This article reviews multiphase descriptions of the fluid mechanics of cytoplasm in crawling cells and growing bacterial biofilms. These two systems involve gels, which are mixtures composed of a polymer network permeated by water. The fluid mechanics of these systems is essential to their biological function and structure. Their mathematical descriptions must account for the mechanics of the polymer, the water, and the interaction between these two phases. This review focuses on multiphase flow models because this framework is natural for including the relative motion between the phases, the exchange of material between phases, and the additional stresses within the network that arise from nonspecific chemical interactions and the action of molecular motors. These models have been successful in accounting for how different forces are generated and transmitted to achieve cell motion and biofilm growth and they have demonstrated how emergent structures develop though the interactions of the two phases. A short description of multiphase flow models of tumor growth is included to highlight the flexibility of the model in describing diverse biological applications. [DOI: 10.2976/1.3291142]
Proteins form the basis of a wide range of biological materials such as hair, skin, bone, spider silk, or cells, which play an important role in providing key functions to biological systems. The focus of this article is to discuss how protein materials are capable of balancing multiple, seemingly incompatible properties such as strength, robustness, and adaptability. To illustrate this, we review bottom‐up materiomics studies focused on the mechanical behavior of protein materials at multiple scales, from nano to macro. We focus on alpha‐helix based intermediate filament proteins as a model system to explain why the utilization of hierarchical structural features is vital to their ability to combine strength, robustness, and adaptability. Experimental studies demonstrating the activation of angiogenesis, the growth of new blood vessels, are presented as an example of how adaptability of structure in biological tissue is achieved through changes in gene expression that result in an altered material structure. We analyze the concepts in light of the universality and diversity of the structural makeup of protein materials and discuss the findings in the context of potential fundamental evolutionary principles that control their nanoscale structure. We conclude with a discussion of multiscale science in biology and de novo materials design.
Evolvability is the property of a biological system to quickly adapt to new requirements. Robustness seems to be the opposite. Nonetheless many biological systems display both properties-a puzzling observation, which has caused many debates over the last decades. A recently published model by Draghi et al. [Nature 463, 353-355 (2010)] elegantly circumvents complications of earlier in silico studies of molecular systems and provides an analytical solution, which is surprisingly independent from parameter choice. Depending on the mutation rate and the number of accessible phenotypes at any given genotype, evolvability and robustness can be reconciled. Further research will need to investigate if these parameter settings adequately represent the range of degrees of freedom covered by natural systems and if natural systems indeed assume a state in which both properties, robustness and evolvability, are featured.
Aging affects all known organisms and has been studied extensively. Yet, the underlying mechanisms are insufficiently understood, possibly due to the multiscale complexity involved in this process: the aging of multicellular organisms depends on the aging of their cells, which depends on molecular events occurring in each cell. However, the aging of unicellular populations seeded in new niches and the aging of metazoans are surprisingly similar, indicating that the multiscale aspects of aging may have been conserved since the beginnings of cellular life on Earth. This underlines the importance of aging research in unicellular organisms such as a recent study by Lorenz et al., [(2009) Proc. Natl. Acad. Sci. U.S.A. 106, 1145-1150]. In their paper, the authors combine computational network identification with extensive experimentation and literature mining to discover and validate numerous regulatory interactions among ten genes involved in the cellular response to glucose starvation. Since low levels of glucose (calorie restriction) have been known to extend the longevity of various eukaryotes, the authors test the effect of Snf1 kinase overexpression on chronological aging and discover that this key regulator of glucose repression and two of its newly discovered synergistic repressors significantly affect the chronological lifespan of baker's yeast.
We review modeling studies concerning cytoskeletal activity of fission yeast. Recent models vary in length and time scales, describing a range of phenomena from cellular morphogenesis to polymer assembly. The components of cytoskeleton act in concert to mediate cell-scale events and interactions such as polarization. The mathematical models reduce these events and interactions to their essential ingredients, describing the cytoskeleton by its bulk properties. On a smaller scale, models describe cytoskeletal subcomponents and how bulk properties emerge.
