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At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic \"toolkit\" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry–based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.

Advances in biosensor technology have made it possible to simultaneously study the activation of multiple signalling network components in the same cell. This approach has been enhanced by novel computational approaches (referred to as computational multiplexing) that can reveal relationships between network nodes imaged in separate cells. Cellular signal transduction occurs in complex and redundant interaction networks, which are best understood by simultaneously monitoring the activation dynamics of multiple components. Recent advances in biosensor technology have made it possible to visualize and quantify the activation of multiple network nodes in the same living cell. The precision and scope of this approach has been greatly extended by novel computational approaches (referred to as computational multiplexing) that can reveal relationships between network nodes imaged in separate cells.

Chemists engaged in reaction discovery tend to report outcomes involving a few, relatively simple reactants. It remains a major challenge to fine-tune reported conditions when the reactants become more structurally complex, as often happens in pharmaceutical research. Lin et al. developed a protocol for rapidly screening different catalytic conditions for C–N coupling across a wide range of complex substrates. The product detection scheme relies on mass spectrometry of nanomole-scale reaction mixtures without any need for intervening chromatography. Science , this issue p. eaar6236 Mass spectrometry is used to screen catalytic conditions for C–N coupling of a wide variety of complex reactants. Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS).

Rho GTPases during cell protrusion The Rho GTPase family acts in concert to regulate cyoskeletal dynamics during processes such as cell motility. In this study, Danuser and colleagues study the coordination of RhoA, Rac1 and Cdc42 during cell migration by simultaneously visualizing two molecules using complementary biosensor designs, and by computationally defining the relationships between individual molecules visualized in separate cells. The latter approach demonstrates that different biosensors, imaged separately, can be freely combined to produce maps of relative signalling activities with seconds and single-micron resolution. These technologies pave the way to defining the dynamics of many proteins in large signal transduction networks. The Rho GTPase family is involved in the control of cytoskeleton dynamics, but the spatiotemporal coordination of each element (Rac1, RhoA and Cdc42) remains unknown. Here, GTPase coordination in mouse embryonic fibroblasts is examined both through simultaneous visualization of two GTPase biosensors and using a computational approach. The GTPases Rac1, RhoA and Cdc42 act together to control cytoskeleton dynamics 1 , 2 , 3 . Recent biosensor studies have shown that all three GTPases are activated at the front of migrating cells 4 , 5 , 6 , 7 , and biochemical evidence suggests that they may regulate one another: Cdc42 can activate Rac1 (ref. 8 ), and Rac1 and RhoA are mutually inhibitory 9 , 10 , 11 , 12 . However, their spatiotemporal coordination, at the seconds and single-micrometre dimensions typical of individual protrusion events, remains unknown. Here we examine GTPase coordination in mouse embryonic fibroblasts both through simultaneous visualization of two GTPase biosensors and using a ‘computational multiplexing’ approach capable of defining the relationships between multiple protein activities visualized in separate experiments. We found that RhoA is activated at the cell edge synchronous with edge advancement, whereas Cdc42 and Rac1 are activated 2 μm behind the edge with a delay of 40 s. This indicates that Rac1 and RhoA operate antagonistically through spatial separation and precise timing, and that RhoA has a role in the initial events of protrusion, whereas Rac1 and Cdc42 activate pathways implicated in reinforcement and stabilization of newly expanded protrusions.

Catalysis-based signal amplification makes optical assays highly sensitive and widely useful in chemical and biochemical research. However, assays must be fine-tuned to avoid signal saturation, substrate depletion and nonlinear performance. Furthermore, once stopped, such assays cannot be restarted, limiting the dynamic range to two orders of magnitude with respect to analyte concentrations. In addition, abundant analytes are difficult to quantify under catalytic conditions due to rapid signal saturation. Herein, we report an approach in which a catalytic reaction competes with a concomitant inactivation of the catalyst or consumption of a reagent required for signal generation. As such, signal generation proceeds for a limited time, then autonomously and reversibly stalls. In two catalysis-based assays, we demonstrate restarting autonomously stalled reactions, enabling accurate measurement over five orders of magnitude, including analyte levels above substrate concentration. This indicates that the dynamic range of catalysis-based assays can be significantly broadened through competitive and reversible deactivation. Assays for catalytic systems—particularly ones with simple colorimetric readouts—are useful for the rapid evaluation of performance. Here, the authors report an assay based on a concurrent colour-forming reaction working across a wide range that can be stopped to allow measurements and subsequently restarted.

