Design patterns are generalized solutions to frequently recurring problems. They were initially developed by architects and computer scientists to create a higher level of abstraction for their designs. Here, we extend these concepts to cell biology to lend a new perspective on the evolved designs of cells' underlying reaction networks. We present a catalog of 21 design patterns divided into three categories: creational patterns describe processes that build the cell, structural patterns describe the layouts of reaction networks, (...) and behavioral patterns describe reaction network function. Applying this pattern language to the E. coli central metabolic reaction network, the yeast pheromone response signaling network, and other examples lends new insights into these systems. (shrink)

The eukaryote cell is one of the most radical innovations in the history of life, and the circumstances of its emergence are still deeply contested. This paper will outline the recent history of attempts to reveal these origins, with special attention to the argumentative strategies used to support claims about the first eukaryote cell. I will focus on two general models of eukaryogenesis: the phagotrophy model and the syntrophy model. As their labels indicate, they are based on claims (...) about metabolic relationships. The first foregrounds the ability to consume other organisms; the second the ability to enter into symbiotic metabolic arrangements. More importantly, however, the first model argues for the autogenous or self-generated origins of the eukaryote cell, and the second for its exogenous or externally generated origins. Framing cell evolution this way leads each model to assert different priorities in regard to cell-biological versus molecular evidence, cellular versus environmental influences, plausibility versus evolutionary probability, and irreducibility versus the continuity of cell types. My examination of these issues will conclude with broader reflections on the implications of eukaryogenesis studies for a philosophical understanding of scientific contestation. (shrink)

The examination of the complex cell biology of the human malaria parasite Plasmodium falciparum usually relies on the time‐consuming generation of transgenic parasites. Here, metabolic labeling and click chemistry are employed as a fast transfection‐independent method for the microscopic examination of protein S‐palmitoylation, an important post‐translational modification during the asexual intraerythrocytic replication of P. falciparum. Applying various microscopy approaches such as confocal, single‐molecule switching, and electron microscopy, differences in the extent of labeling within the different asexual developmental (...) stages of P. falciparum and the host erythrocytes over time are observed. (shrink)

The goal of synthetic biology is to create artificial organisms. To achieve this it is essential to understand what life is. Metabolism-replacement systems, or (M, R)-systems, constitute a theory of life developed by Robert Rosen, characterized in the statement that organisms are closed to efficient causation, which means that they must themselves produce all the catalysts they need. This theory overlaps in part with other current theories, including autopoiesis, the chemoton, and autocatalytic sets, all of them invoking some idea (...) of closure. A simple model of an (M, R)-system has been implemented in the computer, and behaves in ways that may shed light on the requirements for a prebiotic self-organizing system. In addition to a trivial steady state in which nothing happens, it can establish a non-trivial steady state in which all intermediates have finite concentrations, with their rates of degradation balanced by their rates of synthesis. The system can be regenerated from the set of food components plus a single intermediate, and maintain itself in that state indefinitely, despite continuous degradation. At the very low compartment volumes that may have existed in prebiotic conditions, for example in cavities in minerals, or in micelles formed by simple amphiphiles, statistical fluctuations in the numbers of molecules need to be taken into account. With the stochastic approach there is no non-trivial steady state in strict mathematical terms, because the system will always collapse to the trivial state after sufficient time. However, the average time before collapse is so long for volumes greater than $10^{-19}\;{\textsc{l}}$ (much smaller than the volume of the order of $10^{-15}\;{\textsc{l}}$ for a typical bacterial cell) that for practical purposes the self-maintaining state of non-null concentrations becomes significant, recalling the situation of bistability that is observed in deterministic analysis. In turn, there exists a minimum size below which the self-organizing system cannot maintain itself on chemically relevant time scales. The value of the critical volume depends on the particular concentrations and rate constants assumed, but the principle could apply generally. (shrink)

Lymphangiogenesis is an important developmental process that is critical to regulation of fluid homeostasis, immune surveillance and response as well as pathogenesis of a number of diseases, among them cancer, inflammation, and heart failure. Specification, formation, and maturation of lymphatic blood vessels involves an interplay between a series of events orchestrated by various transcription factors that determine expression of key genes involved in lymphangiogenesis. These are traditionally thought to be under control of several key growth factors including vascular growth factor‐C (...) (VEGF‐C) and fibroblast growth factors (FGFs). Recent insights into VEGF and FGF signaling point to their role in control of endothelial metabolic processes such as glycolysis and fatty acid oxidation that, in turn, play a major role in regulation of lymphangiogenesis. These advances have significantly increased our understanding of lymphatic biology and opened new therapeutic vistas. Here we review our current understanding of metabolic controls in the lymphatic vasculature. (shrink)

Cell communication plays a key role in multicellular organisms. In developing embryos as in adult organisms, cells communicate by coordinating their differentiation through the establishment and/or renewal of a variety of cell communication channels. Under both these conditions, cells interact by either receptor signalling, surface recognition of specific cell adhesion molecules or transfer of cytoplasmic components through junctional coupling. In recent years, it has become apparent that cells may also communicate through the extracellular release of microvesicles. They (...) may originate as either exosomes from the endosomal compartment upon fusion of multivesicular bodies with the plasma membrane or be shed directly from the plasma membrane via extensions of the cell surface. Microvesicles may disperse over long distances through body fluids and deliver their molecular cargo onto a variety of target cells. As a general rule, the metabolic fate of these cells is determined by the molecular nature of the vesicular cargo, while targeting itself depends on the affinity of the molecules expressed on the enclosing membrane. In this paper, we will be arguing that intercellular vesicular transfer is substantially different from other types of cell communication, allowing cells and molecules to interact on varying levels. Cells interacting via ligand signalling owe their specificity to the steric coupling with cognate receptor molecules. As such, it is a pure molecular process that affects target cells only upon integration into their responding repertoire. In this relationship, coupled cells are reciprocally adapted to each other through the selection of their respective signalling capacities, following exploration of their receptor specificity. Interaction by intercellular vesicles realizes a substantially different type of cell communication. Vesicular traffic allows donor cells to carry out a horizontal type of gene transfer and target this information over long distances via independently controlled mechanisms. Because of this independence, cells interacting via vesicular traffic are not expected to adapt their signalling correspondences, but to control instead the efficiency of their cargo delivery irrespective of the receptor repertoire expressed by the target tissue. In this paper, the multifaceted functions of the intercellular vesicular traffic will be discussed in a multilevel biosemiotic perspective with the aim of unravelling the cellular mechanisms devised by nature to accomplish communication. (shrink)