The organization of biomotile systems possesses structural and functional hierarchy, building up from single molecules via protein assemblies and cells further up to an organ. A typical example is the hierarchy of cardiac muscle, on the top of which is the heart. The heartbeat is supported by the rhythmic contraction of the muscle cells that is controlled by the Ca(2+) oscillation triggered by periodic electrical excitation of pacemaker cells. Thus, it is usually believed that the heartbeat is governed by the control system based on a sequential one-way chain with the electrical∕chemical information transfer from the upper to the lower level of hierarchy. On the other hand, it has been known for many years that the contractile system of muscle, i.e., skinned muscle fibers and myofibrils, itself possesses the auto-oscillatory properties even in the constant chemical environment. A recent paper [Plaçais, et al. (2009), Phys. Rev. Lett. 103, 158102] demonstrated the auto-oscillatory movement∕tension development in an in vitro motility assay composed of a single actin filament and randomly distributed myosin II molecules, suggesting that the auto-oscillatory properties are inherent to the contractile proteins. Here we discuss how the molecular motors may acquire the higher-ordered auto-oscillatory properties while stepping up the staircase of hierarchy.
The morphogenetic movements, and the embryonic phenotypes they ultimately produce, are the consequence of a series of events that involve signaling pathways, cytoskeletal components, and cell- and tissue-level mechanical interactions. In order to better understand how these events work together in the context of amphibian neurulation, an existing multiscale computational model was augmented. Geometric data for this finite element-based mechanical model were obtained from 3D surface reconstructions of live axolotl embryos and serial sections of fixed specimens. Tissue mechanical properties were modeled using cell-based constitutive equations that include internal force generation and cell rearrangement, and equation parameters were adjusted manually to reflect biochemical changes including alterations in Shroom or the planar-cell-polarity pathway. The model indicates that neural tube defects can arise when convergent extension of the neural plate is reduced by as little as 20%, when it is eliminated on one side of the embryo, when neural ridge elevation is disrupted, when tension in the non-neural ectoderm is increased, or when the ectoderm thickness is increased. Where comparable conditions could be induced in Xenopus embryos, good agreement was found, an important step in model validation. The model reveals the neurulating embryo to be a finely tuned biomechanical system.
The evolution of biocrystallography from the pioneers' time to the present era of global biology is presented in relation to the development of methodological and instrumental advances for molecular sample preparation and structure elucidation over the last 6 decades. The interdisciplinarity of the field that generated cross‐fertilization between physics‐ and biology‐focused themes is emphasized. In particular, strategies to circumvent the main bottlenecks of biocrystallography are discussed. They concern (i) the way macromolecular targets are selected, designed, and characterized, (ii) crystallogenesis and how to deal with physical and biological parameters that impact crystallization for growing and optimizing crystals, and (iii) the methods for crystal analysis and 3D structure determination. Milestones that have marked the history of biocrystallography illustrate the discussion. Finally, the future of the field is envisaged. Wide gaps of the structural space need to be filed and membrane proteins as well as intrinsically unstructured proteins still constitute challenging targets. Solving supramolecular assemblies of increasing complexity, developing a “4D biology” for decrypting the kinematic changes in macromolecular structures in action, integrating these structural data in the whole cell organization, and deciphering biomedical implications will represent the new frontiers.
Despite significant progress in our understanding of the brain at both microscopic and macroscopic scales, the mechanisms by which low‐level neuronal behavior gives rise to high‐level mental processes such as memory still remain unknown. In this paper, we assess the plausibility and quantify the performance of polychronization, a newly proposed mechanism of neuronal encoding, which has been suggested to underlie a wide range of cognitive phenomena. We then investigate the effect of network topology on the reliability with which input stimuli can be distinguished based on their encoding in the form of so‐called polychronous groups or spatiotemporal patterns of spikes. We find that small‐world networks perform an order of magnitude better than random ones, enabling reliable discrimination between inputs even when prompted by increasingly incomplete recall cues. Furthermore, we show that small‐world architectures operate at significantly reduced energetic costs and that their memory capacity scales favorably with network size. Finally, we find that small‐world topologies introduce biologically realistic constraints on the optimal input stimuli, favoring especially the topographic inputs known to exist in many cortical areas. Our results suggest that mammalian cortical networks, by virtue of being both small‐world and topographically organized, seem particularly well‐suited to information processing through polychronization. This article addresses the fundamental question of encoding in neuroscience. In particular, evidence is presented in support of an emerging model of neuronal encoding in the neocortex based on spatiotemporal patterns of spikes.
