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Summary

The shape of a eukaryotic cell or tissue is determined by the actions of the dynamic cytoskeleton pulling or pushing on the ECM or neighboring cells through a set of complex functions. In the previous chapters, we have considered the important elements of cytoskeletal filament dynamics and myosin activation as well as how cell–matrix and cell–cell interactions might affect the cytoskeleton. However, these motile systems must be orchestrated spatially and temporally to produce the correct types of motility for the needed functions of individual cells or of cells in tissues. Because of the dramatic differences in the behavior of individual cells and cells in tissues, we will discuss each type of behavior separately, making this a two-part chapter. In the first part, we will describe individual cell migration and motility, whereas in the second part, we will consider the cooperative processes that occur in tissue formation and remodeling. In both cases, the actin cytoskeleton is dynamic and the major active forces are generated by myosin II. However, there is a different organization of motile functions through the activation of different sites of actin polymerization and myosin activation in the different motile processes. At the individual cell level, we will consider the mechanisms of the few characterized types of motility and how the different elements of the cytoskeleton might be coordinated to produce migration or matrix remodeling. In tissues, the types of motility are dramatically different and the subcellular forces are difficult to measure. Thus, there is a lot of speculation, but some important principles such as the cohesion of the cells in the tissue have emerged. Modeling of the motility processes has started and such models will be very useful in prioritizing experiments to focus on the critical elements that will control each type of motility selectively. The goal in this area is to define the steps in motile functions, how they are coordinated as well as altered by forces or mechanics, and the roles of specific molecules involved.

Cell and tissue shape is critical for the survival of the organism. Because eukaryotic cells form without an exoskeleton, organism structure and shape must be developed using the tools that we have discussed in previous chapters; namely, the cytoskeleton, motor proteins, and extracellular matrices.

Summary

Although the blueprint for the body is built into the DNA sequence, it is still mysterious how a single fertilized egg cell develops into the mature organism. In mammals, the microenvironment of cells is critical for their proper differentiation. This comes from the simple fact that killing cells in a tissue will not seriously alter the development of that tissue, i.e. neighboring cells rapidly fill the gaps both physically and functionally. In other words, the plan for differentiation of the cell is not cell-autonomous but comes from dynamic interactions of the cell with its neighboring cells and matrix. As the single cell becomes a multicellular structure, there are a number of very standard changes in shape that take place. These involve a dynamic mechanical feedback between individual cells and the surrounding tissue. At a protein level, stem cells express many different proteins, which allow them to respond to many different stimuli, and define their differentiation program accordingly. These stimuli will be received from the microenvironment as well as circulating hormones, and will activate a specific set of complex functions that allow the cell to progress to the next step in development. At later times the microenvironment provides mechanical as well as biochemical signals, making it very difficult to take cells out of the embryo and expect them to differentiate properly. Furthermore, mechanical changes in the tissue are critical for proper development, and can only occur through dynamic feedback between the cells, and an ill-defined organ shape parameter. There are a variety of tyrosine kinases that when mutated or deleted will cause major changes in the shape of an organ. Recent findings indicate that many tyrosine kinases are directly linked to mechanosensing, which can explain how they have been genetically linked to the pathways that define shape. As cells differentiate into one of the over 300 different cell types, the set of proteins that are expressed becomes limited. Further, there are major epigenetic changes in nuclei that involve the modification of chromatin to silence genes that are not needed for the specific cell type. Generally, the regularly transcribed genes will not be silenced, whereas those that are not expressed become silenced in heterochromatin. We will discuss how the differentiation process is controlled and how differentiation is manifested both at the cellular and nuclear level.

Summary

In the design of a robust device, it is common to specify all of the ancillary functions needed, and then determine how they interface with other functions in the physical device. The previous chapter discussed how to analyze a complex function in the cellular context by controlling cell phases, so that one can reproducibly analyze the same function in a known cellular context. In the design of a robust device, the designer determines what is needed; however, if the device (cell) was developed over many generations through robust selection processes, many ancillary functions or features may be hidden. The treatment of biological systems as robust devices should include an appreciation for all of the needed functions, the necessary links between them and the dependent parameters, such as ATP, which contribute to larger cellular activity. This complete treatment of the problem can enable one to analyze biological functions with a new perspective. The major difficulty in this approach is that we do not appreciate the complexity of most biological systems in that dietary changes, exercise levels, startle reflexes, and environmental factors such as temperature, bacteria, or viruses can all alter the normal balance of cellular homeostasis. In many of these cases, the organism has compensatory or adaptive mechanisms to minimize the trauma of an abrupt environmental change. This is part of the definition of a robust device. In this chapter, we will discuss how to dissect a primary function into a series of dependent functions and their governing parameters. Although many of those parameters are automatically controlled in cells, knowing that they are important may help to explain why certain perturbations cause unexpected changes in a given function.

