Today we are poised for a transition from the highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of different types of molecules with ...the push of a button. Creating machines that are capable of making many different types of small molecules on demand, akin to that which has been achieved on the macroscale with 3D printers, is challenging. Yet important progress is being made toward this objective with two complementary approaches: 1) Automation of customized synthesis routes to different targets by machines that enable the use of many reactions and starting materials, and 2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale.
Automation is enabling a new Industrial Revolution, this time on the molecular scale. This Minireview provides insights into the ongoing transition from manual to automated organic synthesis. Akin to a 3D printer for molecules, continued progress in this frontier area will democratize innovation on the molecular scale and shift the rate‐limiting step in new molecular function discovery from synthesis to imagination.
As the world warms due to rising greenhouse gas concentrations, the Earth systemmoves toward climate states without societal precedent, challenging adaptation. Past Earth system states offer possible ...model systems for the warming world of the coming decades. These include the climate states of the Early Eocene (ca. 50 Ma), the Mid-Pliocene (3.3–3.0 Ma), the Last Interglacial (129–116 ka), the Mid-Holocene (6 ka), preindustrial (ca. 1850 CE), and the 20th century. Here, we quantitatively assess the similarity of future projected climate states to these six geohistorical benchmarks using simulations from the Hadley Centre Coupled Model Version 3 (HadCM3), the Goddard Institute for Space Studies Model E2-R (GISS), and the Community Climate System Model, Versions 3 and 4 (CCSM) Earth system models. Under the Representative Concentration Pathway 8.5 (RCP8.5) emission scenario, by 2030 CE, future climates most closely resemble Mid-Pliocene climates, and by 2150 CE, they most closely resemble Eocene climates. Under RCP4.5, climate stabilizes at Pliocene-like conditions by 2040 CE. Pliocene-like and Eocene-like climates emerge first in continental interiors and then expand outward. Geologically novel climates are uncommon in RCP4.5 (<1%) but reach 8.7% of the globe under RCP8.5, characterized by high temperatures and precipitation. Hence, RCP4.5 is roughly equivalent to stabilizing at Pliocene-like climates, while unmitigated emission trajectories, such as RCP8.5, are similar to reversing millions of years of long-term cooling on the scale of a few human generations. Both the emergence of geologically novel climates and the rapid reversion to Eocene-like climates may be outside the range of evolutionary adaptive capacity.
Following spinal cord injury (SCI), chronic pain is a common secondary complication with neuropathic pain (NP) cited as one of the most distressing and debilitating conditions leading to poor quality ...of life, depression and sleep disturbances. Neuropathic pain presenting at or below the level of injury is largely refractory to current pharmacological and physical treatments. No consensus on the prevalence of NP post SCI currently exists, hence this systematic review was undertaken. The review comprised three phases: a methodological assessment of databases PubMed, Embase, Web of Knowledge, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library and Physiotherapy Evidence Database (PEDro) identifying potential papers and screening for inclusion criteria by two independent reviewers; data extraction; and finally rating of internal validity and strength of the evidence, using a published valid and reliable scale. Meta‐analysis estimated pooled point prevalence rates using a random effects model. In total, 17 studies involving 2529 patients were included in the review. Overall point prevalence rates for NP were established at 53% (38.58–67.47); 19% (13.26–26.39) for at‐level NP and 27% (19.89–34.61) for below‐level NP, with high heterogeneity noted (I2 = 84–93%). Prevalence rates for NP following SCI are high. Future studies should include established definitions, classification systems and assessment tools for NP at defined time points post SCI to follow the trajectory of this problem across the lifespan and include indices of sleep, mood and interference to allow for appropriate, optimal and timely NP management for each patient.
What does this review add?
This is the first systematic review and meta‐analysis to record pooled point prevalence of neuropathic pain post spinal cord injury at 53%. Additional pooled analysis shows that neuropathic pain is more common below the level of lesion, in patients with tetraplegia, older patients and at 1 year post injury.