Calcium is a ubiquitous second messenger that mediates vital physiological responses such as fertilization, secretion, gene expression, or apoptosis. Given this variety of processes mediated by Ca2+, these signals are highly organized both in time and space to ensure reliability and specificity. This review deals with the spatiotemporal organization of the Ca2+ signaling pathway in electrically nonexcitable cells in which InsP3 receptors are by far the most important Ca2+ channels. We focus on the aspects of this highly regulated dynamical system for which an interplay between experiments and modeling is particularly fruitful. In particular, the importance of the relative densities of the different InsP3 receptor subtypes will be discussed on the basis of a modeling approach linking the steady‐state behaviors of these channels in electrophysiological experiments with their behavior in a cellular environment. Also, the interplay between InsP3 metabolism and Ca2+ oscillations will be considered. Finally, we discuss the relationships between stochastic openings of the Ca2+ releasing channels at the microscopic level and the coordinated, regular behavior observed at the whole cell level on the basis of a combined experimental and modeling approach.
Pancreatic β-cells release insulin in response to increased glucose levels. Compared to isolated β-cells, β-cells embedded within the islets of Langerhans network exhibit a coordinated and greater insulin secretion response to glucose. This coordinated activity is considered to rely on gap-junctions. We investigated the β-cell electrophysiology and the calcium dynamics in islets in response to glucose gradients. While at constant glucose the network of β-cells fires in a correlated fashion, a glucose gradient induces a sharp division into an active and an inactive part. We hypothesized that this sharp transition is mediated by the specific properties of the gap-junctions. We used a mathematical model of the β-cell electrophysiology in islets to discuss possible origins of this sharp transition in electrical activity. In silico, gap-junctions were required for such a transition. However, the small width of transition was only found when a stochastic variability of the expression of key transmembrane proteins, such as the ATP-dependent potassium channel, was included. The agreement with experimental data was further improved by assuming a delay of gap-junction currents, which points to a role of spatial constraints in the β-cell. This result clearly demonstrates the power of mathematical modeling in disentangling causal relationships in complex systems.
The organization of cytoplasm in excitable cells was a largely ignored factor when mathematical models were developed to understand intracellular calcium and secretory behavior. Here we employed a combination of fluorescent evanescent and transmitted light microscopy to explore the F-actin cytoskeletal organization in the vicinity of secretory sites in cultured bovine chromaffin cells. This technique and confocal fluorescent microscopy show chromaffin granules associated with the borders of cortical cytoskeletal cages forming an intricate tridimensional network. Furthermore, the overexpression of SNAP-25 in these cells also reveals the association of secretory machinery clusters with the borders of these cytoskeletal cages. The importance of these F-actin cage borders is stressed when granules appear to interact and remain associated during exocytosis visualized in acridin orange loaded vesicles. These results will prompt us to propose a model of cytoskeletal cages, where the secretory machinery is associated with its borders. Both the calcium level and the secretory response are enhanced in this geometrical arrangement when compared with a random distribution of the secretory machinery that is not restricted to the borders of the cage.