Reductionism--understanding complex processes by breaking them into simpler elements--dominates scientific thinking around the world and has certainly proved a powerful tool, leading to major discoveries in every field of science. But reductionism can be taken too far, especially in the life sciences, where sociobiological thinking has bordered on biological determinism. Thus popular science writers such as Richard Dawkins, author of the highly influential The Selfish Gene, can write that human beings are just "robot vehicles blindly programmed to preserve the selfish (...) molecules known as genes." Indeed, for many in science, genes have become the fundamental unit for understanding human existence: genes determine every aspect of our lives, from personal success to existential despair: genes for health and illness, genes for criminality, violence, and sexual orientation. Others would say that this is reductionism with a vengeance. In Lifelines, biologist Steven Rose offers a powerful alternative to the ultradarwinist claims of Dawkins, E.O. Wilson, Daniel Dennett and others. Rose argues against an extreme reductionist approach that would make the gene the key to understanding human nature, in favor of a more complex and richer vision of life. He urges instead that we focus on the organism and in particular on the organism's lifeline: the trajectory it takes through time and space. Our personal lifeline, Rose points out, is unique--even identical twins, with identical genes at birth, will differ over time. These differences are obviously not embedded in our genes, but come about through our developmental trajectory in which genes, as part of the biochemical orchestra of trillions of cells in each human body, have an important part--but only a part--to play. To illustrate this idea, Rose examines recent research in modern biology, and especially two disciplines--genetics (which looks at the impact of genes on form) and developmental biology (which examines the interaction between the organism and the environment)--and he explores new ideas on biological complexity proposed by scientists such as Stuart Kauffman. He shows how our lifelines are constructed through the interplay of physical forces--such as the intrinsic chemistry of lipids and proteins, and the self-organizing and stabilizing properties of complex metabolic webs--and he reaches a startling conclusion: that organisms are active players in their own fate, not simply the playthings of the gods, nature, or the inevitable workings out of gene-driven natural selection. The organism is both the weaver and the pattern it weaves. Lifelines will be a rallying point for all who seek an alternative to the currently fashionable, deeply determinist accounts which dominate popular science writing and, in fact, crowd the pages of some of the major scientific journals. Based on solid, state-of-the-art research, it not only makes important contributions to our understanding of Darwin and natural selection, but will swing the pendulum back to a richer, more complex view of human nature and of life. (shrink)

Metabolism is a set of chemical reactions, used by living organisms to process chemical compounds in order to take energy and eliminate toxic compounds, for example. Its processes are referred as metabolic pathways. Understanding metabolism is imperative to biology, toxicology and medicine, but the number and complexity of metabolic pathways makes this a difficult task. In our paper, we investigate the use of causal Bayesian networks to model the pathways of yeast saccharomyces cerevisiae metabolism: such a network (...) can be used to draw predictions about the levels of metabolites and enzymes in a particular specimen. We propose a two-stage methodology for causal networks, as follows. First construct a causal network from the network of metabolic pathways. The viability of this causal network depends on the validity of the causal Markov condition. If this condition fails, however, the principle of the common cause motivates the addition of a new causal arrow or a new `hidden' common cause to the network (stage 2 of the model formation process). Algorithms for adding arrows or hidden nodes have been developed separately in a number of papers, and in this paper we combine them, showing how the resulting procedure can be applied to the metabolic pathway problem. Our general approach was tested on neural cell morphology data and demonstrated noticeable improvements in both prediction and network accuracy. (shrink)

Several metabolites serve as substrates for histone modifications and communicate changes in the metabolic environment to the epigenome. Technologies such as metabolomics and proteomics have allowed us to reconstruct the interactions between metabolic pathways and histones. These technologies have shed light on how nutrient availability can have a dramatic effect on various histone modifications. This metabolism–epigenome cross talk plays a fundamental role in development, immune function, and diseases like cancer. Yet, major challenges remain in understanding the interactions between (...) cellular metabolism and the epigenome. How the levels and fluxes of various metabolites impact epigenetic marks is still unclear. Discussed herein are recent applications and the potential of systems biology methods such as flux tracing and metabolic modeling to address these challenges and to uncover new metabolic–epigenetic interactions. These systems approaches can ultimately help elucidate how nutrients shape the epigenome of microbes and mammalian cells. (shrink)

Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new substrates that (...) are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed. (shrink)

Oncogene activation leads to cellular transformation by deregulation of biological processes such as proliferation and metabolism. Paradoxically, this can also sensitize cells to nutrient deprivation, potentially representing an Achilles' heel in early stage tumors. The mechanisms underlying this phenotype include loss of energetic and redox homeostasis as a result of metabolic reprogramming, favoring synthesis of macromolecules. Moreover, an emerging mechanism involving the deregulation of mRNA translation elongation through inhibition of eukaryotic elongation factor 2 kinase (eEF2K) is presented. The potential (...) consequences of eEF2K deregulation leading to cell death under nutrient depletion are discussed. Finally, the relevance of eEF2K as a master regulator of the response to nutrient deprivation in vivo, and its potential exploitation for therapeutic targeting of cancers, are elaborated. Overall, a better understanding of the adaptive mechanisms allowing tumors to circumvent oncogene‐induced hypersensitivity to nutrient deprivation is a promising avenue for uncovering novel therapeutic targets in cancers. (shrink)

