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"Allen, Greg M."
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Saving the world : how forests inspired global efforts to stop climate change from 1770 to the present
\"Saving the World tells the forgotten history of climatic botany, the idea that forests are essential for creating and recycling rain. Long before the spectre of global warming, societies recognized that deforestation caused drastic climate shifts - as early as 1770, concerns over deforestation spurred legislation to combat human-induced climate change. Throughout the twentieth century, climatic botany experienced fluctuating fortunes, influenced by technological advancements and evolving meteorological theories. Remarkably, contemporary scientists are rediscovering the crucial role of forests in rainfall recycling, unaware of the long history of climatic botany.\"-- Provided by publisher.
BOOK
Balance between cell−substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes
Significance Symmetry breaking and motility initiation are required for many physiological and pathological processes, but the mechanical mechanisms that drive symmetry breaking are not well understood. Fish keratocytes break symmetry spontaneously, in the absence of external cues, with myosin-driven actin flow preceding rear retraction. Here we combine experimental manipulations and mathematical modeling to show that the critical event for symmetry breaking is a flow-dependent, nonlinear switch in adhesion strength. Moreover, our results suggest that mechanical feedback among actin network flow, myosin, and adhesion is sufficient to amplify stochastic fluctuations in actin flow and trigger symmetry breaking. Our mechanical model for symmetry breaking in the relatively simple keratocyte provides a framework for understanding motility initiation in more complex cell types.
Cells are dynamic systems capable of spontaneously switching among stable states. One striking example of this is spontaneous symmetry breaking and motility initiation in fish epithelial keratocytes. Although the biochemical and mechanical mechanisms that control steady-state migration in these cells have been well characterized, the mechanisms underlying symmetry breaking are less well understood. In this work, we have combined experimental manipulations of cell−substrate adhesion strength and myosin activity, traction force measurements, and mathematical modeling to develop a comprehensive mechanical model for symmetry breaking and motility initiation in fish epithelial keratocytes. Our results suggest that stochastic fluctuations in adhesion strength and myosin localization drive actin network flow rates in the prospective cell rear above a critical threshold. Above this threshold, high actin flow rates induce a nonlinear switch in adhesion strength, locally switching adhesions from gripping to slipping and further accelerating actin flow in the prospective cell rear, resulting in rear retraction and motility initiation. We further show, both experimentally and with model simulations, that the global levels of adhesion strength and myosin activity control the stability of the stationary state: The frequency of symmetry breaking decreases with increasing adhesion strength and increases with increasing myosin contraction. Thus, the relative strengths of two opposing mechanical forces—contractility and cell−substrate adhesion—determine the likelihood of spontaneous symmetry breaking and motility initiation.
Journal Article
Superman : President Luthor
His fame bolstered after helping to rebuild Gotham City after an earthquake, billionaire Lex Luthor decides to run for the highest office in the land, the American presidency.
Book
Mechanism of shape determination in motile cells
The shape of motile cells is determined by many dynamic processes spanning several orders of magnitude in space and time, from local polymerization of actin monomers at subsecond timescales to global, cell-scale geometry that may persist for hours. Understanding the mechanism of shape determination in cells has proved to be extremely challenging due to the numerous components involved and the complexity of their interactions. Here we harness the natural phenotypic variability in a large population of motile epithelial keratocytes from fish (
Hypsophrys nicaraguensis
) to reveal mechanisms of shape determination. We find that the cells inhabit a low-dimensional, highly correlated spectrum of possible functional states. We further show that a model of actin network treadmilling in an inextensible membrane bag can quantitatively recapitulate this spectrum and predict both cell shape and speed. Our model provides a simple biochemical and biophysical basis for the observed morphology and behaviour of motile cells.
Motile cells: Getting into shape
Cell shape is determined by the interaction of many elements such as the cytoskeleton, cell membrane and interaction of cells with their substrate. Keren
et al
. have analysed the natural cell-to-cell variability in a large population of motile cells (keratocytes) from fish skin to reveal mechanisms of shape determination. They develop a model that accurately predicts both cell shape and speed based on a physically realistic, molecularly detailed model of an actin network treadmilling in an inextensible membrane bag.
Theriot and colleagues use fish keratocytes to study variations in cell shape that occur during motility. They report a model that quantitatively accounts for their experimental measurements and provides an explanation for the observed morphology of motile cells.