In mammals the concentration of blood glucose is kept close to 5 mmol∕l. Different cell types in the islet of Langerhans participate in the control of glucose homeostasis. β-cells, the most frequent type in pancreatic islets, are responsible for the synthesis, storage, and release of insulin. Insulin, released with increases in blood glucose promotes glucose uptake into the cells. In response to glucose changes, pancreatic α-, β-, and δ-cells regulate their electrical activity and Ca(2+) signals to release glucagon, insulin, and somatostatin, respectively. While all these signaling steps are stimulated in hypoglycemic conditions in α-cells, the activation of these events require higher glucose concentrations in β and also in δ-cells. The stimulus-secretion coupling process and intracellular Ca(2+) ([Ca(2+)](i)) dynamics that allow β-cells to secrete is well-accepted. Conversely, the mechanisms that regulate α- and δ-cell secretion are still under study. Here, we will consider the glucose-induced signaling mechanisms in each cell type and the mathematical models that explain Ca(2+) dynamics.
DURING SHORT BURSTS OF NEURONAL ACTIVITY, CHANGES IN THE EFFICACY OF NEUROTRANSMITTER RELEASE ARE GOVERNED PRIMARILY BY TWO COUNTERACTING PROCESSES: (1) Ca(2+)-dependent elevations of vesicle release probability and (2) depletion of synaptic vesicles. The dynamic interplay of both processes contributes to the expression of activity-dependent synaptic plasticity. Here, we exploited various facets of short-term plasticity at the Drosophila neuromuscular junction to dissect these two processes. This enabled us to rigorously analyze different models of synaptic vesicle pools in terms of their size and mobilization properties. Independent of the specific model, we estimate approximately 300 readily releasable vesicles with an average release probability of approximately 50% in 1 mM extracellular calcium ( approximately 5% in 0.4 mM extracellular calcium) under resting conditions. The models also helped interpreting the altered short-term plasticity of the previously reported mutant of the active zone component Bruchpilot (BRP). Finally, our results were independently confirmed through fluctuation analysis. Our data reveal that the altered short-term plasticity observed in BRP mutants cannot be accounted for by delocalized Ca(2+) channels alone and thus suggest an additional role of BRP in short-term plasticity.
As stated in the title of the book by Whitfield and Chakravarthy (2001), calcium is the “grand-master cell signaler” used as messenger in a large number of vital processes such as secretion of hormones and neurotransmitters and muscle contraction and genetic transcription, among others (Whitfield and Chakravarthy, 2001; Augustine, 2001). Regarding the release of neurotransmitters, the vast majority of synapses in the central nervous system are chemical as are all synapses between nerves and muscles. When an action potential invades the terminal, the depolarization opens voltage-sensitive calcium channels, allowing calcium ions to enter the nerve terminal and trigger the transmitter release process. This model, established by Katz and Miledi (1965, 1967) for the release of neurotransmitter in the frog neuromuscular junction, was extended to release processes in neurons, endocrine cells, and many other cell types. Synaptic transmitter is stored in small membrane-bound packets called synaptic vesicles. Transmitter release occurs when vesicles fuse with the nerve terminal membrane and empty their contents into the synaptic cleft. The transmitter release is monitored by recording synaptic potentials in the post-synaptic cell. These result from the summed post-synaptic effect of the transmitter from one or several of these releases. A quantitative understanding of all processes involved greatly benefits from modeling studies of the system in order to confront different experimental data and to test hypothesis that lie far beyond present experimental possibilities. Because of the tiny structures of the synaptic terminals, following the pre- and post-synaptic response is only possible in a very limited number of these structures as, for example, the squid giant synapse and the calyx of Held (Neher, 1996). However, although sharing the same basic mechanisms, the phenomenology of synaptic transmission varies from one to another terminal. In comparison to the release of neurotransmitter by presynaptic terminals, secretion by neuroendocrine or endocrine cells is a relatively slow process with long latencies (Augustine et al., 1985; Llinas et al., 1981). For instance, secretion by chromaffin cells persists for dozens of milliseconds after a short pulse ceases (Chow et al., 1992); these long latencies have also been observed in pancreatic betacells (Eliasson et al., 1997). The existence of endogenous buffers is a plausible explanation for this fact; buffers bind calcium, which is the agent responsible of triggering secretion, delaying in this way the response of secretory vesicles. This hypothesis is confirmed by the effect of exogenously added buffers on the secretion time course in chromaffin cells (Chow et al., 1996) and in betacells (Bokvist et al., 1995). Also, the spatial organization of calcium channels and secretory vesicles has a key influence on the secretory response. In synaptic terminals, the distance between