There are many ways of describing and explaining the properties of living systems; causal, functional, and reductive accounts are necessary but no one account has primacy. The history of biology as a discipline has given excessive authority to reductionism, which collapses higher level accounts, such as social or behavioural ones, into molecular ones. Such reductionism becomes crudely ideological when applied to the human condition, with its claims for genes everything from sexual orientation to compulsive shopping. The current enthusiasm for (...) genetics and ultra-Darwinist accounts, with their selfish-gene metaphors for living processes, misunderstand both the phenomena of development and the interactive role that DNA and the fluid genome play in the cellular orchestra. DNA is not a blueprint, and the four dimensions of life (three of space, one of time) cannot be read off from its one-dimensional strand. Both developmental and evolutionary processes are more than merely instructive or selective; the organism constructs itself, a process known as autopoiesis, through a lifeline trajectory. Because organisms are thermodynamically open systems, living processes are homeodynamic, not homeostatic. The self-organising membrane-bound and energy-utilising metabolic web of the cell must have evolved prior to so-called naked replicators. Evolution is constrained by physics, chemistry, and structure; not all change is powered by natural selection, and not all phenotypes are adaptive. Finally, therefore, living processes are radically indeterminate; like all other living organisms, but to an even greater degree, we make our own future, though in circumstances not of our own choosing. (shrink)

The importation of computational methods into biology is generating novel methodological strategies for managing complexity which philosophers are only just starting to explore and elaborate. This paper aims to enrich our understanding of methodology in integrative systems biology, which is developing novel epistemic and cognitive strategies for managing complex problem-solving tasks. We illustrate this through developing a case study of a bimodal researcher from our ethnographic investigation of two systems biology research labs. The researcher constructed models of (...) metabolic and cell-signaling pathways by conducting her own wet-lab experimentation while building simulation models. We show how this coupling of experiment and simulation enabled her to build and validate her models and also triangulate and localize errors and uncertainties in them. This method can be contrasted with the unimodal modeling strategy in systems biology which relies more on mathematical or algorithmic methods to reduce complexity. We discuss the relative affordances and limitations of these strategies, which represent distinct opinions in the field about how to handle the investigation of complex biological systems. (shrink)

Synthetic genomics is a new field of research in which small DNA pieces are assembled in a series of steps into whole genomes. The highly reduced genomes of host‐associated bacteria are now being used as models for de novo synthesis of small genomes in the laboratory. Bacteria with the smallest genomes identified in nature provide nutrients to their hosts, such as amino acids, co‐factors and vitamins. Comparative genomics of these bacteria enables predictions to be made about the gene sets required (...) for core cellular functions and the associated metabolic network for the biosynthesis of host‐selected compounds. Synthetic biology may ultimately enable researchers to make customized cell‐specific organelles for the production and delivery of drugs to humans and domestic animals. Synthetic genomics may also become the method of choice for functional analyses of genes and genomes from bacteria that cannot be cultivated in the laboratory. (shrink)

