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.
Studies of human movement have proliferated in recent years. This greatly expanded and thoroughly updated reference surveys the literature on the corticospinal control of spinal cord circuits in ...human subjects, showing how different circuits can be studied, their role in normal movement and how they malfunction in disease states. Chapters are highly illustrated and consistently organised, reviewing, for each pathway, the experimental background, methodology, organisation and control, role during motor tasks and changes in patients with CNS lesions. Each chapter concludes with a helpful résumé that can be used independently of the main text to provide practical guidance for clinical studies. The final four chapters bring together the changes in transmission in spinal and corticospinal pathways during movement and how they contribute to the desired movement. This book is essential reading for research workers and clinicians involved in the study, treatment and rehabilitation of movement disorders.
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.
We use 26×106 galaxies from the Dark Energy Survey (DES) Year 1 shape catalogs over 1321 deg2 of the sky to produce the most significant measurement of cosmic shear in a galaxy survey to date. We ...constrain cosmological parameters in both the flat ΛCDM and the wCDM models, while also varying the neutrino mass density. These results are shown to be robust using two independent shape catalogs, two independent photo-z calibration methods, and two independent analysis pipelines in a blind analysis. We find a 3.5% fractional uncertainty on σ8(Ωm/0.3)0.5=0.782−0.027+0.027 at 68% C.L., which is a factor of 2.5 improvement over the fractional constraining power of our DES Science Verification results. In wCDM, we find a 4.8% fractional uncertainty on σ8(Ωm/0.3)0.5=0.777−0.038+0.036 and a dark energy equation-of-state w=−0.95−0.39+0.33. We find results that are consistent with previous cosmic shear constraints in σ8-Ωm, and we see no evidence for disagreement of our weak lensing data with data from the cosmic microwave background. Finally, we find no evidence preferring a wCDM model allowing w≠−1. We expect further significant improvements with subsequent years of DES data, which will more than triple the sky coverage of our shape catalogs and double the effective integrated exposure time per galaxy.
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 Csp3 -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 Csp3 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 Csp3 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 Csp3 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, Csp3 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.
We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source ...photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for S8 = σ8 (Ωm/0.3)0.5 = 0.65 ± 0.04, driven by a low matter density parameter, Ωm = 0.179+0.031−0.038, with σ8 − Ωm posteriors in 2.4σ tension with the DES Y1 3x2pt results, and in 5.6σ with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with x-ray and microwave data, as well as independent constraints on the observable-mass relation from Sunyaev-Zeldovich selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold (λ ≥ 30) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model.
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
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