calcium channels and synaptic vesicles is small and the channel actually becomes part of the molecular release machinery (Clapham, 1995). Neuroendocrine cells show a similar calcium dependence of release as synapses but a strongly different organization of channels and vesicles, biophysical and biochemical properties of large dense core vesicle release in neuroendocrine cells, suggest that the vesicles and channels are separated by a distance of 100–300 nm. The papers of this special issue deal with different aspects of calcium-induced processes in particular cell prototypes, which can be seen as representative of systems having responses with different time scales. The perspective review of Soria et al. (2010) presents an interesting overview of what is known about pancreatic alpha-, beta-, and deltacells. These cells are found in the islets of Langerhans, which are responsible of glucose homeostasis. The word homeostasis makes reference to the maintenance of the constant physiological state and this is, of course, one of the fundamental characteristics of life. The islets of Langerhans are formed by alphacells, which increase the blood glucose level; betacells decrease it; and deltacells, where the precise role of which still needs identifying. Studies on the secretory response of pancreatic cells have a deep impact in public health because its malfunctioning can cause diabetes mellitus, among other diseases. On the other hand, the review by Dupont and Croisier (2010) pointed out a fundamental aspect about calcium: the organization, both in time and space, of the calcium signal inside the cell is crucial in order to determine its specific role. In hepatocytes, for example, a hormone-induced increase in calcium can lead both to the production of glucose but also to apoptosis or necrosis. How is the cell able to decide between such drastically different responses? The specific organization of the intracellular calcium signal seems to be the answer. A modeling approach to this aspect in electrically non excitable cells in which InsP3 receptors are the most important calcium channels, is considered in the clarifying Dupont and Croisier’s paper. In the contributed paper by Hallermann et al. (2010), the authors presented a nice analysis, both theoretical and experimental, of several models of presynaptic vesicle dynamics at the Drosophila neuromuscular junction, evaluating their impact on short-term plasticity at this synapse. Additionally, the authors apply these models to synapses lacking the active zone component Bruchpilot in order to understand the role of this active zone on short-term plasticity. “Plasticity” means how a particular synapse modulates the release of neurotransmitters: some synapses transmit strongly to action potentials but weaken with repeated activation; others transmit weakly at first but strengthen with sustained activity. This is the reason many synapses can be grosso modo classified as facilitating (having a low probability of initial transmitter release and exhibiting facilitation of release during trains of stimuli) or depressing (with high probability of initial release and depression of release during trains). Representative of “moderately slow” secretory processes (neuroendocrine cells) is the paper by Villanueva et al. (2010), which proposed a model of cytoskeletal cages in bovine chromaffin cells, where the secretory machinery associated with its borders. In this way, the organization of cytoplasm in excitable cells, which has been a factor usually ignored in mathematical models describing the role of intracellular calcium in neuroendocrine cells, provocatively emerges as a possible key factor for the understanding of the secretory response in these cells. Finally, an interesting theoretical study on the betacell (the slowest of the party, from a secretory point of view) activity in islets is presented in the paper by Meyer-Hermann and Benninger (2010). Pancreatic betacell communications in the Langerhans islet at the electrical level is mainly mediated by gap-junctions of connexin 36. The authors combine a mathematical model of betacell electrophysiology with a model for gap-junctions in order to explain experimental observations.
Despite their evolutionary significance, little is known about the adaptation dynamics of genomically rewired cells in evolution. We have confronted yeast cells carrying a rewired regulatory circuit with a severe and unforeseen challenge. The essential HIS3 gene from the histidine biosynthesis pathway was placed under the exclusive regulation of the galactose utilization system. Glucose containing medium strongly represses the GAL genes including HIS3 and these rewired cells are required to operate this essential gene. We show here that although there were no adapted cells prior to the encounter with glucose, a large fraction of cells adapted to grow in this medium and this adaptation was stably inherited. The adaptation relied on individual cells that switched into an adapted state and, thus, the adaptation was due to a response of many individual cells to the change in environment and not due to selection of rare advantageous phenotypes. The adaptation of numerous individual cells by heritable phenotypic switching in response to a challenge extends the common evolutionary framework and attests to the adaptive potential of regulatory circuits.
