with 20 % by mass 2,5-diphenyloxazole as the primary dopant and 0.1 % by mass 9,9-dimethyl-2,7-distyrylfluorene as the secondary dopant in printed scintillator samples.
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Understanding the factors that cause endangered populations to either grow or decline is crucial for preserving biodiversity. Conservation efforts often address extrinsic threats, such as environmental degradation and overexploitation, that can limit the recovery of endangered populations. Genetic factors such as inbreeding depression can also affect population dynamics but these effects are rarely measured in the wild and thus often neglected in conservation efforts. Here we show that inbreeding depression strongly influences the population dynamics of an endangered killer whale population, despite genomic signatures of purging of deleterious alleles via natural selection. We find that the 'Southern Residents', which are currently endangered despite nearly 50 years of conservation efforts, exhibit strong inbreeding depression for survival. Our population models suggest that this inbreeding depression limits population growth and predict further decline if the population remains genetically isolated and typical environmental conditions continue. The Southern Residents also had more inferred homozygous deleterious alleles than three other, growing, populations, further suggesting that inbreeding depression affects population fitness. These results demonstrate that inbreeding depression can substantially limit the recovery of endangered populations. Conservation actions focused only on extrinsic threats may therefore fail to account for key intrinsic genetic factors that also limit population growth.
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Depresión Endogámica , Orca , Animales , Endogamia , Orca/genética , Dinámica Poblacional , Selección GenéticaRESUMEN
Quantitative models that simulate the inheritance and evolution of fitness-linked traits offer a method for predicting how environmental or anthropogenic perturbations can affect the dynamics of wild populations. Random mating between individuals within populations is a key assumption of many such models used in conservation and management to predict the impacts of proposed management or conservation actions. However, recent evidence suggests that non-random mating may be underestimated in wild populations and play an important role in diversity-stability relationships. Here we introduce a novel individual-based quantitative genetic model that incorporates assortative mating for reproductive timing, a defining attribute of many aggregate breeding species. We demonstrate the utility of this framework by simulating a generalized salmonid lifecycle, varying input parameters, and comparing model outputs to theoretical expectations for several eco-evolutionary, population dynamic scenarios. Simulations with assortative mating systems resulted in more resilient and productive populations than those that were randomly mating. In accordance with established ecological and evolutionary theory, we also found that decreasing the magnitude of trait correlations, environmental variability, and strength of selection each had a positive effect on population growth. Our model is constructed in a modular framework so that future components can be easily added to address pressing issues such as the effects of supportive breeding, variable age structure, differential selection by sex or age, and fishery interactions on population growth and resilience. With code published in a public Github repository, model outputs may easily be tailored to specific study systems by parameterizing with empirically generated values from long-term ecological monitoring programs.
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Many energy technologies that can provide reliable, low-carbon electricity generation are confined to nations that have access to robust technical and economic capabilities, either on their own or through geopolitical alliances. Equally important, these nations maintain a degree of institutional capacity that could lower the risks associated with deploying emergent energy technologies such as advanced nuclear or carbon capture and storage. The complexity, expense, and scrutiny that come with building these facilities make them infeasible choices for most nations. This paradigm is slowly changing, as the pressing need for low-carbon electricity generation and ongoing efforts to develop modular nuclear and carbon capture technologies have opened the door for potentially wider markets, including in nations without substantial institutional capacity. Here, using advanced nuclear technologies as our testbed, we develop new methods to evaluate national readiness for deploying complex energy infrastructure. Specifically, we use Data Envelopment Analysis-a method that eliminates the need for expert judgment-to benchmark performance across nations. We find that approximately 80% of new nuclear deployment occurs in nations that are in the top two quartiles of institutional and economic performance. However, 85% of potential low-carbon electricity demand growth is in nations that are in the bottom two quartiles of performance. We offer iconic paradigms for deploying nuclear power in each of these clusters of nations if the goal is to mitigate risk. Our research helps redouble efforts by industry, regulators, and international development agencies to focus on areas where readiness is low and risk correspondingly higher.
