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Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease
No full textSignals from G-protein-coupled receptors (GPCRs) are the most frequently targeted pathways of currently prescribed therapeutics. Rather than being a simple switch, it is now evident that a given receptor can directly initiate multiple signals, and biasing to achieve signal selectivity based on agonist structure is possible. Biased agonists could direct therapeutically favorable pathways while avoiding counterproductive or adverse reaction pathways. For obstructive lung diseases, β₂-adrenergic receptor (β₂AR) agonists act at these receptors on airway smooth muscle (ASM) cells to open the airways by relaxing ASM, improving airflow and morbidity. However, these receptors signal to the G protein Gs (increasing cAMP and promoting relaxation), but also to β-arrestin (promoting desensitization and a loss of effectiveness). Indeed, β-agonist use is associated with adverse events in asthma pathogenesis and clinical outcomes which are related to desensitization. β-agonists favoring Gs coupling over β-arrestin binding would provide a means of tailoring bronchodilator therapy. In this review, we show how combinatorial methods with a 40 million compound agnostic library led to a new class of biased β-agonists that do not desensitize, providing an opportunity to personalize therapy in patients who experience poor efficacy or adverse effects from traditional balanced agonists
Radio bursts from among the oldest stars
No full textLuminous bursts of radio emission are linked to highly magnetized neutron stars known as magnetars. Now, bursts have been detected from a globular star cluster, an environment thought to be devoid of magnetars
Extending the Baseline for SMC X-1's Spin and Orbital Behavior with NuSTAR Stray Light
No full textStrayCats, the catalog of NuSTAR stray light observations, contains data from bright X-ray sources that fall within crowded source regions. These observations offer unique additional data with which to monitor sources such as X-ray binaries that show variable timing behavior. In this work, we present a timing analysis of stray light data of the high-mass X-ray binary SMC X-1, the first scientific analysis of a single source from the StrayCats project. We describe the process of screening stray light data for scientific analysis, verify the orbital ephemeris, and create both time- and energy-resolved pulse profiles. We find that the orbital ephemeris of SMC X-1 is unchanged and confirm a long-term spin-up rate of ν ̇ = (2.52 ± 0.03) × 10⁻¹¹ Hz s⁻¹. We also note that the shape of SMC X-1's pulse profile, while remaining double peaked, varies significantly with time and only slightly with energy
Challenges of Measuring Soluble Mn(III) Species in Natural Samples
No full textSoluble Mn(III)–L complexes appear to constitute a substantial portion of manganese (Mn) in many environments and serve as critical high-potential species for biogeochemical processes. However, the inherent reactivity and lability of these complexes—the same chemical characteristics that make them uniquely important in biogeochemistry—also make them incredibly difficult to measure. Here we present experimental results demonstrating the limits of common analytical methods used to quantify these complexes. The leucoberbelin-blue method is extremely useful for detecting many high-valent Mn species, but it is incompatible with the subset of Mn(III) complexes that rapidly decompose under low-pH conditions—a methodological requirement for the assay. The Cd-porphyrin method works well for measuring Mn(II) species, but it does not work for measuring Mn(III) species, because additional chemistry occurs that is inconsistent with the proposed reaction mechanism. In both cases, the behavior of Mn(III) species in these methods ultimately stems from inter- and intramolecular redox chemistry that curtails the use of these approaches as a reflection of ligand-binding strength. With growing appreciation for the importance of high-valent Mn species and their cycling in the environment, these results underscore the need for additional method development to enable quantifying such species rapidly and accurately in nature
Mechanically Gated Formation of Donor–Acceptor Stenhouse Adducts Enabling Mechanochemical Multicolor Soft Lithography
