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Nitrogen fixation by legumes results from a symbiotic partnership between plant and microbes. These together elaborate nodules on the plant roots that house the bacteria. Tsikou et al. identified a microRNA made in the aboveground shoots of Lotus japonicus that translocates to the plant's roots. In the roots, the microRNA posttranscriptionally regulates a key suppressor of symbiosis, thus keeping the uninfected root susceptible to productive infection by symbiotic bacteria. Science , this issue p. 233 A microRNA made in the shoot regulates microbial nodulation in Lotus roots. Nitrogen-fixing root nodules on legumes result from two developmental processes, bacterial infection and nodule organogenesis. To balance symbiosis and plant growth, legume hosts restrict nodule numbers through an inducible autoregulatory process. Here, we present a mechanism where repression of a negative regulator ensures symbiotic susceptibility of uninfected roots of the host Lotus japonicus . We show that microRNA miR2111 undergoes shoot-to-root translocation to control rhizobial infection through posttranscriptional regulation of the symbiosis suppressor TOO MUCH LOVE in roots. miR2111 maintains a susceptible default status in uninfected hosts and functions as an activator of symbiosis downstream of LOTUS HISTIDINE KINASE1–mediated cytokinin perception in roots and HYPERNODULATION ABERRANT ROOT FORMATION1, a shoot factor in autoregulation. The miR2111- TML node ensures activation of feedback regulation to balance infection and nodulation events.

The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host–guest interactions to endow proteins with prosthetic functionality. Specifically, a series of cucurbit[7]uril (CB[7])–PEG conjugates are shown to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity interaction between CB[7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy.

Strong-field phenomena in optical nanostructures have enabled the integration of nanophotonics, plasmonics and attosecond spectroscopy. For example, tremendous excitement was sparked by reports of nanostructure-enhanced high-harmonic generation. However, there is growing tension between the great promise held by extreme-ultraviolet and attosecond-pulse generation on the nanoscale, and the lack of successful implementations. Here, we address this problem in a study of highly nonlinear optical processes in gas-exposed bow-tie nanoantennas. We find multiphoton- and strong-field-induced atomic excitation and ionization resulting in extreme-ultraviolet fluorescence, as well as third- and fifth-harmonic generation intrinsic to the nanostructures. Identifying the intensity-dependent spectral fingerprint of atomic fluorescence, we gauge local plasmonic fields. Whereas intensities sufficient for high-harmonic generation are indeed achieved in the near-field, the nanoscopic volume is found to prohibit an efficient conversion. Our results illustrate opportunities and challenges in highly nonlinear plasmonics and its extension to the extreme ultraviolet. It has been suggested that plasmonic nanostructures could boost nonlinear optical processes in atoms. However, an incomplete understanding of the complex physics in such systems has hampered attempts to harness this idea in applications. An in-depth study now shows that phenomena such as high-harmonic generation might in fact be limited by the tiny volumes involved at the nanoscale.

Significance Self-administered insulin is the most important therapeutic to provide control over blood glucose levels for patients with type-1 diabetes. However, standard insulin therapy introduces a number of complications and subsequent issues with control of blood glucose levels. Here, we prepared a derivative of insulin with a molecular switch to provide glucose-mediated activation of the insulin molecule, toward the generation of more autonomous therapy with improved blood glucose control. This modified insulin, when administered in a diabetic mouse model, restores blood glucose levels following a glucose challenge (i.e., a simulated meal) faster than both standard insulin and a clinically used long-lasting insulin derivative. Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.

Optogenetics is the genetic approach for controlling cellular processes with light. It provides spatiotemporal, quantitative and reversible control over biological signaling and metabolic processes, overcoming limitations of chemically inducible systems. However, optogenetics lags in plant research because ambient light required for growth leads to undesired system activation. We solved this issue by developing plant usable light-switch elements (PULSE), an optogenetic tool for reversibly controlling gene expression in plants under ambient light. PULSE combines a blue-light-regulated repressor with a red-light-inducible switch. Gene expression is only activated under red light and remains inactive under white light or in darkness. Supported by a quantitative mathematical model, we characterized PULSE in protoplasts and achieved high induction rates, and we combined it with CRISPR–Cas9-based technologies to target synthetic signaling and developmental pathways. We applied PULSE to control immune responses in plant leaves and generated Arabidopsis transgenic plants. PULSE opens broad experimental avenues in plant research and biotechnology. PULSE is an optogenetic tool that consists of two modules with different wavelength sensitivities. Their interplay enables optogenetic access to gene expression in plants independently of ambient light.

