Organic synthesis: march of the machines.

Organic synthesis is changing; in a world where budgets are constrained and the environmental impacts of practice are scrutinized, it is increasingly recognized that the efficient use of human resource is just as important as material use. New technologies and machines have found use as methods for transforming the way we work, addressing these issues encountered in research laboratories by enabling chemists to adopt a more holistic systems approach in their work. Modern developments in this area promote a multi-disciplinary approach and work is more efficient as a result. This Review focuses on the concepts, procedures and methods that have far-reaching implications in the chemistry world. Technologies have been grouped as topics of opportunity and their recent applications in innovative research laboratories are described.The authors gratefully acknowledge support from UK Engineering and Physical Sciences Research Council (SVL and RMM), Woolf Fisher Trust (DEF) and Pfizer Worldwide Research and Development (CB, RJI).This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/anie.201410744/abstract

Machine-Assisted Organic Synthesis.

In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies

Engineering Resilient Space Systems

Several distinct trends will influence space exploration missions in the next decade. Destinations are becoming more remote and mysterious, science questions more sophisticated, and, as mission experience accumulates, the most accessible targets are visited, advancing the knowledge frontier to more difficult, harsh, and inaccessible environments. This leads to new challenges including: hazardous conditions that limit mission lifetime, such as high radiation levels surrounding interesting destinations like Europa or toxic atmospheres of planetary bodies like Venus; unconstrained environments with navigation hazards, such as free-floating active small bodies; multielement missions required to answer more sophisticated questions, such as Mars Sample Return (MSR); and long-range missions, such as Kuiper belt exploration, that must survive equipment failures over the span of decades. These missions will need to be successful without a priori knowledge of the most efficient data collection techniques for optimum science return. Science objectives will have to be revised ‘on the fly’, with new data collection and navigation decisions on short timescales. Yet, even as science objectives are becoming more ambitious, several critical resources remain unchanged. Since physics imposes insurmountable light-time delays, anticipated improvements to the Deep Space Network (DSN) will only marginally improve the bandwidth and communications cadence to remote spacecraft. Fiscal resources are increasingly limited, resulting in fewer flagship missions, smaller spacecraft, and less subsystem redundancy. As missions visit more distant and formidable locations, the job of the operations team becomes more challenging, seemingly inconsistent with the trend of shrinking mission budgets for operations support. How can we continue to explore challenging new locations without increasing risk or system complexity? These challenges are present, to some degree, for the entire Decadal Survey mission portfolio, as documented in Vision and Voyages for Planetary Science in the Decade 2013–2022 (National Research Council, 2011), but are especially acute for the following mission examples, identified in our recently completed KISS Engineering Resilient Space Systems (ERSS) study: 1. A Venus lander, designed to sample the atmosphere and surface of Venus, would have to perform science operations as components and subsystems degrade and fail; 2. A Trojan asteroid tour spacecraft would spend significant time cruising to its ultimate destination (essentially hibernating to save on operations costs), then upon arrival, would have to act as its own surveyor, finding new objects and targets of opportunity as it approaches each asteroid, requiring response on short notice; and 3. A MSR campaign would not only be required to perform fast reconnaissance over long distances on the surface of Mars, interact with an unknown physical surface, and handle degradations and faults, but would also contain multiple components (launch vehicle, cruise stage, entry and landing vehicle, surface rover, ascent vehicle, orbiting cache, and Earth return vehicle) that dramatically increase the need for resilience to failure across the complex system. The concept of resilience and its relevance and application in various domains was a focus during the study, with several definitions of resilience proposed and discussed. While there was substantial variation in the specifics, there was a common conceptual core that emerged—adaptation in the presence of changing circumstances. These changes were couched in various ways—anomalies, disruptions, discoveries—but they all ultimately had to do with changes in underlying assumptions. Invalid assumptions, whether due to unexpected changes in the environment, or an inadequate understanding of interactions within the system, may cause unexpected or unintended system behavior. A system is resilient if it continues to perform the intended functions in the presence of invalid assumptions. Our study focused on areas of resilience that we felt needed additional exploration and integration, namely system and software architectures and capabilities, and autonomy technologies. (While also an important consideration, resilience in hardware is being addressed in multiple other venues, including 2 other KISS studies.) The study consisted of two workshops, separated by a seven-month focused study period. The first workshop (Workshop #1) explored the ‘problem space’ as an organizing theme, and the second workshop (Workshop #2) explored the ‘solution space’. In each workshop, focused discussions and exercises were interspersed with presentations from participants and invited speakers. The study period between the two workshops was organized as part of the synthesis activity during the first workshop. The study participants, after spending the initial days of the first workshop discussing the nature of resilience and its impact on future science missions, decided to split into three focus