In the five years since its inception, HFSP Journal has made great progress. The journal has established itself as a well-regarded quarterly, publishing cutting-edge research at the interface of life and other advanced sciences. It gained its first impact factor last summer—an impressive 1.786—reflecting a very high standard of research published in the inaugural volumes. The paper of Riedel-Kruse et al. (2007), “How molecular motors shape the flagellar beat” and the study of Amitai et al. (2007), “Latent evolutionary potentials under the neutral mutational drift of an enzyme” are but two highlights among many. Now the journal is taking another step forward. In 2011, HFSP Journal will become Frontiers in Life Science and will be published by Taylor & Francis. After the current issue, Human Frontier Science Program will no longer manage the journal. The editor-in-chief, however, will continue to have complete control over editorial policy. What differences will you see? First, the journal will move to Taylor & Francis’ InformaWorld platform, where articles will be published in PDF and HTML and in advance of the printed issue whenever possible. Online files of the journal’s first four volumes will transfer across to InformaWorld and readers will benefit from sophisticated tools such as RSS content feeds and social bookmarks to enable easy linking to blogs and reference management platforms. Authors will still be able to pay for papers to become open access on publication. And the journal will continue to appear in both printed and online form. For the immediate future, submissions should be directed to the editorial manager (http://www.editorialmanager.com/hfspj). Later in the year, they will transfer to a dedicated ScholarOne Manuscripts site. We will contact authors nearer the time to explain how this will work. The Taylor & Francis Group has a long tradition of publishing in life science. Garland Science’s Molecular Biology of the Cell, now in its fourth edition, has been a phenomenally popular text. It forms part of an extensive book program, which is complemented by research journals including Critical Reviews in Biochemistry and Molecular Biology, Molecular Membrane Biology, Xenobiotica, Animal Biotechnology, Growth Factors, Microcirculation, Biocatalysis and Biotransformation, Critical Reviews in Microbiology, Artificial Cells, Blood Substitutes and Biotechnology, Food Biotechnology, and Nucleosides, Nucleotides and Nucleic Acids.
Neural activity can be captured by state-of-the-art optical imaging methods although the analysis of the resulting data sets is often manual and not standardized. Therefore, laboratories using large-scale calcium imaging eagerly await software toolboxes that can automate the process of identifying cells and inferring spikes. An algorithm proposed and implemented in a recent paper by Mukamel et al. [Neuron 63, 747-760 (2009)] used independent component analysis and offers significant improvements over conventional methods. The approach should be widely applicable, as tested with data obtained from the mouse cerebellum, neocortex, and spinal cord. The emergence of analysis tools in parallel with the rapid advances in optical imaging is an exciting development that will stimulate new discoveries and further elucidate the functions of neural circuits.
Understanding causal relationships between genotypes and phenotypes is a long-standing aim in genetics. In addition to high-throughput technologies that allow the measurement of many DNA variants it is possible to measure gene expression in specific tissues using array technology. "Systems genetics" is an emerging discipline that combines dense data on genotypes, gene expression, and outcome phenotypes to answer fundamental questions about causal pathways from genotype to phenotype. A recent paper by Chen et al. [Mol. Syst. Biol. 5, 310 (2009)] addressed the question of whether relative levels of mRNA expression help to elucidate causal paths from genotype to phenotype, using drug resistance in yeast as a model. The authors show that data on genetic markers and on gene expression, measured in a drug-free environment, can be combined to predict the growth of a yeast strain in the presence of a drug. They argue that their prediction can be used to identify causal pathways and for a subset of the genes used in prediction, the authors demonstrate that these genes cause an effect on drug sensitivity by deleting the gene or overexpressing it or swapping alleles between strains of yeast. This approach can also be applied to other species, including humans, and may become a tool in the study of personalized medicine.