An ocean on Enceladus ocean: the sodium test Images from the Cassini spacecraft showed erupting plumes of water vapour and ice particles on Saturn's moon Enceladus, prompting speculation a subsurface ocean might be acting as a source of liquid water. Two groups this week report evidence relevant to the search for this subsurface ocean. The results, at first sight contradictory, leave the ocean a possibility, though still a hypothetical one. Postberg et al . used the Cassini Cosmic Dust Analyser to determine the chemical composition of ice grains in Saturn's E-ring, which consists largely of material from Enceladus. They find a population of E-ring grains rich in sodium salts, which should be possible only if the plumes originate from liquid water. Schneider et al . used Earth-based spectroscopic telescopes to search for sodium emission in the gas plumes erupting from Enceladus and found none. This is inconsistent with a direct supply from a salty ocean and suggests alternative eruption sources such as a deep ocean, a freshwater reservoir or ice. Or if there is a salty reservoir of water, some process not yet determined must be preventing the sodium from escaping into space. Saturn's moon Enceladus emits plumes of water vapour and ice particles from fractures near its south pole, raising the possibility of a subsurface ocean. Minor organic or siliceous components, identified in many ice grains, could be evidence of interaction between Enceladus' rocky core and liquid water; however it has been unclear whether the water is still present today or if it has frozen. Now, the identification of a population of E-ring grains that are rich in sodium salts suggests that the plumes originate from liquid water. Saturn's moon Enceladus emits plumes of water vapour and ice particles from fractures near its south pole 1 , 2 , 3 , 4 , 5 , suggesting the possibility of a subsurface ocean 5 , 6 , 7 . These plume particles are the dominant source of Saturn’s E ring 7 , 8 . A previous in situ analysis 9 of these particles concluded that the minor organic or siliceous components, identified in many ice grains, could be evidence for interaction between Enceladus’ rocky core and liquid water 9 , 10 . It was not clear, however, whether the liquid is still present today or whether it has frozen. Here we report the identification of a population of E-ring grains that are rich in sodium salts (∼0.5–2% by mass), which can arise only if the plumes originate from liquid water. The abundance of various salt components in these particles, as well as the inferred basic pH, exhibit a compelling similarity to the predicted composition of a subsurface Enceladus ocean in contact with its rock core 11 . The plume vapour is expected to be free of atomic sodium. Thus, the absence of sodium from optical spectra 12 is in good agreement with our results. In the E ring the upper limit for spectroscopy 12 is insufficiently sensitive to detect the concentrations we found.

We derive a closed-form solution for Tobin's Q in a stochastic dynamic framework. We show analytically that investment is positively related to Tobin's Q and cash flow, even in the absence of adjustment costs or financing frictions. Both Q and investment move in the same direction as expected revenue growth, so changes in expected revenue growth induce Q and investment to comove positively. Similarly, shocks to current cash flow, arising from shocks to the user cost of capital in our model, cause investment and cash flow per unit of capital to comove positively. Furthermore, we show that this alternative mechanism for the relationship among investment, Q, and cash flow delivers larger cash flow effects for smaller-and faster-growing firms, as observed in the data. Moreover, the empirically small sensitivity of investment to Tobin's Q does not imply implausibly large adjustment costs in our model (since there are no adjustment costs). Calibrating the model generates values of Q similar to those in the data; investment is more sensitive to cash flow than it is to ß, and both responses are of empirically plausible magnitudes.

Arising from S. Kim et al. Nature453, 757–760 (2008)10.1038/nature07012 ; Kim et al. reply Plasmonic nanostructures offer unique possibilities for enhancing linear and nonlinear optical processes 1 , 2 , 3 , 4 , 5 , 6 . Recently, Kim et al. 7 reported nanostructure-enhanced high harmonic generation (HHG). Here, using nearly identical conditions, we demonstrate extreme-ultraviolet (EUV) emission from gas-exposed nanostructures, but come to entirely different conclusions: instead of HHG, we observe line emission of neutral and ionized gas atoms. We also discuss fundamental physical aspects limiting nanostructure-based HHG.

The abolition of slavery in the nineteenth and twentieth centuries was a long process. In terms of the economic views of abolitionists, there has been an excessive focus on the economic ideas of liberal abolitionists and their approach to “Civilization, Christianity, and Commerce.” However, there was a “developmental abolitionism” that has received little attention. Afro-American Martin R. Delany and Liberian James S. Payne were writers who approached abolitionism through this developmentalism. They favored more interventionist measures aimed at building the material power and national autonomy of Black nations to undercut the power of slave-using African chiefs, to provide indigenous Africans with employment, and to undermine the profitability of slave-based cotton production in the Americas. They also implicitly and indirectly approached labor scarcity with solutions ranging from promoting labor-saving technology to cultivating national prosperity that would improve emigration to Africa or increase birth rates.

Glucose-responsive insulin is a therapeutic that modulates its potency, concentration or dosing relative to a patient’s dynamic glucose concentration. This Perspective summarizes some of the recent accomplishments in this field as well as discussing new computational algorithms that may aid in the development of such therapeutics. The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.