The aluminum–air (or oxygen) battery has received intense attention in the past because of its excellent benefits such as low cost and high energy density, but due to the challenging issues such as hydrogen evolution and inactive oxide film formation on the Al surface, it could not be fully applied. In this study, 1-Ethyl 3-Methyl Imidazolium Chloride ([EmIm]Cl) and aluminum chloride (AlCl3) are applied to resolve the aforementioned issues. Ex situ component-level and in situ cell-level open circuit voltage (OCV) tests combined with the physics-based model analyses were conducted to investigate the electrochemical reaction behaviors of the Al–air cell. Especially, the effect of aluminum oxide formation on the anode- and cathode-side reactions were analyzed in detail. The oxide film formed at the Al surface strongly was found to significantly impede the electrochemical reaction at the surface, and the film growth was controlled by decreasing the surface tension by aggressive anions. In the cathode side, the aluminum oxide precipitated in the porous cathode electrode was found to decrease the porous reaction area and block reactant access into the reaction sites. The effects of O2 solubility in the electrolyte, initial porosity and thickness of the porous electrode are compared in detailed, and optimal thickness is suggested.

We apply matched molecular pair (MMP) analysis to data from ChirBase, which contains literature reports of chromatographic enantioseparations. For the 19 chiral stationary phases we examined, we were able to identify 289 sets of pairs where there is a statistically significant and consistent difference in enantioseparation due to a small chemical change. In many cases these changes highlight enantioselectivity differences between pairs or small families of closely related molecules that have for many years been used to probe the mechanisms of chromatographic chiral recognition; for example, the comparison of N-H vs. N-Me analytes to determine the criticality of an N-H hydrogen bond in chiral molecular recognition. In other cases, statistically significant MMPs surfaced by the analysis are less familiar or somewhat puzzling, sparking a need to generate and test hypotheses to more fully understand. Consequently, mining of appropriate datasets using MMP analysis provides an important new approach for studying and understanding the process of chromatographic enantioseparation.

Core activities of process chemistry involve the synthesis of drug candidates at a scale that supports clinical evaluations and the creation of a manufacturing process that is safe, robust, and cost effective. Innovative problem solving has always been a key element in process chemistry and will be increasingly important for addressing emerging challenges in science, globalization, and commoditization. The acquisition and creation of platform chemical technologies that enable rapid problem solving through the use of high-throughput experimentation will continue to be an important focus going forward. Linking and deploying platforms throughout the discovery-development continuum is expected to enable drug discovery. Increasing collaboration with academia will also become more important for accessing technical solutions and providing the next generation of innovative problem solvers.

Traditional scientific conferences can be costly and time-consuming, and certainly aren't 'green', with participants travelling long distances to attend. Are there advantages to meetings held in the virtual world, and can they really offer equally satisfying — or even better — experiences compared with the real world?

The passage of leukocytes across the endothelium and into arterial walls is a critical step in the development of atherosclerosis. Previously, we showed in vitro that the RhoG guanine nucleotide exchange factor SGEF (Arhgef26) contributes to the formation of ICAM-1-induced endothelial docking structures that facilitate leukocyte transendothelial migration. To further explore the in vivo role of this protein during inflammation, we generated SGEF-deficient mice. When crossed with ApoE null mice and fed a Western diet, mice lacking SGEF showed a significant decrease in the formation of atherosclerosis in multiple aortic areas. A fluorescent biosensor revealed local activation of RhoG around bead-clustered ICAM-1 in mouse aortic endothelial cells. Notably, this activation was decreased in cells from SGEF-deficient aortas compared to wild type. In addition, scanning electron microscopy of intimal surfaces of SGEF(-/-) mouse aortas revealed reduced docking structures around beads that were coated with ICAM-1 antibody. Similarly, under conditions of flow, these beads adhered less stably to the luminal surface of carotid arteries from SGEF(-/-) mice. Taken together, these results show for the first time that a Rho-GEF, namely SGEF, contributes to the formation of atherosclerosis by promoting endothelial docking structures and thereby retention of leukocytes at athero-prone sites of inflammation experiencing high shear flow. SGEF may therefore provide a novel therapeutic target for inhibiting the development of atherosclerosis.