groups, each with a particular thrust, to explore specific ideas further and develop material needed for the second workshop. The three focus groups and areas of exploration were: 1. Reference missions: address/refine the resilience needs by exploring a set of reference missions 2. Capability survey: collect, document, and assess current efforts to develop capabilities and technology that could be used to address the documented needs, both inside and outside NASA 3. Architecture: analyze the impact of architecture on system resilience, and provide principles and guidance for architecting greater resilience in our future systems The key product of the second workshop was a set of capability roadmaps pertaining to the three reference missions selected for their representative coverage of the types of space missions envisioned for the future. From these three roadmaps, we have extracted several common capability patterns that would be appropriate targets for near-term technical development: one focused on graceful degradation of system functionality, a second focused on data understanding for science and engineering applications, and a third focused on hazard avoidance and environmental uncertainty. Continuing work is extending these roadmaps to identify candidate enablers of the capabilities from the following three categories: architecture solutions, technology solutions, and process solutions. The KISS study allowed a collection of diverse and engaged engineers, researchers, and scientists to think deeply about the theory, approaches, and technical issues involved in developing and applying resilience capabilities. The conclusions summarize the varied and disparate discussions that occurred during the study, and include new insights about the nature of the challenge and potential solutions: 1. There is a clear and definitive need for more resilient space systems. During our study period, the key scientists/engineers we engaged to understand potential future missions confirmed the scientific and risk reduction value of greater resilience in the systems used to perform these missions. 2. Resilience can be quantified in measurable terms—project cost, mission risk, and quality of science return. In order to consider resilience properly in the set of engineering trades performed during the design, integration, and operation of space systems, the benefits and costs of resilience need to be quantified. We believe, based on the work done during the study, that appropriate metrics to measure resilience must relate to risk, cost, and science quality/opportunity. Additional work is required to explicitly tie design decisions to these first-order concerns. 3. There are many existing basic technologies that can be applied to engineering resilient space systems. Through the discussions during the study, we found many varied approaches and research that address the various facets of resilience, some within NASA, and many more beyond. Examples from civil architecture, Department of Defense (DoD) / Defense Advanced Research Projects Agency (DARPA) initiatives, ‘smart’ power grid control, cyber-physical systems, software architecture, and application of formal verification methods for software were identified and discussed. The variety and scope of related efforts is encouraging and presents many opportunities for collaboration and development, and we expect many collaborative proposals and joint research as a result of the study. 4. Use of principled architectural approaches is key to managing complexity and integrating disparate technologies. The main challenge inherent in considering highly resilient space systems is that the increase in capability can result in an increase in complexity with all of the 3 risks and costs associated with more complex systems. What is needed is a better way of conceiving space systems that enables incorporation of capabilities without increasing complexity. We believe principled architecting approaches provide the needed means to convey a unified understanding of the system to primary stakeholders, thereby controlling complexity in the conception and development of resilient systems, and enabling the integration of disparate approaches and technologies. A representative architectural example is included in Appendix F. 5. Developing trusted resilience capabilities will require a diverse yet strategically directed research program. Despite the interest in, and benefits of, deploying resilience space systems, to date, there has been a notable lack of meaningful demonstrated progress in systems capable of working in hazardous uncertain situations. The roadmaps completed during the study, and documented in this report, provide the basis for a real funded plan that considers the required fundamental work and evolution of needed capabilities. Exploring space is a challenging and difficult endeavor. Future space missions will require more resilience in order to perform the desired science in new environments under constraints of development and operations cost, acceptable risk, and communications delays. Development of space systems with resilient capabilities has the potential to expand the limits of possibility, revolutionizing space science by enabling as yet unforeseen missions and breakthrough science observations. Our KISS study provided an essential venue for the consideration of these challenges and goals. Additional work and future steps are needed to realize the potential of resilient systems—this study provided the necessary catalyst to begin this process

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.We are grateful to the Swiss National Science Foundation (DNT), the Ralph Raphael fellowship (RJI), the German Academic Exchange Service DAAD (SF), the Royal Society Newton International Fellowship (ZEW), Pfizer Worldwide Research and Development (CB) and the EPSRC (SVL, SF and ZEW, grant nº EP/K0099494/1) for financial support. The Labtrix Start was kindly loaned by Chemtrix BV and the liquid-liquid phase separator by Zaiput Flow Technologies (we are grateful to Dr Andrea Adamo for technical support with this device).This is the final version. It was first published by the Royal Society of Chemistry at http://dx.doi.org/10.1039/C4OB02105

Cyclopropanation using flow-generated diazo compounds.