What general conclusions can be drawn about the reception of zymase, its relation to the larger shift from a protoplasm to an enzyme theory of life, and its status as a social phenomenon?The most striking and to me unexpected pattern is the close correlation between attitude toward zymase and professional background. The disbelief of the fermentation technologists, Will, Delbrück, Wehmer, and even Stavenhagen, was as sharp and unanimous as the enthusiasm of the immunologists and enzymologists, Duclaux, Roux, Fernback, and Bertrand, (...) and of Pfeffer, the experimental plant physiologist. Other skeptics—Voit, Kupffer, and Fischer—were conservatives in traditional fields. In all these cases it seems clear that professional commitments and outlook profoundly influenced the reception of zymase.In some cases there is a correlation with a specific earlier statement favoring the protoplasm theory or predicting a fermentation enzyme. Reynolds Green is a striking case of both. In 1893 he stated his belief that life processes in higher plants and fungi were identical, both being mediated by protoplasm.109 Thus he claimed that digestion was not carried out by enzymes, as in higher animals, but by the whole protoplasm, and so too fermentation in yeast: “All the metabolic processes must be carried out in the unicellular organism in the same mass of protoplasm.”110 But Green also insisted that there was no essential difference between “organized” and “unorganized ferments”; enzymes were simply more highly differentiated and specialized forms of primitive protoplasm. He spoke of “the alcoholic ferment” (that is, enzyme), and of intracellular enzymes—very advanced beliefs for 1893. Thus it is understandable why Green saw no reason to doubt his first negative results with yeast juice, and rushed into print. But it is also understandable that he persisted and soon became an outspoken advocate of Buchner's view; like Wroblewski and Pfeffer, he had already accepted the idea of an intracellular fermentation enzyme.The physiological chemists also fit the pattern in a special way. Physiological chemistry is generally regarded as the source of biochemistry; indeed, many early biochemists were trained in physiological chemistry, and imbibed there a progressive interest in enzymes and metabolism. It is not surprising, therefore, that on the whole Neumeister, Madfadyen, Wroblewski, and Loew accepted cell-free fermentation. But what is surprising, and significant, is the diversity of opinion in this group, from Abeles' living protoplasm to Wroblewski's organized array of active proteins. The feelings of the physiological chemists were mixed, and there was enough of the old protoplasm view in Macfadyen's and even Wroblewski's views to allow Buchner to see them as attacks on zymase. The ideas of physiological chemistry were also changing; the idea of protoplasm was already adjusting to the new interest in enzymes in the early 1890's. But in contrast to immunochemistry, the change in physiological chemistry was gradual, uneven, undramatic, and relatively invisible. For the new biochemistry, the tradition of physiological chemistry was the source of traditional conservatism as well as of new ideas of enzymes.In general, then, I claim that it was not experimental facts that determined attitudes toward zymase so much as previous commitments, experience, and expectations. Initially, at least, zymase was less a determinant of opinion than a touchstone of pre-existing opinion. Like a prism, it revealed the spectrum of existing attitudes toward vital phenomena.Also relevant here is the fact that the experimental evidence was entirely ambiguous; the interpretation of Buchner's experiments with antiseptics or dried yeast depended entirely on how far one was willing to stretch the scope of the terms “protoplasm” and “enzyme”. Likewise, how important one judged the instability of zymase to be, or the low level of in vitro activity, depended largely on one's point of view. There was no crucial experiment, no certain proof. Logically zymase could be regarded as protoplasm. A. Fischer did so in 1900;111 Macfadyen was still wavering in 1907;112 and Beijerinck was holding out as late as 1916.113 There were undoubtedly others. Besides the special case of Reynolds Green and the technologists, there are no recorded cases of conversion.But if there was no evidence to convert a dedicated protoplasmist, there was plenty to encourage a dedicated belief in the enzyme theory, and that, I believe, is precisely what happened. The arguments of Buchner et al in support of zymase had the greatest effect not on the protoplasmists but on those who were already predisposed toward the biochemical view. The zymase debate enabled the emerging group of biochemists to recognizethemselves as a group with a community of out-look and objectives; it brought the issue of protoplasm vs. enzyme into the open and gave it a specific and concrete issue on which to turn. The debate sharpened the biochemists' awareness that their point of view was becoming the new mainstream of biochemical thought.All this of course had an important secondary effect on those who opposed the new view, or who were not immediately concerned with it. After the zymase debate, it would have been almost impossible to ignore the new ideas; the dramatic and wide publicity the debate enjoyed would have made it difficult not to take sides. Buchner's successful defense of zymase itself became an important influence on opinion; the new movement had to be looked at with respect. But the primary effect of the debate, I assert, was on those who were already inclined to the new view. The outcome was not a mass conversion of individuals, nor the ejection of one idea by another. The sides probably did not change much; the real change was in the way each side regarded itself and its place in history. The zymase debate may perhaps best be regarded as a process of selection. Buchner's party became aware of itself as the new progressive point of view, while those holding the traditional view could no longer expound it publicly without appearing obstinate or old-fashioned. Thus the way was clear for the gradually wider establishment of the new ideas, especially among the new generation of biochemists. In this specific sense, the acceptance of zymase was a social phenomenon.This way of looking at the zymase debate also illuminates its coincidence with the emergence of biochemistry as a profession. The new professional trappings and organizations were the social manifestation of the new self-awareness gained from the zymase controversy. One of the most important effects on those disposed toward the new view was the awareness of an intellectual community and of the need to give that community social forms. The almost mythical importance of Buchner's “victory” over the old protoplasm theory that later became current is readily understandable. It was a useful ideology for a group anxious to assert the novelty of their approach, a novelty which they in fact felt quite keenly.But if the primary effect of the zymase controversy was on those predisposed to accept zymase, then obviously the success of zymase depended on the fact that change had already begun to occur. Indeed, one of the most striking, and again unexpected, results of this study is the extent to which the importance of enzymes was already recognized in the early 1890's. The new immunology clearly pointed the way. Macfadyen and Hans Buchner were looking for active proteins inside the cell in 1893. Reynolds Green, Wroblewski, and Pfeffer had all anticipated the discovery of a fermentation enzyme. Other discoveries in enzymology in the 1890's pointed the same way.114 Moreover, it is clear from this study that the old protoplams theory was adapting to the new discoveries concerning the importance of enzymes. The sidechains of the old protoplasm molecule were simply reinterpreted as enzymes, as in Wroblewski's theory, for example, or in Paul Ehrlich's extremely influential “sidechain theory” of antibody formation (1897). Despite the later views of Hopkins et al., the old protoplasm and the new enzyme theories were not irreconcilable; a continuity of development had already begun when zymase came so dramatically on the scene. Buchner himself observed that the difference between the two views had become largely verbal; in retrospect we might say, not verbal, but social and historical. The gap between the continuous change in ideas and the contemporary feeling of sharply discontnuous change is a measure of the elusive but real social and historical implications of the zymase debate, of the demise of an old establishment, and the emergence of a new.In retrospect, then, it is clear that a trend was already under way in various quarters when zymase appeared. But it was still a collection of isolated and dispersed events. The zymase controversy made the trend visible and gave it a dramatic unity. The debate influenced those who had already begun to change. It was so effective because things had begun to change and because it coincided with the direction of that trend. (shrink)

The concept of the energid (which refers to “energy,” or “vital force”; in modern terms, adenosine triphosphate, ATP) is that the smallest unity of life is the nucleus and the amount of protoplasm the nucleus can “control” metabolically. The concept of the cell as a nucleus-protoplasm “unit” confined by either a cell membrane or cell wall (e.g., mammalian or land plant cells) is rejected. Examples of multinucleate organisms such as coenocytic algae are presented as “proof of concept” (...) of the energid. [Abstract and keywords not in original.]. (shrink)

Organismal death has long been considered the irreversible ending of an organism's integrated functioning as a whole. However, the persistence of functionality in organs, tissues, and cells postmortem, as seen in organ donation, raises questions about the mechanisms underlying this resilience. Recent research reveals that various factors, such as environmental conditions, metabolic activity, and inherent survival mechanisms, influence postmortem cellular functionality and transformation. These findings challenge our understanding of life and death, highlighting the potential for certain cells to grow (...) and form new multicellular entities. This opens new avenues in biology and medicine, expanding our comprehension of life's complexity. (shrink)

Scale-free network models describe many natural and social phenomena. In particular, networks of interacting components of a living cell were shown to possess scale-free properties. A recent study(1) compares the system-level properties of metabolic and information networks in 43 archaeal, bacterial and eukaryal species and claims that the scale-free organization of these networks is more conserved during evolution than their content. BioEssays 24:105–109, 2002. Published 2002 Wiley Periodicals, Inc.

