Williams J H Jr Fundamentals Of Applied Dynamics 254
Robinette Stiles
Deuterium NMR spectroscopy has been used to study the director dynamics of the nematic liquid-crystal system cetyl trimethylammonium bromide/D2O under the action of applied viscous torques. Shear forces were applied using a custom-built Couette cell that was introduced into an NMR superconducting magnet, so that its rotational axis was parallel to the magnetic field direction, along which the liquid-crystal director originally aligned. Subsequently, the inner cylinder of the cell was rotated continuously at different rates using a stepper motor. The resulting time evolution and ultimate steady-state orientation of the director, governed by the competition between the applied viscous torque with elastic and magnetic terms, was measured via observed changes in the deuterium spectrum. Using a simple gearbox allowed unprecedented access to a low-shear-rate regime in which, above a threshold shear rate, the director of part of the sample was observed to reorient, while the remaining part still aligned with the magnetic field. Subsequent increases in the applied rotational rate were found to increase the relative proportion of the orienting fraction. Spatially resolved NMR spectra showed that the orienting and field-aligned fractions formed separated bands across the gap of the Couette cell, with director reorientation being initiated at the moving inner wall. The behavior was found to be consistent with the often ignored variation in velocity gradient manifest across the gap of a cylindrical cell, so that as the angular frequency of the inner cylinder was increased the radial location of the critical shear rate required for reorientation traversed the gap. Once the applied rotational rate was sufficient to reorient the director of the entire sample, the dependence of the exhibited steady-state orientation on the average applied shear rate was measured. These results could be fitted to an analytical solution of the force-balance equation, made tractable by the assumption that the elasticity term was of minor significance and could be ignored. Additionally, the use of a numerical solution of the full force-balance equation, which explicitly includes elasticity and secondary flow and additionally allows the time evolution of the director orientation to be calculated, was investigated.
N2 - Fundamental ecological research is both intrinsically interesting and provides the basic knowledge required to answer applied questions of importance to the management of the natural world. The 100th anniversary of the British Ecological Society in 2013 is an opportune moment to reflect on the current status of ecology as a science and look forward to high-light priorities for future work. To do this, we identified 100 important questions of fundamental importance in pure ecology. We elicited questions from ecologists working across a wide range of systems and disciplines. The 754 questions submitted (listed in the online appendix) from 388 participants were narrowed down to the final 100 through a process of discussion, rewording and repeated rounds of voting. This was done during a two-day workshop and thereafter. The questions reflect many of the important current conceptual and technical pre-occupations of ecology. For example, many questions concerned the dynamics of environmental change and complex ecosystem interactions, as well as the interaction between ecology and evolution. The questions reveal a dynamic science with novel subfields emerging. For example, a group of questions was dedicated to disease and micro-organisms and another on human impacts and global change reflecting the emergence of new subdisciplines that would not have been foreseen a few decades ago. The list also contained a number of questions that have perplexed ecologists for decades and are still seen as crucial to answer, such as the link between population dynamics and life-history evolution. Synthesis. These 100 questions identified reflect the state of ecology today. Using them as an agenda for further research would lead to a substantial enhancement in understanding of the discipline, with practical relevance for the conservation of biodiversity and ecosystem function.
AB - Fundamental ecological research is both intrinsically interesting and provides the basic knowledge required to answer applied questions of importance to the management of the natural world. The 100th anniversary of the British Ecological Society in 2013 is an opportune moment to reflect on the current status of ecology as a science and look forward to high-light priorities for future work. To do this, we identified 100 important questions of fundamental importance in pure ecology. We elicited questions from ecologists working across a wide range of systems and disciplines. The 754 questions submitted (listed in the online appendix) from 388 participants were narrowed down to the final 100 through a process of discussion, rewording and repeated rounds of voting. This was done during a two-day workshop and thereafter. The questions reflect many of the important current conceptual and technical pre-occupations of ecology. For example, many questions concerned the dynamics of environmental change and complex ecosystem interactions, as well as the interaction between ecology and evolution. The questions reveal a dynamic science with novel subfields emerging. For example, a group of questions was dedicated to disease and micro-organisms and another on human impacts and global change reflecting the emergence of new subdisciplines that would not have been foreseen a few decades ago. The list also contained a number of questions that have perplexed ecologists for decades and are still seen as crucial to answer, such as the link between population dynamics and life-history evolution. Synthesis. These 100 questions identified reflect the state of ecology today. Using them as an agenda for further research would lead to a substantial enhancement in understanding of the discipline, with practical relevance for the conservation of biodiversity and ecosystem function.
