The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review (...) much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD+ and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age‐related pathologies, which are caused by or exacerbated by senescent cells in vivo. (shrink)

Critical cellular functions, including stem cell maintenance, fate determination, and cellular behavior, are governed by canonical Wnt signaling, an evolutionarily conserved pathway whose intracellular signal is transduced by β‐catentin. Emerging evidence suggests that canonical Wnt signaling influences cellular aging, indicating that increases in Wnt signaling delay age‐related deficits.1 However, recent Science papers suggest that Wnt signaling accelerates the onset of aging.2,3 In an attempt to resolve this paradox and clarify how Wnt signaling affects aging, we provide a (...) selective review of research relevant to Wnt signaling and aging. BioEssays 30:102–106, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

More than one researcher is currently proposing that the notion of information become an important element for defining living systems as well as for explaining conditions that make their origins possible. During the pre-biotic era, the type of compounds encountered would mainly have been very simple in nature and might have been immersed in the natural dynamic of the physical world and in processes of self-organization. It is furthermore quite possible that they formed a relationship between and among certain types (...) of processes that here we are specifically proposing as central for the emergence of cell organization. Consequently, an important initial step towards constructing a theory of biological information is to ask ourselves the question: how do biological systems process information? In this way, we will be contributing to the proposals of this paper where we seek to identify general principles that govern biological computing and that deal with biosemiotic approaches as they are defended in naturalistic normative terms. (shrink)

We present a distributed control modeling approach for an automated manufacturing system based on the dynamics of one-dimensional cellular automata. This is inspired by the fact that both cellular automata and manufacturing systems are discrete dynamical systems where local interactions given among their elements can lead to complex dynamics, despite the simple rules governing such interactions. The cellular automaton model developed in this study focuses on two states of the resources of a manufacturing system, namely, busy or (...) idle. However, the interaction among the resources such as whether they are shared at different stages of the manufacturing process determines the global dynamics of the system. A procedure is shown to obtain the local evolution rule of the automaton based on the relationships among the resources and the material flow through the manufacturing process. The resulting distributed control of the manufacturing system appears to be heterarchical, and the evolution of the cellular automaton exhibits a Class II behavior for some given disordered initial conditions. (shrink)

Implicit God-like and ghost-in-the-machine metaphors underlie much current thinking about genomes. Although many criticisms of such views exist, none have succeeded in substituting a different, widely accepted view. Viewing the genome with its protein packaging as a brain gets rid of Gods and ghosts while plausibly integrating machine and information-based views. While the ‘wetware’ of brains and genomes are very different, many fundamental principles of how they function are similar. Eukaryotic cells are compound entities in which case the nuclear genome (...) might best be thought of more as a government than simply as a brain. (shrink)

Teleological variations of non-deterministic processes are defined. The immediate past of a system defines the state from which the ordinary (non-teleological) dynamical law governing the system derives different possible present states. For every possible present state, again a number of possible states for the next time step can be defined, and so on. After k time steps, a selection criterion is applied. The present state leading to the selected state after k time steps is taken to be the effective present (...) state. Hence, the present state of a system is defined by its past in the sense that the past determines the possible states that are to be considered, and by its future in the sense that the selection of a possible future state determines the effective present state. A system that obeys this type of teleological dynamics may have significantly better performance than its non-teleological counterpart. The basic reason is that evolutions that are less optimal for the present time step, but which lead to a higher optimality after k time steps, may be preferred. This abstract concept of teleology is implemented for two concrete systems. First, it is applied to a general method for function approximation and classification problems. The method at issue treats all problems handled by conventional connectionism, and is suited for information with inner structure also. Second, it is applied to a dynamics in which forms of maximal homogeneity have to be produced. The relevance of the latter dynamics for generative art is illustrated. The teleology is `deep' in the sense that it is situated at the cellular level, in contradistinction with the teleology that is usually met in cognitive contexts, and which refers to macroscopic processes such as making plans. It is conjectured that deep level teleology is useful for machines, even though the issue if natural systems use this teleology is left open. (shrink)

Cellular pattern formations of some epithelia are believed to be governed by the direct lateral inhibition rule of cell differentiation. That is, initially equivalent cells are all competent to differentiate, but once a cell has differentiated, the cell inhibits its immediate neighbors from following this pathway. Such a differentiation repeats until all non-inhibited cells have differentiated. The cellular polygonal patterns can be characterized by the numbers of undifferentiated cells and differentiated ones. When the differentiated cells become large in (...) size, the polygonal pattern is deformed since more cells are needed to enclose the large cell. An actual example of such a cellular pattern was examined. The pupal wing epidermis of a butterfly Pieris rapae shows a transition of the equivalent-size cell pattern to the pattern involving large cells. The process of the transition was analyzed by using the method of weighted Voronoi tessellation that is useful for treatment of irregularly sized polygons. The analysis supported that the pattern transition of the early stage of the pupal wing epidermis is governed by the lateral inhibition rule. The differentiation takes place in order of largeness, but not smallness, of the apical polygonal area in the differentiating region of the pupal wing. (shrink)

Secretion is a fundamental cellular process involving the regulated release of intracellular products from cells. Physiological functions such as neurotransmission, or the release of hormones and digestive enzymes, are all governed by cell secretion. Anomalies in the processes involved in secretion contribute to the development and progression of diseases such as diabetes and other hormonal disorders. To unravel the mechanisms that govern such diseases, it is essential to understand how hormones, growth factors and neurotransmitters are synthesized and processed, and (...) how their signals are recognized, amplified and transmitted by intracellular signaling pathways in the target cells. Here, we discuss diverse aspects of the detailed mechanisms involved in secretion based on mathematical models. The models range from stochastic ones describing the trafficking of secretory vesicles to deterministic ones investigating the regulation of cellular processes that underlie hormonal secretion. In all cases, the models are closely related to experimental results and suggest theoretical predictions for the secretion mechanisms. (shrink)