Assembly of minimal genomes revealed many genes encoding unknown functions. Three overlooked functional categories account for some of them. Cells are prone to make errors and age. As a first key function, discrimination between proper and changed entities is indispensable. Discrimination requires management of information, an authentic, yet abstract, cur- rency of reality. For example proteins age, sometimes very fast. The cell must identify, then get rid of old proteins without destroying young ones. Implementing discrimination in cells leads to (...) the second set of functions, usually ignored. Being abstract, information must nevertheless be embodied into material entities, with unavoidable idiosyncratic properties. This brings about novel unmet needs. Hence, the buildup of cells elicits specific but awkward material implementations, ‘kludges’ that become essential under particular settings, while difficult to identify. Finally, a third functional category char- acterizes the need for growth, with metabolic implementations allowing the cell to put together the growth of its cytoplasm, membranes, and genome, spanning different spatial dimensions. Solving this metabolic quandary, critical for engineering novel synthetic biology chassis, uncovered an unexpected role for CTP synthetase as the coordinator of nonhomothetic growth. Because a significant number of SynBio constructs aim at creating cell factories we expect that they will be attacked by viruses (it is not by chance that the function of the CRISPR system was identified in industrial settings). Substantiating the role of CTP, natural selection has dealt with this hurdle via synthesis of the antimetabolite 30-deoxy-30,40-didehydro- CTP, recruited for antiviral immunity in all domains of life. (shrink)

One observes regulation at every biological level. Organisms, cells, and biochemical processes operate efficiently, normally wasting neither material nor energy, and adjusting their functions to external influences. Nature evidently has evolved mechanisms specifically dedicated to regulation at many levels. What is the molecular basis of this control?In the 1950s these molecular control mechanisms began to be explored seriously. The discoveries of feedback inhibition of enzyme activity were important because they gave an initial example of how regulation is achieved at the (...) molecular level. We showed that certain enzymes are composed of two parts, one for catalysis and another distinct part present only to regulate this catalysis. Catalytic activity can be either stimulated or inhibited when a small molecule in the environment combines with the enzyme's regulatory site. In particular, a final product of a metabolic pathway generates a feedback loop which automatically limits its own excessive production, by combining with the regulatory site of an early enzyme in that pathway. Later studies showed that catalytic and regulatory structures of some enzymes could be separated physically.The discovery of regulatory sites and their interaction with molecules unrelated to their substrates was the basis for the generalized allosteric concept. This concept extends the regulatory site idea to a wide variety of processes such as control of gene expression, hormone action, and cellular growth. (shrink)

Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of (...) diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metabolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science. (shrink)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation for (...) calcium dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

Upon starvation and growth arrest, Escherichia coli cells gradually lose their ability to reproduce. These apparently sterile/nonculturable cells initially remain intact and metabolically active and the underlying molecular mechanism behind this sterility is something of an enigma in bacteriology. Three different models have been proposed to explain this phenomenon. The first theory suggests that starving cells become nonculturable due to cellular deterioration, are moribund, and show some of the same signs of senescence as aging organisms. The two other theories suggest (...) that genetically programmed pathways, rather than stochastic deterioration, trigger nonculturability. One “program” theory suggests that nonculturability is the culmination of an adaptive pathway generating dormant survival forms, similar to spore formation in differentiating bacteria. The other “program” theory states that starved cells lose viability due to activation of genetic modules mediating programmed cell death. The different models will be reviewed and evaluated in light of recent data on the physiology and molecular biology of growth‐arrested E. coli cells. BioEssays 25:204–211, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

During the last few months, several pioneer genome‐wide transcriptomic, proteomic and metabolomic studies have revolutionised the understanding of bacterial biological processes, leading to a picture that resembles eukaryotic complexity. Technological advances such as next‐generation high‐throughput sequencing and high‐density oligonucleotide microarrays have allowed the determination, in several bacteria, of the entire boundaries of all expressed transcripts. Consequently, novel RNA‐mediated regulatory mechanisms have been discovered including multifunctional RNAs. Moreover, resolution of bacterial proteome organisation (interactome) and global protein localisation (localizome) have unveiled an (...) unanticipated complexity that highlights the significance of protein multifunctionality and localisation in the cell. Also, analysis of a complete bacterial metabolic network has again revealed a high fraction of multifunctional enzymes and an unexpectedly high level of metabolic responses and adaptation. Altogether, these novel approaches have permitted the deciphering of the entire physiological landscape of one of the smallest bacteria, Mycoplasma pneumoniae. Here, we summarise and discuss recent findings aimed at defining the blueprint of any prokaryote. (shrink)

Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites of production, (...) plant developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

Graphical AbstractIt was recently discovered that the enzyme CTP synthase forms filamentous sub-cellular structures (called cytophidia) that seem to be highly conserved from prokaryotes to eukaryotes and whose functions still need to be elucidated.