No full textMechanochromism is one of the most widely developed areas in the quickly emerging field of polymer mechanochemistry. Stress-sensitive molecules called mechanophores are designed to undergo productive chemical transformations in response to mechanical force including changes in color that are useful for sensing and patterning. A variety of mechanochromic mechanophores have been developed, but modulating the photophysical properties of the mechanically generated dyes generally requires the independent preparation of discrete derivatives. Here we introduce a mechanophore platform enabling mechanically gated multicolor chromogenic reactivity. The mechanophore is based on an activated furan precursor to donor–acceptor Stenhouse adducts (DASAs) masked as a hetero-Diels–Alder adduct. Mechanochemical activation of the mechanophore unveils the DASA precursor and subsequent reaction with a secondary amine generates an intensely colored DASA photoswitch. Critically, the color and photochemical properties of the DASA are controlled by the identity of the amine and thus a single mechanophore can be differentiated post-activation to produce a wide range of functionally diverse DASA compounds. We highlight the unique reactivity of this system by establishing the concept of mechanochemical multicolor soft lithography whereby a complex multicolor composite image is printed into a mechanochemically active elastomer through an iterative process of localized compression and reaction with different amines. Our results demonstrate the first example of multicolor pattern reproduction from a single mechanophore, empowering the fabrication of complex stimuli-responsive materials and paving the way for applications in patterning, sensing, and encryption
ALMA High-resolution Multiband Analysis for the Protoplanetary Disk around TW Hya
No full textWe present a high-resolution (2.5 au) multiband analysis of the protoplanetary disk around TW Hya using Atacama Large Millimeter/submillimeter Array (ALMA) long baseline data at Bands 3, 4, 6, and 7. We aim to reconstruct a high-sensitivity millimeter continuum image and revisit the spectral index distribution. The imaging is performed by combining new ALMA data at Bands 4 and 6 with available archive data. Two methods are employed to reconstruct the images: multifrequency synthesis (MFS) and the fiducial image-oriented method, where each band is imaged separately and the frequency dependence is fitted pixel by pixel. We find that MFS imaging with a second-order Taylor expansion can reproduce the frequency dependence of the continuum emission between Bands 3 and 7 in a manner consistent with previous studies, and that it is a reasonable method for reconstructing the spectral index map. The image-oriented method provides a spectral index map consistent with the MFS imaging, but with a two times lower resolution. Mock observations of an intensity model were conducted to validate the images from the two methods. We find that the MFS imaging provides a high-resolution spectral index distribution with an uncertainty of β), and dust temperature. The derived parameters are consistent with previous works, and the enhancement of β within the intensity gaps is also confirmed, supporting a deficit of millimeter-sized grains within the gaps
Harmonizing model organism data in the Alliance of Genome Resources
No full textThe Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein–protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides
Integrated silicon carbide electro-optic modulator
No full textOwing to its attractive optical and electronic properties, silicon carbide is an emerging platform for integrated photonics. However an integral component of the platform is missing—an electro-optic modulator, a device which encodes electrical signals onto light. As a non-centrosymmetric crystal, silicon carbide exhibits the Pockels effect, yet a modulator has not been realized since the discovery of this effect more than three decades ago. Here we design, fabricate, and demonstrate a Pockels modulator in silicon carbide. Specifically, we realize a waveguide-integrated, small form-factor, gigahertz-bandwidth modulator that operates using complementary metal-oxide-semiconductor (CMOS)-level voltages on a thin film of silicon carbide on insulator. Our device is fabricated using a CMOS foundry compatible fabrication process and features no signal degradation, no presence of photorefractive effects, and stable operation at high optical intensities (913 kW/mm²), allowing for high optical signal-to-noise ratios for modern communications. Our work unites Pockels electro-optics with a CMOS foundry compatible platform in silicon carbide
Reaction Mechanisms, Kinetics, and Improved Catalysts for Ammonia Synthesis from Hierarchical High Throughput Catalyst Design
No full textThe Haber–Bosch (HB) process is the primary chemical synthesis technique for industrial production of ammonia (NH₃) for manufacturing nitrate-based fertilizer and as a potential hydrogen carrier. The HB process alone is responsible for over 2% of all global energy usage to produce more than 160 million tons of NH₃ annually. Iron catalysts are utilized to accelerate the reaction, but high temperatures and pressures of atmospheric nitrogen gas (N₂) and hydrogen gas (H₂) are required. A great deal of research has aimed at increased performance over the last century, but the rate of progress has been slow. This Account focuses on determining the atomic-level reaction mechanism for HB synthesis of NH₃ on the Fe catalysts used in industry and how to use this knowledge to suggest greatly improved catalysts via a novel paradigm of catalyst rational design.