We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.We are grateful to Pfizer Worldwide Research and Development (CB, RJI and JMH), the Swiss National Science Foundation (DNT), CAPES (RL, no 9865/13-6) and the EPSRC (SVL, grant no EP/K0099494/1 and no EP/K039520/1) for financial support.This is the final published article, originally published in Organic & Biomolecular Chemistry, 2015,13, 2550-2554 DOI: 10.1039/C5OB00019

Sprinting after having sprinted: Prior high-intensity stochastic cycling impairs the winning strike for gold

Bunch riding in closed circuit cycling courses and some track cycling events are often typified by highly variable power output and a maximal sprint to the finish. How criterium style race demands affect final sprint performance however, is unclear. We studied the effects of 1 h variable power cycling on a subsequent maximal 30 s sprint in the laboratory. Nine well-trained male cyclists/triathletes (O2peak 4.9 ± 0.4 Lmin -1 ; mean ± SD) performed two 1 h cycling trials in a randomized order with either a constant (CON) or variable (VAR) power output matched for mean power output. The VAR protocol comprised intervals of varying intensities (40-135% of maximal aerobic power) and durations (10 to 90 s). A 30 s maximal sprint was performed before and immediately after each 1 h cycling trial. When compared with CON, there was a greater reduction in peak (-5.1 ± 6.1%; mean ± 90% confidence limits) and mean (-5.9 ± 5.2%) power output during the 30 s sprint after the 1 h VAR cycle. Variable power cycling, commonly encountered during criterium and triathlon races can impair an optimal final sprint, potentially compromising race performance. Athletes, coaches, and staff should evaluate training (to improve repeat sprint-ability) and race-day strategies (minimize power variability) to optimize the final sprint