Recent research shows that a faulty or sub‐optimally operating metabolic network can often be rescued by the targeted removal of enzyme‐coding genes – the exact opposite of what traditional gene therapy would suggest. Predictions go as far as to assert that certain gene knockouts can restore the growth of otherwise nonviable gene‐deficient cells. Many questions follow from this discovery: What are the underlying mechanisms? How generalizable is this effect? What are the potential applications? Here, I approach these questions from (...) the perspective of compensatory perturbations on networks. Relations are drawn between such synthetic rescues and naturally occurring cascades of reaction inactivation, as well as their analogs in physical and other biological networks. I specially discuss how rescue interactions can lead to the rational design of antagonistic drug combinations that select against resistance and how they can illuminate medical research on cancer, antibiotics, and metabolic diseases. Editor's suggested further reading in BioEssaysThe evolutionary context of robust and redundant cell biological mechanisms AbstractReprogramming cell fates: reconciling rarity with robustness Abstract. (shrink)

Darwinian evolution can be simply stated: natural selection of inherited variations increasing differential reproduction. However, formulated thus, links with biochemistry, cell biology, ecology, and population dynamics remain unclear. To understand interactive contributions of chance and selection, higher levels of biological organization (e.g., endosymbiosis), complexities of competing selection forces, and emerging biological novelties (such as eukaryotes or meiotic sex), we must analyze actual examples. Focusing on mitochondria, I will illuminate how biology makes sense of life's evolution, and the (...) concepts involved. First, looking at the bacterium – mitochondrion transition: merging with an archaeon, it lost its independence, but played a decisive role in eukaryogenesis, as an extremely efficient aerobic ATP generator and internal ROS source. Second, surveying later mitochondrion adaptations and diversifications illustrates concepts such as constructive neutral evolution, dynamic interactions between endosymbionts and hosts, the contingency of life histories, and metabolic reprogramming. Without oxygen, mitochondria disappear; with (intermittent) oxygen diversification occurs in highly complex ways, especially upon (temporary) phototrophic substrate supply. These expositions show the Darwinian model to be a highly fruitful paradigm. (shrink)

The origin of the eukaryotic cell nucleus and the selective forces that drove its evolution remain unknown and are a matter of controversy. Autogenous models state that both the nucleus and endoplasmic reticulum (ER) derived from the invagination of the plasma membrane, but most of them do not advance clear selective forces for this process. Alternative models proposing an endosymbiotic origin of the nucleus fail to provide a pathway fully compatible with our knowledge of cell biology. We (...) propose here an evolutionary scenario that reconciles both an ancestral endosymbiotic origin of the eukaryotic nucleus (endosymbiosis of a methanogenic archaeon within a fermentative myxobacterium) with an autogenous generation of the contemporary nuclear membrane and ER from the bacterial membrane. We specifically state two selective forces that operated sequentially during its evolution: (1) metabolic compartmentation to avoid deleterious co‐existence of anabolic (autotrophic synthesis by the methanogen) and catabolic (fermentation by the myxobacterium) pathways in the cell, and (2) avoidance of aberrant protein synthesis due to intron spreading in the ancient archaeal genome following mitochondrial acquisition and loss of methanogenesis. BioEssays 28: 525–533, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

In this chapter we offer a critical analysis of organizational models about the process of origins of life and, thereby, a reflection about life itself (understood in a general, minimal sense). We begin by demarcating the idea of organization as an explanatory construct, linking it to the complex relationships and transformations that the material parts of (proto-)biological systems establish to maintain themselves under non-equilibrium dynamic conditions. The diverse ways in which this basic idea has been applied within the prebiotic field (...) are then reviewed in relative detail. We distinguish between “network” and “protocell” approaches, discussing their specific implications and explaining the greater relevance of the latter in the current state of affairs. Despite the key role that such organizational approaches play (and should keep playing) to advance on the problem of primordial biogenesis, the second half of our contribution is devoted to argue that they must be combined with other explanatory accounts, which go beyond the physiology of any single (proto-)organism. With that aim, we underline the fundamental differences between the autonomous, metabolic dynamics that individual (proto-)cells perform and the evolutionary and ecological dynamics that take place in a collective and trans-generational dimension. Apart from obvious gaps in the characteristic temporal and spatial scales involved, the corresponding causal and interactive regimes also reveal themselves as neatly distinct, what is reflected in the unpaired functional integration and the agent behavior displayed by biological individuals. Nevertheless, any living organism (and life in a wider, general sense) derives from the deep interweaving of those two phenomenological domains: namely, the “individual-metabolic” and the “collective-evolutionary” domains. At the end of the chapter, we propose the principle of dynamical decoupling as the core idea to develop a more comprehensive theoretical framework to understand how this intricate, causally asymmetric connection must be articulated during the actual process of biogenesis (as it happened here on Earth or anywhere else in the universe), so that life’s minimal complexity threshold is reached. (shrink)

Current research on the neural basis of consciousness is based mainly on neuroimaging, physiology and psychophysics. This target article reviews what is known about biochemical factors that may contribute to the development of consciousness, based on loss of consciousness (i.e., coma). There are two theories of the biochemical mode of action of general anaesthetics. One is that anaesthesia is a direct (i.e., not receptor-mediated) effect of the anaesthetic on cellular neurophysiological function; the other is that some alteration of receptor function (...) occurs. General anaesthetics are mainly GABA agonists but some (such as ketamine) are glutamate antagonists. They also affect other systems, particularly cholinergic ones. There are various comas of metabolic origin. For example, a combination of small doses of the iron chelators desferrioxamine and prochlorperazine induce a profound and long lasting coma in humans. The mechanisms that might mediate this include redox mechanisms at the glutamate synapse, post-synaptic endocytosis of dopamine and iron, and intracellular iron-dopamine complexes, which are powerful dismuters of the superoxide anion. New findings in cell biology relating to endocytosis and recycling of receptors are discussed in a wider context. These biochemical events may induce coma by two mechanisms: (i) Consciousness may depend on widespread cortical (or cortico-thalamic) activation. (ii) Whereas these biochemical changes are widespread, only the changes in a subset of consciousness' neurons may count. An experimental program to distinguish between these two alternatives is proposed. (shrink)