We determined the full reaction mechanism on the two most active surfaces for the HB process, Fe(111) and Fe(211)R. We used density functional theory (DFT) to predict the free-energy barriers for all 12 important reactions and the 34 most important 2 × 2 surface configurations. Then we incorporated the mechanism into kinetic Monte Carlo (kMC) simulations run for several hours of real time to predict turnover frequencies (TOFs). The predicted TOFs are within experimental error, indicating that the predicted barriers are within 0.04 eV of experiment.
With this level of accuracy, we are poised to use DFT to improve the catalyst. Rather than forming bulk alloys with uniform concentration, we aimed at finding additives that strongly prefer near-surface sites so that minor amounts of the additive might lead to dramatic improvements. However, even for a single additive, the combinations of surface species and reactions multiplies significantly, with ∼48 reaction steps to examine and nearly 100 surface configurations per 2 × 2 site. To make it practical to examine tens of dopant candidates, we developed the hierarchical high-throughput catalysis screening (HHTCS) approach, which we applied to both the Fe(111) and Fe(211) surfaces. For HHTCS, we identified the most important 4 reaction steps out of 12 for the two surfaces to examine >50 dopant cases, where we required performance at each step no worse than for pure Fe. With HHTCS, the computational cost is about 1% of that for doing the full reaction mechanism, allowing us to do ≈50 cases in about 1/2 the time it took to do pure Fe(111). The new leads identified with HHTCS are then validated with full mechanistic studies.
For Fe(111), we predict three high-performance dopants that strongly prefer the second layer: Co with a rate 8 times higher, Ni with a rate 16 times higher, and Si with a rate 43 times higher, at 400 °C and 20 atm. We also found four dopants that strongly prefer the top layer and improve performance: Pt or Rh 3 times faster and Pd or Cu 2 times faster. For Fe(211), the best dopant was found to be second-layer Co with a rate 3 times faster than that for the undoped surface.
The DFT/kMC data were used to predict reshaping of the catalyst particles under reaction conditions and how to tune dopant content so as to maximize catalytic area and thus activity. Finally, we show how to validate our mechanistic modeling via a comparison between theoretical and experimental operando spectroscopic signatures
Sample-Efficient Adaptive Calibration of Quantum Networks Using Bayesian Optimization
No full textAll physical systems employed for quantum information tasks must act as unbiased carriers of encoded quantum states. Ensuring such indistinguishability of information carriers is a major challenge in many quantum information applications, including advanced quantum communication protocols. For photons, the workhorses of quantum communication networks, it is difficult to obtain and maintain their indistinguishability because of environment-induced transformations and loss imparted by communication channels, especially in noisy scenarios. Conventional strategies to mitigate these transformations often require hardware or software overhead that is restrictive (e.g., adding noise), infeasible (e.g., on a satellite), or time-consuming for deployed networks. Here we propose and develop resource-efficient Bayesian optimization techniques to rapidly and adaptively calibrate the indistinguishability of individual photons for quantum networks using only information derived from their measurement. To experimentally validate our approach, we demonstrate the optimization of Hong-Ou-Mandel interference between two photons–a central task in quantum networking– finding rapid, efficient, and reliable convergence towards maximal photon indistinguishability in the presence of high loss and shot noise. We expect our resource-optimized and experimentally friendly methodology will allow fast and reliable calibration of indistinguishable quanta, a necessary task in distributed quantum computing, communications, and sensing, as well as for fundamental investigations