‘Systems Biology’ has been defined as the study of how interactions between specific components of biological systems give rise to that system's function and behavior. For example, the proteins and the cell phase in clathrin-mediated endocytosis. Operationally, many have approached these questions by using protein expression, and interactomics data to generate models with a number of experimentally determined reaction constants. The problem that occurs in many cases is that the system is too poorly constrained and therefore the models are built with too many adjustable parameters. A rule of thumb in mathematical modelling is that you can model the shape of an elephant with four adjustable parameters and get it to walk with a fifth.

Summary

The generation of force and the active transport of material over long distances are processes that are important in a number of complex functions. Both force generation and transport are driven by molecular motors that utilize the energy derived from ATP hydrolysis to move along polar filaments of the cytoskeleton. This movement generates the forces needed for synthesis, packaging, and transport of cellular components, and enables the cell to do work and maintain tension in tissues. The best-understood motor proteins are myosin and kinesin, which move on actin filaments and microtubules, respectively. Other motor proteins that move on DNA, on RNA, and on the protein backbones have roles in synthesis, packaging, and degradation processes. In a broad view, molecular motors couple the Brownian movements of proteins (vibrational, rotational, or translational) to the dissipation of energy (from ATP or GTP hydrolysis, or from coupling to a proton gradient). The three major types of motors, myosin, kinesin, and AAA superfamily of ATPases, are significantly different in their designs and functions. Although single-molecule studies have provided many insights into the mechanisms of motor protein function, the rules that control their motility are not well understood. The mechanisms that regulate motor protein activity are complex yet highly important because the level of force and/or displacement that is generated must be tightly controlled in order for the complex functions to be carried out properly (for more background on motors, see Howard, 2000).

Motor protein complexes constitute a major class of proteins that are needed for many functions, as outlined in the textbox above. Analyses of the genetics of motor proteins have been somewhat frustrating because knocking out individual motor proteins often produces ‘unremarkable’ phenotypes. For example, individual myosin I motor proteins, which represent a diverse group of single-headed motor proteins, can be knocked out in the amoeboid cells of Dictyostelium discoideum, with little effect. Only when several myosin I proteins are knocked out do cells show significant changes in function. In the early days of protein knockouts, this result was viewed by many as an indication that the myosin I proteins were unimportant and young faculty were discouraged from working on them because it would be doubly hard to get tenure.

Summary

Our time is characterised by various international disputes. Without the establishment of effective mechanisms for peacefully settling these disputes, it would be difficult to achieve sustainable peace in the international community. Hence peaceful settlement of international disputes should be a crucial subject in international relations.

The peaceful settlement of international disputes is interdisciplinary by nature and it can be approached from multiple disciplines. International law is one of the disciplines that provide an important insight into this subject. Indeed, the peaceful settlement of international disputes is one of the essential functions of international law. This book seeks to provide readers with a systematic overview of multiple means of international dispute settlement in international law. In so doing, this book attempts to consider the question regarding whether and to what extent international law can contribute to peacefully settling international disputes and achieving sustainable peace. In this regard, it must be stressed that development of procedures for the peaceful settlement of international disputes is a prerequisite to the achievement of sustainable peace in the international community.

This book is divided into two parts. Part I, which consists of Chapters 1 to 7, examines traditional means of the settlement of inter-State disputes. This Part examines both diplomatic and legal means of international dispute settlement: negotiation, good office, mediation, inquiry, conciliation, dispute settlement through the United Nations, inter- State arbitration and the International Court of Justice.

Part II, which consists of Chapters 8 to 12, deals with international dispute settlement systems in particular fields. This part addresses the dispute settlement system under the United Nations Convention on the Law of the Sea, the WTO dispute settlement system, the peaceful settlement of international environmental disputes and disputes involving non-State actors. Finally, the role of the peaceful settlement of international disputes is examined in a broad context focusing on the interaction between international dispute settlement, the principle of the non-use of force secured by the collective security system, and disarmament.