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Soft materials that exhibit compliance, programmability, and reconfigurability can have a transformative impact as electronic skin for applications in wearable electronics/soft robotics. There has been significant progress in soft conductive materials; however, achieving electrically controlled and reversible changes in conductivity and circuit connectivity remains challenging. To overcome this limitation, a soft material architecture with reconfigurable conductive networks of silver flakes embedded within a hydrogel matrix is presented. The conductive networks can be reversibly created/disconnected through various stimuli, including current, humidity, or temperature. Such stimuli affect electrical connectivity of the hydrogel by controlling its water content, which can be modulated by evaporation under ambient conditions (passive dehydration), evaporation through electrical Joule heating (active dehydration), or absorption of additional water (rehydration). The resulting change in electrical conductivity is reversible and repeatable, endowing the composite with on-demand reconfigurable conductivity. To highlight this material's unique properties, it is shown that conductive traces can be reconfigured after severe damage and revert to lower conductivity after rehydration. Additionally, a quadruped robot is demonstrated that can respond to stimuli by changing direction following exposure to excess water, thereby achieving reprogrammable locomotion behaviors.
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The increasing feasibility of assembling large genomic datasets for non-model species presents both opportunities and challenges for applied conservation and management. A popular theme in recent studies is the search for large-effect loci that explain substantial portions of phenotypic variance for a key trait(s). If such loci can be linked to adaptations, 2 important questions arise: 1) Should information from these loci be used to reconfigure conservation units (CUs), even if this conflicts with overall patterns of genetic differentiation? 2) How should this information be used in viability assessments of populations and larger CUs? In this review, we address these questions in the context of recent studies of Chinook salmon and steelhead (anadromous form of rainbow trout) that show strong associations between adult migration timing and specific alleles in one small genomic region. Based on the polygenic paradigm (most traits are controlled by many genes of small effect) and genetic data available at the time showing that early-migrating populations are most closely related to nearby late-migrating populations, adult migration differences in Pacific salmon and steelhead were considered to reflect diversity within CUs rather than separate CUs. Recent data, however, suggest that specific alleles are required for early migration, and that these alleles are lost in populations where conditions do not support early-migrating phenotypes. Contrasting determinations under the US Endangered Species Act and the State of California's equivalent legislation illustrate the complexities of incorporating genomics data into CU configuration decisions. Regardless how CUs are defined, viability assessments should consider that 1) early-migrating phenotypes experience disproportionate risks across large geographic areas, so it becomes important to identify early-migrating populations that can serve as reliable sources for these valuable genetic resources; and 2) genetic architecture, especially the existence of large-effect loci, can affect evolutionary potential and adaptability.
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Oncorhynchus mykiss , Salmón , Alelos , Animales , Evolución Biológica , Especies en Peligro de Extinción , Oncorhynchus mykiss/genética , Salmón/genéticaRESUMEN
Five effects of correction of the asymptotic potential error in density functionals are identified that significantly improve calculated properties of molecular excited states involving charge-transfer character. Newly developed materials-science computational methods are used to demonstrate how these effects manifest in materials spectroscopy. Connection is made considering chlorophyll-a as a paradigm for molecular spectroscopy, 22 iconic materials as paradigms for 3D materials spectroscopy, and the VN - defect in hexagonal boron nitride as an example of the spectroscopy of defects in 2D materials pertaining to nanophotonics. Defects can equally be thought of as being "molecular" and "materials" in nature and hence bridge the relms of molecular and materials spectroscopies. It is concluded that the density functional HSE06, currently considered as the standard for accurate calculations of materials spectroscopy, should be replaced, in most instances, by the computationally similar but asymptotically corrected CAM-B3LYP functional, with some specific functionals for materials-use only providing further improvements.
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We present a small molecule chemotype, identified by an orthogonal drug screen, exhibiting nanomolar activity against members of all the six viral families causing most human respiratory viral disease, with a demonstrated barrier to resistance development. Antiviral activity is shown in mammalian cells, including human primary bronchial epithelial cells cultured to an air-liquid interface and infected with SARS-CoV-2. In animals, efficacy of early compounds in the lead series is shown by survival (for a coronavirus) and viral load (for a paramyxovirus). The drug target is shown to include a subset of the protein 14-3-3 within a transient host multi-protein complex containing components implicated in viral lifecycles and in innate immunity. This multi-protein complex is modified upon viral infection and largely restored by drug treatment. Our findings suggest a new clinical therapeutic strategy for early treatment upon upper respiratory viral infection to prevent progression to lower respiratory tract or systemic disease. One Sentence Summary: A host-targeted drug to treat all respiratory viruses without viral resistance development.