Early in the 20th century, Charles Manning Child attributed organismal gradients in metabolism to interactions among groups of cells. Metabolic gradients are now firmly grounded in redox chemistry, yet modern work on metabolic signaling has consistently focused on the cellular level. Multicellular redox regulation, however, may occur when redox state is determined by the behavior of a group of cells. For instance, typically an abundance of substrate will shift the redox state of mitochondria in the direction of reduction, (...) leading to increased reactive oxygen species (ROS). These ROS, in turn, may modify the conformation and activity of proteins involved in signaling pathways, resulting in phenotypic changes. In contrast, if substrate triggers the contractions of a muscular structure comprising mitochondrion‐rich cells, the resulting metabolic demand may shift the redox state in the direction of oxidation, with a corresponding decrease of ROS and different phenotypic effects. Indeed, colonial hydroids exemplify this process. Parallel examples may occur whenever mitochondria are concentrated in cells of structures that can respond to environmental perturbations with increased metabolic demand. In these circumstances, predicting the direction of metabolic signaling may require an understanding of events at the organismal level. BioEssays 28:72–77, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Biology is seen not merely as a privileged oppressor of women but as a co-victim of masculinist social assumptions. We see feminist critique as one of the normative controls that any scientist must perform whenever analyzing data, and we seek to demonstrate what has happened when this control has not been utilized. Narratives of fertilization and sex determination traditionally have been modeled on the cultural patterns of male/female interaction, leading to gender associations being placed on cells and their components. (...) We also find that when gender biases are controlled, new perceptions of these intracellular and extracellular relationships emerge. (shrink)

Synthetic biology (SynBio) covers two main areas: application engineering, exemplified by metabolic engi- neering, and the design of life from artificial building blocks. As the general public is often reluctant to embrace synthetic approaches, preferring nature to artifice, its immediate future will depend very much on the public’s reaction to the unmet needs created by the pervasive demands of sustainability. On the other hand, this reluctance should not have a negative impact on research that will now take into (...) account the existence of the multiple transitions that cells face over time. The ages of life—birth, development, maturation, senescence and death—reflect specific key transitions and have, until now, rarely been taken into account in SynBio designs. This results in a mismatch between novelty and the very long evolutionary time that led to the existing chassis [remember that this is the common term used to describe the cellular framework as seen by synthetic biologists (de Lorenzo & Danchin, 2008)]. It also implies that, in general, transitions between growth stages will be taken into account with the appro- priate embodiment of highly specific processes. This is particularly important when adapting new models to their host, whether natural or artificial. Adaptation fol- lows two stages, short-term accommodation of new entities and long-term assimilation into the cell as a whole. This requires discrimination between classes of entities. We suggest that proteins playing the essential role of Maxwell’ demons, here named Maxwell’s dis- criminators (MxDs) to refer to their original function, will permit the assimilation and accommodation of artificial constructs. As a consequence, we can foresee that class discrimination, beyond mere recognition, will be implemented in SynBio 2.0, leading to an authentic par- adigm shift (Kuhn, 1996), based on conceptions that embody information as a genuine currency of reality. (shrink)

The emerging field of synthetic biology aims to engineer novel biological entities. The envisioned future bio-based economy builds largely on “cell factories”: organisms that have been metabolically engineered to sustainably produce substances for human ends. In this paper, we argue that synthetic biology’s goal of creating efficient production vessels for industrial applications implies a set of ontological assumptions according to which living organisms are machines. Traditionally, a machine is understood as a technological, isolated and controllable production unit (...) consisting of parts. But modified organisms, or hybrids, require us to think beyond the machine paradigm and its associated dichotomies between artificial and natural, organisms and artefacts. We ask: How may we conceptualise hybrids beyond limiting ontological categories? Our main claim is that the hybrids created by synthetic biology should be considered not as machines but as metabolic systems. We shall show how the philosophical account of metabolism can inform an ontology of hybrids that moves beyond what we call the “machine ontology”, considering that metabolism enables thinking beyond the dominant dichotomies and allows us to understand and design lifeforms in a bio-based economy. Thus, the aim of this paper is twofold: first, to develop the philosophical ontology of hybrids, and second, to move synthetic biology beyond the problematically limiting view of hybrids. (shrink)

Stem cell scientists and ethicists have focused intently on questions relevant to the developmental stage and developmental capacities of stem cells. Comparably less attention has been paid to an equally important set of questions about the nature of stem cells, their common characteristics, their non‐negligible differences and their possible developmental species specificity. Answers to these questions are essential to the project of justly inferring anything about human stem cell biology from studies in non‐human model systems—and so to (...) the possibility of eventually developing human therapies based on stem cell biology. After introducing and discussing these questions, I conclude with a brief discussion of the creation of novel model systems in stem cell biology: human‐to‐animal embryonic chimeras. Such novel model systems may help to overcome obstacles to extrapolation, but they are also scientifically and ethically contentious. BioEssays 26:1005‐1012, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl glycerol; R59022, DAG kinase inhibitor; AA, (...) arachidonic acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

Examining stem cell biology from a philosophy of science perspective, this book clarifies the field's central concept, the stem cell, as well as its aims, methods, models, explanations and evidential challenges. The first chapters discuss what stem cells are, how experiments identify them, and why these two issues cannot be completely separated. The basic concepts, methods and structure of the field are set out, as well as key limitations and challenges. The second part of the book shows (...) how rigorous explanations emerge from stem cell experiments, and compares these to other kinds of scientific explanation. Model organisms, the role of genes, and the significance of collaboration are also discussed. The last part of the book considers relations to systems biology and clinical medicine, arguing that both the mathematical models of the former, and ethical principles of the latter, are necessary for stem cell biology to deliver on its promises. (shrink)