The study and optimization of small molecule function is often impeded by the time-intensive and specialist-dependent process that is typically used to make such compounds. In contrast, general and ...automated platforms have been developed for making peptides, oligonucleotides, and increasingly oligosaccharides, where synthesis is simplified to iterative applications of the same reactions. Inspired by the way natural products are biosynthesized via the iterative assembly of a defined set of building blocks, we developed a platform for small molecule synthesis involving the iterative coupling of haloboronic acids protected as the corresponding N-methyliminodiacetic acid (MIDA) boronates. Here we summarize our efforts thus far to develop this platform into a generalized and automated approach for small molecule synthesis. We and others have employed this approach to access many polyene-based compounds, including the polyene motifs found in >75% of all polyene natural products. This platform further allowed us to derivatize amphotericin B, the powerful and resistance-evasive but also highly toxic last line of defense in treating systemic fungal infections, and thereby understand its mechanism of action. This synthesis-enabled mechanistic understanding has led us to develop less toxic derivatives currently under evaluation as improved antifungal agents. To access more Csp(3)-containing small molecules, we gained a stereocontrolled entry into chiral, non-racemic α-boryl aldehydes through the discovery of a chiral derivative of MIDA. These α-boryl aldehydes are versatile intermediates for the synthesis of many Csp(3) boronate building blocks that are otherwise difficult to access. In addition, we demonstrated the utility of these types of building blocks in accessing pharmaceutically relevant targets via an iterative Csp(3) cross-coupling cycle. We have further expanded the scope of the platform to include stereochemically complex macrocyclic and polycyclic molecules using a linear-to-cyclized strategy, in which Csp(3) boronate building blocks are iteratively assembled into linear precursors that are then cyclized into the cyclic frameworks found in many natural products and natural product-like structures. Enabled by the serendipitous discovery of a catch-and-release protocol for generally purifying MIDA boronate intermediates, the platform has been automated. The synthesis of 14 distinct classes of small molecules, including pharmaceuticals, materials components, and polycyclic natural products, has been achieved using this new synthesis machine. It is anticipated that the scope of small molecules accessible by this platform will continue to expand via further developments in building block synthesis, Csp(3) cross-coupling methodologies, and cyclization strategies. Achieving these goals will enable the more generalized synthesis of small molecules and thereby help shift the rate-limiting step in small molecule science from synthesis to function.
Abstract
Observations of young open clusters (OCs) show a bimodal distribution of rotation periods that has been difficult to explain with existing stellar spin-down models. Detailed ...magnetohydrodynamic (MHD) stellar wind simulations have demonstrated that surface magnetic field morphology has a strong influence on wind-driven angular momentum loss. Observations suggest that faster rotating stars store a larger fraction of their magnetic flux in higher-order multipolar components of the magnetic field. In this work, we present an entirely predictive new model for stellar spin-down that accounts for the stellar surface magnetic field configuration. We show how a magnetic complexity that evolves from complex toward simple configurations as a star spins down can explain the salient features of stellar rotation evolution, including the bimodal distribution of both slow and fast rotators seen in young OCs.
Within the Charlotte, North Carolina, to Atlanta, Georgia, megaregion (Charlanta), the Atlanta metropolitan area has been shown to augment proximal cloud‐to‐ground (CG) lightning occurrence. Although ...numerous studies have documented this “urban lightning effect” (ULE) with regard to CG lightning, relatively few have investigated urban effects on distributions of total lightning (TL). Moreover, there has yet to be a study of the ULE using TL observations from the Geostationary Lightning Mapper (GLM). In an effort to fill this gap, we investigated spatial distributions of TL around the cities of Atlanta, GA, Greenville, SC, and Charlotte, NC, using GLM data collected during the warm seasons of 2018–2021. Analyses reveal augmentation of TL intensity and frequency over the major cities of Atlanta and Charlotte, with a diminished urban signal over the smaller city of Greenville. This work also demonstrated the potential efficacy of the emerging satellite‐based TL climatology in ULE studies.
Plain Language Summary
Studies using ground‐based lightning detection networks have revealed an “urban lightning effect” (ULE) around major cities. In 2016, the U.S. launched a weather satellite with a unique lightning mapping instrument. This study, possibly for the first time, demonstrated the ability to utilize space‐based observation of total lightning to detect the ULE within the Charlotte, North Carolina, to Atlanta, Georgia, urban corridor. The study also paves the way for future ULE analyses as the satellite lightning data record lengthens.
Key Points
The urban lightning effect (ULE) is detectable in Geostationary Lightning Mapper total lightning observations
The ULE is most discernible in the larger metropolitan areas of the Charlotte, NC, to Atlanta, GA, urban corridor
The emerging Geostationary Lightning Mapper data set enables a new generation of urban lightning studies as the record lengthens
Efficient access to chiral C(sp3) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report ...that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp3) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable α-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp3-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp3) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis.
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