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Vessel traffic is prevalent throughout marine environments. However, we often have a limited understanding of vessel impacts on marine wildlife, particularly cetaceans, due to challenges of studying fully-aquatic species. To investigate vessel and acoustic effects on cetacean foraging behavior, we attached suction-cup sound and movement tags to endangered Southern Resident killer whales in their summer habitat while collecting geo-referenced proximate vessel data. We identified prey capture dives using whale kinematic signatures and found that the probability of capturing prey increased as salmon abundance increased, but decreased as vessel speed increased. When vessels emitted navigational sonar, whales made longer dives to capture prey and descended more slowly when they initiated these dives. Finally, whales descended more quickly when noise levels were higher and vessel approaches were closer. These findings advance a growing understanding of vessel and sound impacts on marine wildlife and inform efforts to manage vessel impacts on endangered populations.
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Orca , Acústica , Animales , Salmón , SonidoRESUMEN
Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαß isolation. TCR transfer to primary CD8+ T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8+ T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.
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Linfocitos T CD8-positivos/inmunología , Carcinogénesis/inmunología , Epítopos de Linfocito T/inmunología , Neoplasias Pulmonares/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Traslado Adoptivo , Alelos , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Mutación , Péptidos/genética , Péptidos/inmunología , Proteómica , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Density functionals with asymptotic corrections to the long-range potential provide entry-level methods for calculations on molecules that can sustain charge transfer, but similar applications in materials science are rare. We describe an implementation of the CAM-B3LYP range-separated functional within the Vienna Ab-initio Simulation Package (VASP) framework, together with its analytical functional derivatives. Results obtained for eight representative materials: aluminum, diamond, graphene, silicon, NaCl, MgO, 2D h-BN, and 3D h-BN, indicate that CAM-B3LYP predictions embody mean-absolute deviations (MAD) compared to HSE06 that are reduced by a factor of six for lattice parameters, four for quasiparticle band gaps, three for the lowest optical excitation energies, and six for exciton binding energies. Further, CAM-B3LYP appears competitive compared to ab initio G0 W0 and Bethe-Salpeter equation approaches. The CAM-B3LYP implementation in VASP was verified by comparison of optimized geometries and reaction energies for isolated molecules taken from the ACCDB database, evaluated in large periodic unit cells, to analogous results obtained using Gaussian basis sets. Using standard GW pseudopotentials and energy cutoffs for the plane-wave calculations and the aug-cc-pV5Z basis set for the atomic-basis ones, the MAD in energy for 1738 chemical reactions was 0.34 kcal mol-1 , while for 480 unique bond lengths this was 0.0036 Å; these values reduced to 0.28 kcal mol-1 (largest error 0.94 kcal mol-1 ) and 0.0009 Å by increasing the plane-wave cutoff energy to 850 eV.
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Understanding diet is critical for conservation of endangered predators. Southern Resident killer whales (SRKW) (Orcinus orca) are an endangered population occurring primarily along the outer coast and inland waters of Washington and British Columbia. Insufficient prey has been identified as a factor limiting their recovery, so a clear understanding of their seasonal diet is a high conservation priority. Previous studies have shown that their summer diet in inland waters consists primarily of Chinook salmon (Oncorhynchus tshawytscha), despite that species' rarity compared to some other salmonids. During other times of the year, when occurrence patterns include other portions of their range, their diet remains largely unknown. To address this data gap, we collected feces and prey remains from October to May 2004-2017 in both the Salish Sea and outer coast waters. Using visual and genetic species identification for prey remains and genetic approaches for fecal samples, we characterized the diet of the SRKWs in fall, winter, and spring. Chinook salmon were identified as an important prey item year-round, averaging ~50% of their diet in the fall, increasing to 70-80% in the mid-winter/early spring, and increasing to nearly 100% in the spring. Other salmon species and non-salmonid fishes, also made substantial dietary contributions. The relatively high species diversity in winter suggested a possible lack of Chinook salmon, probably due to seasonally lower densities, based on SRKW's proclivity to selectively consume this species in other seasons. A wide diversity of Chinook salmon stocks were consumed, many of which are also at risk. Although outer coast Chinook samples included 14 stocks, four rivers systems accounted for over 90% of samples, predominantly the Columbia River. Increasing the abundance of Chinook salmon stocks that inhabit the whales' winter range may be an effective conservation strategy for this population.