Summary

Main Issues

The role of international institutions is increasingly important in various fields of international relations and this is equally true in the peaceful settlement of international disputes. In particular, the role of the United Nations is crucial owing to its universal membership and its political authority. Here consideration must be given to the role of the Security Council, General Assembly and the Secretary-General in international dispute settlement. The interrelationship between the United Nations and regional international institutions also merits discussion. This chapter will seek to examine the principal issues of international dispute settlement through the United Nations, focusing particularly on the following issues:

Summary

Despite a lack of exoskeleton, isolated animal cells normally exhibit stable, nonspherical shapes with excess membrane area. To maintain cell shape, the plasma membrane conforms to a cytoskeleton located inside the cell, but the membrane surface area to cell volume ratio determines how extensively the membrane can conform. In a few cases, such as endothelial cells in capillary tubes, the cytoskeleton alone can support the cell shape. In most cases, however, the cytoskeleton is dynamic, and defines the cell shape in concert with the cell volume, and the effect of contracting against external contacts, or adhesions. Modulation of these adhesions, whether they are between adjacent cells, or cells and matrices, provide the stimuli to initiate cytoskeleton dynamics. These dynamics, which include filament assembly and disassembly, typically determine any changes in the shape of the cell. Actin filaments are often assembled from adhesion sites or sites of membrane extension, both of which lie primarily at the cell periphery. They are then pulled inward and disassemble in a process known as ‘actin treadmilling.’ Actin filaments are contracted by myosin and this creates tension in the cytoskeleton and is responsible for tissue organization and the cohesive property of cells. Paradoxically, the rapid loss of contractile force increases filament dynamics, and cytoskeleton assembly. Cohesion of cells over longer periods is stabilized by intermediate filaments. These appear to be the safety net that prevents acute fracture of cells in epithelia under tension. Microtubules, on the other hand, help stabilize and define cell polarity and structure. Microtubules originate from the microtubule-organizing center (MTOC) and provide directional pathways on which motors will transport membranous organelles and other cellular components. During mitosis, the dynamic microtubules of the mitotic spindle play critical roles in the transport of chromosomes to the daughter cells. Thus, the cytoskeleton is a dynamic, mechanically active component of the cell that is responsible for shaping the cell and its environment as well as for organizing the intracellular organelles.

The cytoskeleton is comprised of three long filament systems; specifically, microtubules, actin filaments, and intermediate filaments. These filaments are crosslinked by motor proteins or multivalent binding proteins, which serve to stabilize the cytoskeleton, and provide it with dynamic qualities including the ability to disassemble, reassemble, and contract. As evidenced by photobleaching recovery experiments, filament subunit exchange occurs on the timescale of minutes for actin and microtubules.

Summary

Cellular functions have evolved over time to better enable organisms to survive major environmental challenges (see Chapter 1). Improvements to basic functions or new functions that more successfully supported survival were preserved and shared between organisms, either by infections or by interbreeding. Because the environment is constantly changing, the complex functions have evolved to be robust so that they will work under many different conditions and the design principles of robust devices (see text box below) can be used to understand them. A complex function involves multiple functional modules coordinated to perform a complex task. In this chapter, we will describe a general approach to understanding the features of complex functions and how the functional modules that underlie complex functions may be linked to yield the desired emergent properties across different scales. An emergent property is the outcome of many steps and many modules in a complex function. We suggest that models of complex functions violating the principles of robust devices are likely to be wrong. Furthermore, we will describe why it is important to quantitatively measure the performance of complex biological functions (outputs) under different circumstances (inputs) to better test models of different complex functions.

Principles of Robust Machines with Standard Functions

We propose that cells are highly engineered, robust machines. They are also very small machines where all actions are dominated by diffusion. The stochastic nature of diffusion processes can account for some of the observed biological variability. However, biological systems have devised mechanisms to use diffusion to drive muscle movements and to direct the shaping of the organism. Evolutionary refinements of the basic mechanisms of biological systems enable them to reproducibly create organisms of diverse shapes using the information encoded in the DNA. Thus, fruit flies with the same DNA will look the same as well as identical twins. In the case of the twins the development took many years and yet they often do look identical. Thus, the robustness of the biological systems extends to making reliable decisions using inherently noisy stochastic processes. Because it seems that the cells that form the basis of biological systems are robust machines, the complex functions that they utilize should follow the design principles of robust devices (Figure 2.1, from Thomas et al., 2004).

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12 - Adjusting Cell Shape and Forces with Dynamic Filament Networks

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18 - Moving from Omnipotency to Death

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Contents

17 - Integration of Cellular Functions for Decision Making

Summary

Chapter 1 - A Tour of the Solar System

10 - Moving and Maintaining Functional Assemblies with Motors

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Preface

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4 - International Dispute Settlement through the United Nations

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9 - Structuring a Cell by Cytoskeletal Filaments

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2 - Complex Functions of Robust Machines with Emergent Properties

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6 - Crystal Systems and Theoretical Density

20 - Cement and Concrete

28 - Dielectrics and Ferroelectrics

29 - Magnetism

22 - Surfaces and Surface Properties

15 - Solid Solutions and Phase Diagrams

Index

10 - Metals and Steel

25 - Diffusion and Ionic Conductivity

24 - Thermal Properties

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