Engineering Resilient Space Systems

Several distinct trends will influence space exploration missions in the next decade. Destinations are becoming more remote and mysterious, science questions more sophisticated, and, as mission experience accumulates, the most accessible targets are visited, advancing the knowledge frontier to more difficult, harsh, and inaccessible environments. This leads to new challenges including: hazardous conditions that limit mission lifetime, such as high radiation levels surrounding interesting destinations like Europa or toxic atmospheres of planetary bodies like Venus; unconstrained environments with navigation hazards, such as free-floating active small bodies; multielement missions required to answer more sophisticated questions, such as Mars Sample Return (MSR); and long-range missions, such as Kuiper belt exploration, that must survive equipment failures over the span of decades. These missions will need to be successful without a priori knowledge of the most efficient data collection techniques for optimum science return. Science objectives will have to be revised ‘on the fly’, with new data collection and navigation decisions on short timescales. Yet, even as science objectives are becoming more ambitious, several critical resources remain unchanged. Since physics imposes insurmountable light-time delays, anticipated improvements to the Deep Space Network (DSN) will only marginally improve the bandwidth and communications cadence to remote spacecraft. Fiscal resources are increasingly limited, resulting in fewer flagship missions, smaller spacecraft, and less subsystem redundancy. As missions visit more distant and formidable locations, the job of the operations team becomes more challenging, seemingly inconsistent with the trend of shrinking mission budgets for operations support. How can we continue to explore challenging new locations without increasing risk or system complexity? These challenges are present, to some degree, for the entire Decadal Survey mission portfolio, as documented in Vision and Voyages for Planetary Science in the Decade 2013–2022 (National Research Council, 2011), but are especially acute for the following mission examples, identified in our recently completed KISS Engineering Resilient Space Systems (ERSS) study: 1. A Venus lander, designed to sample the atmosphere and surface of Venus, would have to perform science operations as components and subsystems degrade and fail; 2. A Trojan asteroid tour spacecraft would spend significant time cruising to its ultimate destination (essentially hibernating to save on operations costs), then upon arrival, would have to act as its own surveyor, finding new objects and targets of opportunity as it approaches each asteroid, requiring response on short notice; and 3. A MSR campaign would not only be required to perform fast reconnaissance over long distances on the surface of Mars, interact with an unknown physical surface, and handle degradations and faults, but would also contain multiple components (launch vehicle, cruise stage, entry and landing vehicle, surface rover, ascent vehicle, orbiting cache, and Earth return vehicle) that dramatically increase the need for resilience to failure across the complex system. The concept of resilience and its relevance and application in various domains was a focus during the study, with several definitions of resilience proposed and discussed. While there was substantial variation in the specifics, there was a common conceptual core that emerged—adaptation in the presence of changing circumstances. These changes were couched in various ways—anomalies, disruptions, discoveries—but they all ultimately had to do with changes in underlying assumptions. Invalid assumptions, whether due to unexpected changes in the environment, or an inadequate understanding of interactions within the system, may cause unexpected or unintended system behavior. A system is resilient if it continues to perform the intended functions in the presence of invalid assumptions. Our study focused on areas of resilience that we felt needed additional exploration and integration, namely system and software architectures and capabilities, and autonomy technologies. (While also an important consideration, resilience in hardware is being addressed in multiple other venues, including 2 other KISS studies.) The study consisted of two workshops, separated by a seven-month focused study period. The first workshop (Workshop #1) explored the ‘problem space’ as an organizing theme, and the second workshop (Workshop #2) explored the ‘solution space’. In each workshop, focused discussions and exercises were interspersed with presentations from participants and invited speakers. The study period between the two workshops was organized as part of the synthesis activity during the first workshop. The study participants, after spending the initial days of the first workshop discussing the nature of resilience and its impact on future science missions, decided to split into three focus groups, each with a particular thrust, to explore specific ideas further and develop material needed for the second workshop. The three focus groups and areas of exploration were: 1. Reference missions: address/refine the resilience needs by exploring a set of reference missions 2. Capability survey: collect, document, and assess current efforts to develop capabilities and technology that could be used to address the documented needs, both inside and outside NASA 3. Architecture: analyze the impact of architecture on system resilience, and provide principles and guidance for architecting greater resilience in our future systems The key product of the second workshop was a set of capability roadmaps pertaining to the three reference missions selected for their representative coverage of the types of space missions envisioned for the future. From these three roadmaps, we have extracted several common capability patterns that would be appropriate targets for near-term technical development: one focused on graceful degradation of system functionality, a second focused on data understanding for science and engineering applications, and a third focused on hazard avoidance and environmental uncertainty. Continuing work is extending these roadmaps to identify candidate enablers of the capabilities from the following three categories: architecture solutions, technology solutions, and process solutions. The KISS study allowed a collection of diverse and engaged engineers, researchers, and scientists to think deeply about the theory, approaches, and technical issues involved in developing and applying resilience capabilities. The conclusions summarize the varied and disparate discussions that occurred during the study, and include new insights about the nature of the challenge and potential solutions: 1. There is a clear and definitive need for more resilient space systems. During our study period, the key scientists/engineers we engaged to understand potential future missions confirmed the scientific and risk reduction value of greater resilience in the systems used to perform these missions. 2. Resilience can be quantified in measurable terms—project cost, mission risk, and quality of science return. In order to consider resilience properly in the set of engineering trades performed during the design, integration, and operation of space systems, the benefits and costs of resilience need to be quantified. We believe, based on the work done during the study, that appropriate metrics to measure resilience must relate to risk, cost, and science quality/opportunity. Additional work is required to explicitly tie design decisions to these first-order concerns. 3. There are many existing basic technologies that can be applied to engineering resilient space systems. Through the discussions during the study, we found many varied approaches and research that address the various facets of resilience, some within NASA, and many more beyond. Examples from civil architecture, Department of Defense (DoD) / Defense Advanced Research Projects Agency (DARPA) initiatives, ‘smart’ power grid control, cyber-physical systems, software architecture, and application of formal verification methods for software were identified and discussed. The variety and scope of related efforts is encouraging and presents many opportunities for collaboration and development, and we expect many collaborative proposals and joint research as a result of the study. 4. Use of principled architectural approaches is key to managing complexity and integrating disparate technologies. The main challenge inherent in considering highly resilient space systems is that the increase in capability can result in an increase in complexity with all of the 3 risks and costs associated with more complex systems. What is needed is a better way of conceiving space systems that enables incorporation of capabilities without increasing complexity. We believe principled architecting approaches provide the needed means to convey a unified understanding of the system to primary stakeholders, thereby controlling complexity in the conception and development of resilient systems, and enabling the integration of disparate approaches and technologies. A representative architectural example is included in Appendix F. 5. Developing trusted resilience capabilities will require a diverse yet strategically directed research program. Despite the interest in, and benefits of, deploying resilience space systems, to date, there has been a notable lack of meaningful demonstrated progress in systems capable of working in hazardous uncertain situations. The roadmaps completed during the study, and documented in this report, provide the basis for a real funded plan that considers the required fundamental work and evolution of needed capabilities. Exploring space is a challenging and difficult endeavor. Future space missions will require more resilience in order to perform the desired science in new environments under constraints of development and operations cost, acceptable risk, and communications delays. Development of space systems with resilient capabilities has the potential to expand the limits of possibility, revolutionizing space science by enabling as yet unforeseen missions and breakthrough science observations. Our KISS study provided an essential venue for the consideration of these challenges and goals. Additional work and future steps are needed to realize the potential of resilient systems—this study provided the necessary catalyst to begin this process