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Alimentación Animal/análisis , Conducta Predatoria/fisiología , Salmón/genética , Salmonidae/genética , Análisis de Secuencia de ADN/veterinaria , Orca/fisiología , Animales , Colombia Británica , Conservación de los Recursos Naturales , Especies en Peligro de Extinción , Heces/química , Secuenciación de Nucleótidos de Alto Rendimiento , Ríos , Salmón/clasificación , Salmonidae/clasificación , Estaciones del Año , WashingtónRESUMEN
Variation in age at maturity is an important contributor to life history and demographic variation within and among species. The optimal age at maturity can vary by sex, and the ability of each sex to evolve towards its fitness optimum depends on the genetic architecture of maturation. Using GWAS of RAD sequencing data, we show that age at maturity in Chinook salmon exhibits sex-specific genetic architecture, with age at maturity in males influenced by large (up to 20 Mb) male-specific haplotypes. These regions showed no such effect in females. We also provide evidence for translocation of the sex-determining gene between two different chromosomes. This has important implications for sexually antagonistic selection, particularly that sex linkage of adaptive genes may differ within and among populations based on chromosomal location of the sex-determining gene. Our findings will facilitate research into the genetic causes of shifting demography in Chinook salmon as well as a better understanding of sex determination in this species and Pacific salmon in general.
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Cromosomas , Salmón , Animales , Femenino , Ligamiento Genético , Haplotipos , Masculino , Salmón/genéticaRESUMEN
Soft actuators that undergo programmable shape change in response to a stimulus are enabling components of future soft robots and other soft machines. Strategies to power these actuators often require the incorporation of rigid, electrically conductive materials into the soft actuator, thus limiting the compliance and shape change of the material. In this study, we develop a 4D-printable composite composed of liquid crystal elastomer (LCE) matrix with dispersed droplets of eutectic gallium indium alloy (EGaIn). Using deformable EGaIn droplets in place of rigid conductive fillers preserves the compliance and shape-morphing properties of the LCE. The process enables 4D-printed LCE actuators capable of photothermal and electrothermal actuation. At low liquid metal (LM) concentrations (71 wt %), the composite actuator exhibits a photothermal response upon irradiation of near-IR light. Printed actuators with a twisted nematic configuration are capable of bending angles of 150° at 800 mW cm-2. At higher LM concentrations (88 wt %), the embedded LM droplets can form percolating networks that conduct electricity and enable electrical Joule heating of the LCE. Actuation strain ranging from 5 to 12% is controlled by the amount of electrical power that is delivered to the composite. We also introduce a method for multimaterial printing of monolithic structures where the LM filler loading is spatially varied. These multifunctional materials exhibit innate responsivity where the actuator behaves as an electrical switch and can report one of two states (on/off). These multiresponsive, 4D-printable composites enable multifunctional, mechanically active structures that can be powered with IR light or low DC voltages.
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Single-photon emitters (SPEs) in hexagonal boron nitride (hBN) have garnered increasing attention over the last few years due to their superior optical properties. However, despite the vast range of experimental results and theoretical calculations, the defect structure responsible for the observed emission has remained elusive. Here, by controlling the incorporation of impurities into hBN via various bottom-up synthesis methods and directly through ion implantation, we provide direct evidence that the visible SPEs are carbon related. Room-temperature optically detected magnetic resonance is demonstrated on ensembles of these defects. We perform ion-implantation experiments and confirm that only carbon implantation creates SPEs in the visible spectral range. Computational analysis of the simplest 12 carbon-containing defect species suggest the negatively charged [Formula: see text] defect as a viable candidate and predict that out-of-plane deformations make the defect environmentally sensitive. Our results resolve a long-standing debate about the origin of single emitters at the visible range in hBN and will be key to the deterministic engineering of these defects for quantum photonic devices.