OBSERVATIONS We investigate cancer treatment as a game theoretic contest between the physician's therapy and the cancer cells' resistance strategies. This game has 2 critical asymmetries: (1) Only the physician can play rationally. Cancer cells, like all evolving organisms, can only adapt to current conditions; they can neither anticipate nor evolve adaptations for treatments that the physician has not yet applied. (2) It has a distinctive leader-follower (or "Stackelberg") dynamics; the "leader" oncologist plays first and the "follower" cancer cells then respond and adapt to therapy. Current treatment protocols for metastatic cancer typically exploit neither asymmetry. By repeatedly administering the same drug(s) until disease progression, the physician "plays" a fixed strategy even as the opposing cancer cells continuously evolve successful adaptive responses. Furthermore, by changing treatment only when the tumor progresses, the physician cedes leadership to the cancer cells and treatment failure becomes nearly inevitable. Without fundamental changes in strategy, standard-of-care cancer therapy typically results in "Nash solutions" in which no unilateral change in treatment can favorably alter the outcome.
N2 - IMPORTANCE While systemic therapy for disseminated cancer is often initially successful, malignant cells, using diverse adaptive strategies encoded in the human genome, almost invariably evolve resistance, leading to treatment failure. Thus, the Darwinian dynamics of resistance are formidable barriers to all forms of systemic cancer treatment but rarely integrated into clinical trial design or included within precision oncology initiatives.OBSERVATIONS We investigate cancer treatment as a game theoretic contest between the physician's therapy and the cancer cells' resistance strategies. This game has 2 critical asymmetries: (1) Only the physician can play rationally. Cancer cells, like all evolving organisms, can only adapt to current conditions; they can neither anticipate nor evolve adaptations for treatments that the physician has not yet applied. (2) It has a distinctive leader-follower (or "Stackelberg") dynamics; the "leader" oncologist plays first and the "follower" cancer cells then respond and adapt to therapy. Current treatment protocols for metastatic cancer typically exploit neither asymmetry. By repeatedly administering the same drug(s) until disease progression, the physician "plays" a fixed strategy even as the opposing cancer cells continuously evolve successful adaptive responses. Furthermore, by changing treatment only when the tumor progresses, the physician cedes leadership to the cancer cells and treatment failure becomes nearly inevitable. Without fundamental changes in strategy, standard-of-care cancer therapy typically results in "Nash solutions" in which no unilateral change in treatment can favorably alter the outcome.CONCLUSIONS AND RELEVANCE Physicians can exploit the advantages inherent in the asymmetries of the cancer treatment game, and likely improve outcomes, by adopting more dynamic treatment protocols that integrate eco-evolutionary dynamics and modulate therapy accordingly. Implementing this approach will require new metrics of tumor response that incorporate both ecological (ie, size) and evolutionary (ie, molecular mechanisms of resistance and relative size of resistant population) changes.
AB - IMPORTANCE While systemic therapy for disseminated cancer is often initially successful, malignant cells, using diverse adaptive strategies encoded in the human genome, almost invariably evolve resistance, leading to treatment failure. Thus, the Darwinian dynamics of resistance are formidable barriers to all forms of systemic cancer treatment but rarely integrated into clinical trial design or included within precision oncology initiatives.OBSERVATIONS We investigate cancer treatment as a game theoretic contest between the physician's therapy and the cancer cells' resistance strategies. This game has 2 critical asymmetries: (1) Only the physician can play rationally. Cancer cells, like all evolving organisms, can only adapt to current conditions; they can neither anticipate nor evolve adaptations for treatments that the physician has not yet applied. (2) It has a distinctive leader-follower (or "Stackelberg") dynamics; the "leader" oncologist plays first and the "follower" cancer cells then respond and adapt to therapy. Current treatment protocols for metastatic cancer typically exploit neither asymmetry. By repeatedly administering the same drug(s) until disease progression, the physician "plays" a fixed strategy even as the opposing cancer cells continuously evolve successful adaptive responses. Furthermore, by changing treatment only when the tumor progresses, the physician cedes leadership to the cancer cells and treatment failure becomes nearly inevitable. Without fundamental changes in strategy, standard-of-care cancer therapy typically results in "Nash solutions" in which no unilateral change in treatment can favorably alter the outcome.CONCLUSIONS AND RELEVANCE Physicians can exploit the advantages inherent in the asymmetries of the cancer treatment game, and likely improve outcomes, by adopting more dynamic treatment protocols that integrate eco-evolutionary dynamics and modulate therapy accordingly. Implementing this approach will require new metrics of tumor response that incorporate both ecological (ie, size) and evolutionary (ie, molecular mechanisms of resistance and relative size of resistant population) changes.
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