Sprinting After Having Sprinted: Prior High-Intensity Stochastic Cycling Impairs the Winning Strike for Gold

Bunch riding in closed circuit cycling courses and some track cycling events are often typified by highly variable power output and a maximal sprint to the finish. How criterium style race demands affect final sprint performance however, is unclear. We studied the effects of 1 h variable power cycling on a subsequent maximal 30 s sprint in the laboratory. Nine well-trained male cyclists/triathletes (O2peak 4.9 ± 0.4 L⋅min-1; mean ± SD) performed two 1 h cycling trials in a randomized order with either a constant (CON) or variable (VAR) power output matched for mean power output. The VAR protocol comprised intervals of varying intensities (40–135% of maximal aerobic power) and durations (10 to 90 s). A 30 s maximal sprint was performed before and immediately after each 1 h cycling trial. When compared with CON, there was a greater reduction in peak (-5.1 ± 6.1%; mean ± 90% confidence limits) and mean (-5.9 ± 5.2%) power output during the 30 s sprint after the 1 h VAR cycle. Variable power cycling, commonly encountered during criterium and triathlon races can impair an optimal final sprint, potentially compromising race performance. Athletes, coaches, and staff should evaluate training (to improve repeat sprint-ability) and race-day strategies (minimize power variability) to optimize the final sprint

Prediction of malignant transformation in oral epithelial dysplasia using machine learning.

A machine learning algorithm (MLA) has been applied to a Fourier transform infrared spectroscopy (FTIR) dataset previously analysed with a principal component analysis (PCA) linear discriminant analysis (LDA) model. This comparison has confirmed the robustness of FTIR as a prognostic tool for oral epithelial dysplasia (OED). The MLA is able to predict malignancy with a sensitivity of 84 ± 3% and a specificity of 79 ± 3%. It provides key wavenumbers that will be important for the development of devices that can be used for improved prognosis of OED

Evolution of Taxis Responses in Virtual Bacteria: Non-Adaptive Dynamics

Bacteria are able to sense and respond to a variety of external stimuli, with responses that vary from stimuli to stimuli and from species to species. The best-understood is chemotaxis in the model organism Escherichia coli, where the dynamics and the structure of the underlying pathway are well characterised. It is not clear, however, how well this detailed knowledge applies to mechanisms mediating responses to other stimuli or to pathways in other species. Furthermore, there is increasing experimental evidence that bacteria integrate responses from different stimuli to generate a coherent taxis response. We currently lack a full understanding of the different pathway structures and dynamics and how this integration is achieved. In order to explore different pathway structures and dynamics that can underlie taxis responses in bacteria, we perform a computational simulation of the evolution of taxis. This approach starts with a population of virtual bacteria that move in a virtual environment based on the dynamics of the simple biochemical pathways they harbour. As mutations lead to changes in pathway structure and dynamics, bacteria better able to localise with favourable conditions gain a selective advantage. We find that a certain dynamics evolves consistently under different model assumptions and environments. These dynamics, which we call non-adaptive dynamics, directly couple tumbling probability of the cell to increasing stimuli. Dynamics that are adaptive under a wide range of conditions, as seen in the chemotaxis pathway of E. coli, do not evolve in these evolutionary simulations. However, we find that stimulus scarcity and fluctuations during evolution results in complex pathway dynamics that result both in adaptive and non-adaptive dynamics depending on basal stimuli levels. Further analyses of evolved pathway structures show that effective taxis dynamics can be mediated with as few as two components. The non-adaptive dynamics mediating taxis responses provide an explanation for experimental observations made in mutant strains of E. coli and in wild-type Rhodobacter sphaeroides that could not be explained with standard models. We speculate that such dynamics exist in other bacteria as well and play a role linking the metabolic state of the cell and the taxis response. The simplicity of mechanisms mediating such dynamics makes them a candidate precursor of more complex taxis responses involving adaptation. This study suggests a strong link between stimulus conditions during evolution and evolved pathway dynamics. When evolution was simulated under conditions of scarce and fluctuating stimulus conditions, the evolved pathway contained features of both adaptive and non-adaptive dynamics, suggesting that these two types of dynamics can have different advantages under distinct environmental circumstances