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Soft composites that use droplets of gallium-based liquid metal (LM) as the dispersion phase have the potential for transformative impact in multifunctional material engineering. However, it is unclear whether percolation pathways of LM can support high electrical conductivity in a wide range of matrix materials. This issue is addressed through an approach to LM composite synthesis that focuses on the interrelated effects of matrix curing/solidification and droplet formation. The combined influence of LM concentration, particle size, and sedimentation is explored. By developing this approach, the functionalities that have been demonstrated with LM composites can be generalized to other matrix materials that impart additional functionality. Specifically, composites are synthesized using a biodegradable/reprocessable plastic (polycaprolactone), a hydrogel (poly(vinyl alcohol)), and a processable rubber (a styrene-ethylene-butylene-styrene derivative) to demonstrate wide applicability. This method enables synthesis of composites: i) with high stretchability and negligible electromechanical coupling (>600% strain); ii) with Joule-heated healing and reprocessability; iii) with electrical and mechanical self-healing; and iv) that can be printed. This approach to controlled assembly represents a widely applicable technique for creating new classes of LM composites with unprecedented multifunctionality.
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Elastomers embedded with micro- and nanoscale droplets of liquid metal (LM) alloys like eutectic gallium-indium (EGaIn) can exhibit unique combinations of elastic, thermal, and electrical properties that are difficult to achieve using rigid filler. For composites with sufficient concentrations of liquid metal, the LM droplets can form percolating networks that conduct electricity and deform with the surrounding elastomer as the composite is stretched. Surprisingly, experimental measurements performed on LM-embedded elastomers (LMEEs) show that the total electrical resistance of the composite increases only slightly even as the elastomer is stretched to several times its natural length. In contrast, Pouillet's law would predict an exponential increase in resistance (Ω) with stretch (λ) due to the incompressibility of liquid metal and elastomer. In this manuscript, we perform a computational analysis to examine the unique electromechanical properties of conductive LMEE composites. Our analysis suggests that the gauge factor that quantifies electromechanical coupling (i.e. G = {ΔΩ/Ω0}/λ) decreases with increasing tortuosity of the conductive pathways formed by the connected LM droplets. A dimensionless parameter for path tortuosity can be used to estimate G for statistically homogeneous LMEE composites. These results rationalize experimental observations and provide insight into the influence of liquid metal droplet assembly on the functionality of the composite.
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Composites of liquid crystal elastomer (LCE) that are electrically conductive have the potential to function as soft "artificial muscle" actuators that can be reversibly stimulated with electrical Joule-heating. Conductivity can be achieved by embedding the LCE with droplets of an alloy of gallium and indium that is liquid at room temperature. These soft artificial muscles are capable of >50% reversible actuation with an applied load. The key to actuation at high loadings of liquid metal (LM) is that the droplets deform with the surrounding matrix. By controlling the size of LM droplets through simple processing techniques, we show that the actuator properties of the LM-LCE muscle can be tuned. For example, composites with smaller liquid metal particles (ca. 10 µm or less) are stiffer than those with larger liquid metal particles (ca. >100 µm) and are capable of greater force output. However, smaller particles reduce actuation strain and composites with large particles exhibit significantly greater stroke length. Such tunability in actuation properties permits the fabrication of specialized soft artificial muscles, where processing of the composite controls actuation strain and actuation force.
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This report summarizes progress made in understanding properties such as zero-phonon-line energies, emission and absorption polarizations, electron-phonon couplings, strain tuning and hyperfine coupling of single photon emitters in hexagonal boron nitride. The primary aims of this research are to discover the chemical nature of the emitting centres and to facilitate deployment in device applications. Critical analyses of the experimental literature and data interpretation, as well as theoretical approaches used to predict properties, are made. In particular, computational and theoretical limitations and challenges are discussed, with a range of suggestions made to overcome these limitations, striving to achieve realistic predictions concerning the nature of emitting centers. A symbiotic relationship is required in which calculations focus on properties that can easily be measured, whilst experiments deliver results in a form facilitating mass-produced calculations.