Journal Article
Rethinking cancer targeting strategies in the era of smart cell therapeutics
In the past several decades, the development of cancer therapeutics has largely focused on precision targeting of single cancer-associated molecules. Despite great advances, such targeted therapies still show incomplete precision and the eventual development of resistance due to target heterogeneity or mutation. However, the recent development of cell-based therapies such as chimeric antigen receptor (CAR) T cells presents a revolutionary opportunity to reframe strategies for targeting cancers. Immune cells equipped with synthetic circuits are essentially living computers that can be programmed to recognize tumours based on multiple signals, including both tumour cell-intrinsic and microenvironmental. Moreover, cells can be programmed to launch broad but highly localized therapeutic responses that can limit the potential for escape while still maintaining high precision. Although these emerging smart cell engineering capabilities have yet to be fully implemented in the clinic, we argue here that they will become much more powerful when combined with machine learning analysis of genomic data, which can guide the design of therapeutic recognition programs that are the most discriminatory and actionable. The merging of cancer analytics and synthetic biology could lead to nuanced paradigms of tumour recognition, more akin to facial recognition, that have the ability to more effectively address the complex challenges of treating cancer.This Perspective outlines the preclinical emergence of smart cell therapeutics, which when paired with machine learning analysis of genomic data could be implemented in the clinic to both enhance tumour recognition and prevent tumour escape.
Journal Article
An immune-based tool platform for in vivo cell clearance
Immunological targeting of pathological cells has been successful in oncology and is expanding to other pathobiological contexts. Here, we present a flexible platform that allows labeling cells of interest with the surface-expressed model antigen ovalbumin (OVA), which can be eliminated via either antigen-specific T cells or newly developed OVA antibodies. We demonstrate that hepatocytes can be effectively targeted by either modality. In contrast, pro-fibrotic fibroblasts associated with pulmonary fibrosis are only eliminated by T cells in initial experiments, which reduced collagen deposition in a fibrosis model. This new experimental platform will facilitate development of immune-based approaches to clear potential pathological cell types in vivo.
Journal Article
Myosin II contributes to cell-scale actin network treadmilling through network disassembly
Myosin II in cell motility
In animals, most cells when on the move migrate using a crawling motion, in which the front of the cell is propelled forward by the force provided by polymerization of actin filaments. Cell biologists have generally assumed that the rear of the crawling cell is then pushed forward by a contractile force generated by non-muscle myosin II. Observations of fish keratocytes in motion now show that no actual contraction is required for rear retraction. Rather, the myosin II has a direct role in facilitating actin network treadmilling via actin disassembly.
Eukaryotic cells crawl through a process in which the front of the cell is propelled forwards by the force provided by polymerization of actin filaments. These must be disassembled at the rear of the cell to allow sustained motility. It is now shown that non-muscle myosin II protein is needed for the disassembly of actin networks at the rear of crawling cells.
Crawling locomotion of eukaryotic cells is achieved by a process dependent on the actin cytoskeleton
1
: protrusion of the leading edge requires assembly of a network of actin filaments
2
, which must be disassembled at the cell rear for sustained motility. Although ADF/cofilin proteins have been shown to contribute to actin disassembly
3
, it is not clear how activity of these locally acting proteins could be coordinated over the distance scale of the whole cell. Here we show that non-muscle myosin II has a direct role in actin network disassembly in crawling cells. In fish keratocytes undergoing motility, myosin II is concentrated in regions at the rear with high rates of network disassembly. Activation of myosin II by ATP in detergent-extracted cytoskeletons results in rear-localized disassembly of the actin network. Inhibition of myosin II activity and stabilization of actin filaments synergistically impede cell motility, suggesting the existence of two disassembly pathways, one of which requires myosin II activity. Our results establish the importance of myosin II as an enzyme for actin network disassembly; we propose that gradual formation and reorganization of an actomyosin network provides an intrinsic destruction timer, enabling long-range coordination of actin network treadmilling in motile cells.
Journal Article
Bayesian, statistics and marketing
The past decade has seen a dramatic increase in the use of Bayesian methods in marketing due, in part, to computational and modelling breakthroughs, making its implementation ideal for many marketing problems. Bayesian analyses can now be conducted over a wide range of marketing problems, from new product introduction to pricing, and with a wide variety of different data sources. Bayesian Statistics and Marketing describes the basic advantages of the Bayesian approach, detailing the nature of the computational revolution. Examples contained include household and consumer panel data on product purchases and survey data, demand models based on micro-economic theory and random effect models used to pool data among respondents. The book also discusses the theory and practical use of MCMC methods.
eBook
Synthetic Hybrid Receptors for Safer and Programmable T Cell Therapy
Engineered T cell therapies have achieved significant clinical success in hematological malignancies but remain largely ineffective in solid tumors. Overcoming this limitation requires strategies that enhance T cell function while avoiding systemic immune toxicities and pathological T cell states. Existing approaches typically rely on constitutive gene overexpression or suppression to augment potency or remodel the tumor microenvironment, but these strategies frequently lead to dysregulated immune activation and dose-limiting toxicity. Here, we present Hybrid Receptors (Hybrid-Rs), a modular receptor platform that integrates features of chimeric antigen receptors (CARs) and SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) to couple antigen-dependent T cell activation with programmable gene regulation. Hybrid-Rs enable precise, context-dependent control of T cell potency, differentiation states, and conditional expression of secreted immunotherapeutic payloads with otherwise prohibitive toxicity. Hybrid-Rs are readily humanized and compatible with precision genome editing in primary human T cells, providing a direct and practical path to clinical translation.
Journal Article