Cell biologists, including those seeking molecular mechanistic explanations of cellular phenomena, frequently rely on experimental strategies focused on identifying the cellular context relevant to their investigations. We suggest that such practices can be understood as a guided decomposition strategy, where molecular explanations of phenomena are defined in relation to natural contextual (cell) boundaries. This “top-down” strategy contrasts with “bottom-up” reductionist approaches where well-defined molecular structures and activities are orphaned by their displacement from actual biological functions. We focus on (...) the central role of microscopic imaging in cell biology to uncover possible constraints on the system. We show how identified constraints are used heuristically to limit possible mechanistic explanations to those that are biologically meaningful. Historical examples of this process described here include discovery of the mechanism of oxidative phosphorylation in mitochondria, molecular explanation of the first steps in protein secretion, and identification of molecular motors. We suggest that these instances are examples of a form of downward causation or, more specifically, constraining relations, where higher-level structures and variables delimit and enable lower-level system states. The guided decomposition strategy in our historical cases illustrates the irreducibility of experimentally identified constraints in explaining biological activities of cells. Rather than viewing decomposition and recomposition as separate epistemic activities, we contend that they need to be iteratively integrated to account for the ontological complexity of multi-level systems. (shrink)

Developing models of biological mechanisms, such as those involved in respiration in cells, often requires collaborative effort drawing upon techniques developed and information generated in different disciplines. Biochemists in the early decades of the 20th century uncovered all but the most elusive chemical operations involved in cellular respiration, but were unable to align the reaction pathways with particular structures in the cell. During the period 1940-1965 cell biology was emerging as a new discipline and made distinctive contributions (...) to understanding the role of the mitochondrion and its component parts in cellular respiration. In particular, by developing techniques for localizing enzymes or enzyme systems in specific cellular components, cell biologists provided crucial information about the organized structures in which the biochemical reactions occurred. Although the idea that biochemical operations are intimately related to and depend on cell structures was at odds with the then-dominant emphasis on systems of soluble enzymes in biochemistry, a reconceptualization of energetic processes in the 1960s and 1970s made it clear why cell structure was critical to the biochemical account. This paper examines how numerous excursions between biochemistry and cell biology contributed a new understanding of the mechanism of cellular respiration. (shrink)

Stem cell biology is driven by experiment. Its major achievements are striking experimental productions: "immortal" human cell lines from spare embryos (Thomson et al. 1998); embryo-like cells from "reprogrammed" adult skin cells (Takahashi and Yamanaka 2006); muscle, blood and nerve tissue generated from stem cells in culture (Lanza et al. 2009, and references therein). Well-confirmed theories are not so prominent, though stem cell biologists do propose and test hypotheses at a profligate rate. 1 This paper aims (...) to characterize the role of experiment in stem cell biology, so as to answer the following question: how do experiments contribute to our knowledge of stem cells and related phenomena? The .. (shrink)

Microbial systems biology has made enormous advances in relating microbial physiology to the underlying biochemistry and molecular biology. By meticulously studying model microorganisms, in particular Escherichia coli and Saccharomyces cerevisiae, increasingly comprehensive computational models predict metabolic fluxes, protein expression, and growth. The modeling rationale is that cells are constrained by a limited pool of resources that they allocate optimally to maximize fitness. As a consequence, the expression of particular proteins is at the expense of others, causing trade‐offs (...) between cellular objectives such as instantaneous growth, stress tolerance, and capacity to adapt to new environments. While current computational models are remarkably predictive for E. coli and S. cerevisiae when grown in laboratory environments, this may not hold for other growth conditions and other microorganisms. In this contribution, we therefore discuss the relationship between the instantaneous growth rate, limited resources, and long‐term fitness. We discuss uses and limitations of current computational models, in particular for rapidly changing and adverse environments, and propose to classify microbial growth strategies based on Grimes's CSR framework. (shrink)

Graphical AbstractBottom-up metabolic systems biology is of particular relevance to biochemists. The jargon of bottom-up metabolic systems biology however represents a major obstacle that needs to be overcome by a prospective practitioner in this emerging field. Herein, we diminish this early hurdle by providing a lexicon of the most important terms.

Between 1940 and 1970 pioneers in the new field of cell biology discovered the operative parts of cells and their contributions to cell life. They offered mechanistic accounts that explained cellular phenomena by identifying the relevant parts of cells, the biochemical operations they performed, and the way in which these parts and operations were organised to accomplish important functions. Cell biology was a revolutionary science but in this book it also provides fuel for yet another (...) revolution, one that focuses on the very conception of science itself. Laws have traditionally been regarded as the primary vehicle of explanation, but in the emerging philosophy of science it is mechanisms that do the explanatory work. Bechtel emphasises how mechanisms were discovered, focusing especially on the way in which new instruments made these inquiries possible. He also describes how new journals and societies provided institutional structure to this new enterprise. (shrink)

Ubiquitination plays a central role in the regulation of stem cell self‐renewal, propagation, and differentiation. In this review, the functions of ubiquitin dynamics in a myriad of cellular processes, acting along side the pluripotency network, to regulate embryonic stem cell identity are highlighted. The implication of deubiquitinases (DUBs) and E3 Ubiquitin (Ub) ligases in cellular functions beyond protein degradation is reported, including key functions in the regulation of mRNA stability, protein translation, and intra‐cellular trafficking; and how it affects (...) cell metabolism, the micro‐environment, and chromatin organization is discussed. Finally, unsolved issues in the field are emphasized and will need to be tackled in order to fully understand the contribution of ubiquitin dynamics to stem cell self‐renewal and differentiation. (shrink)

The conserved ribosomal protein uS3 in eukaryotes has long been known as one of the essential components of the small (40S) ribosomal subunit, which is involved in the structure of the 40S mRNA entry pore, ensuring the functioning of the 40S subunit during translation initiation. Besides, uS3, being outside the ribosome, is engaged in various cellular processes related to DNA repair, NF‐kB signaling pathway and regulation of apoptosis. This review is devoted to recent data opening new horizons in understanding the (...) roles of uS3 in such processes as the assembly and maturation of 40S subunits, ensuring proper structure of 48S pre‐initiation complexes, regulation of initiation and ribosome‐based RNA quality control pathways. Besides, we summarize novel results on the participation of the protein in processes beyond translation and consider biomedical implications of previously known and recently found extra‐ribosomal functions of uS3, primarily, in oncogenesis. (shrink)