For many decades, access to human biological samples, such as cells, tissues, organs, blood, and sub-cellular materials such as DNA, for use in biomedical research, has been central in understanding the nature and transmission of diseases across the globe. However, the limitations of current ethical and regulatory frameworks in sub-Saharan Africa to govern the collection, export, storage and reuse of these samples have resulted in inconsistencies in practice and a number of ethical concerns for sample donors, researchers and research (...) ethics committees. This paper examines stakeholders’ perspectives of and responses to the ethical issues arising from these research practices. (shrink)

Research in the neurosciences continues to provide evidence that sleep plays a role in the processes of learning and memory. There is less of a consensus, however, regarding the precise stages of memory development during which sleep is considered a requirement, simply favorable, or not important. This article begins with an overview of recent studies regarding sleep and learning, predominantly in the procedural memory domain, and is measured against our current understanding of the mechanisms that govern memory formation. Based on (...) these considerations, I offer a new neurocognitive framework of procedural learning, consisting first of acquisition, followed by two specific stages of consolidation, one involving a process of stabilization, the other involving enhancement, whereby delayed learning occurs. Psychophysiological evidence indicates that initial acquisition does not rely fundamentally on sleep. This also appears to be true for the stabilization phase of consolidation, with durable representations, resistant to interference, clearly developing in a successful manner during time awake (or just time, per se). In contrast, the consolidation stage, resulting in additional/enhanced learning in the absence of further rehearsal, does appear to rely on the process of sleep, with evidence for specific sleep-stage dependencies across the procedural domain. Evaluations at a molecular, cellular, and systems level currently offer several sleep specific candidates that could play a role in sleep-dependent learning. These include the upregulation of select plasticity-associated genes, increased protein synthesis, changes in neurotransmitter concentration, and specific electrical events in neuronal networks that modulate synaptic potentiation. Key Words: consolidation; enhancement; learning; memory; plasticity; sleep; stabilization. (shrink)

New definitions are proposed for communication and language. Communication is defined as the evolution of physical, biochemical, cellular, community, and technological information exchange. Language is defined as community communication whereby the information exchanged comprises evolving individual and group-constructed knowledge and beliefs, that are enacted, narrated, or otherwise conveyed by evolving rule-governed and meaningful symbol systems, that are grounded, interpreted, and used from within evolving embodied, cognitive, ecological, sociocultural, and technological niches. These definitions place emphasis on the evolutionary aspects of (...) communication and language, and they are here differentiated from four older paradigms that instead focus either on the referential or social aspects of language, or the informational or semantic aspects of communication. In contrast with these paradigms, the definitions proposed here for communication and language are in line with a pluralistic evolutionary worldview, one that necessitates the recognition that a multitude of units, levels, mechanisms and processes are involved in bringing forth communication and language. (shrink)

Leibniz coined the word “dynamics,” but his own dynamics has never been completed. However, there are many illuminating ideas scattered in his writings on dynamics and metaphysics. In this paper, I will present my own interpretation of Leibniz’s dynamics and metaphysics. To my own surprise, Leibniz’s dynamics and metaphysics are incredibly flexible and modern. In particular, the metaphysical part, namely Monadology, can be interpreted as a theory of information in terms of monads, which generate both physical phenomena and mental phenomena. (...) The phenomena, i.e., how the world of monads appears to each monad must be distinguished from its internal states, which Leibniz calls perceptions, and the phenomena must be understood as the results of these states and God’s coding. My distinctive claim is that most interpreters ignored this coding. His dynamics and metaphysics can provide a framework good enough for enabling Einstein’s special relativity. And finally, his dynamics and metaphysics can provide a very interesting theory of space and time. In Part 1, we will focus on the relationship between metaphysics and dynamics. Leibniz often says that dynamics is subordinated to metaphysics. We have to take this statement seriously, and we have to investigate how dynamics and metaphysics are related. To this question, I will give my own answer, based on my informational interpretation. On my view, Leibniz’s metaphysics tries, among others, to clarify the following three: How each monad is programmed. How monads are organized into many groups, each of which is governed by a dominant monad ; this can be regarded as a precursor of von Neumann’s idea of cellular automata. And how the same structure is repeated in sub-layers of the organization. This structure is best understood in terms of the hierarchy of programs, a nested structure going down from the single dominant program to subprograms, which again controls respective subprograms, and ad infinitum. If we may use a modern term, this is a sort of recursion, although Leibniz himself did not know this word. And one of my major discoveries is that the same recursive structure is repeated in the phenomenal world, the domain of dynamical investigations. Recursion of what, you may ask. I will argue that it is elastic collision. For Leibniz, aside from inertial motions, dynamical changes of motion are brought about by elastic collisions, at any level of the infinite divisibility of matter. This nicely corresponds to the recursive structure of the program of a monad, or of the program of an organized group of monads. This is the crux of his claim that dynamics is subordinated to metaphysics. Moreover, the program of any monad is teleological, whereas the phenomenal world is governed by efficient cause of dynamics. And it is natural that the pre-established harmony is there, since God is the ultimate programmer, as well as the creator. (shrink)

This essay evaluates the moral logic of ‘liberal eugenics’: the ideal of genetic control which leaves decisions about what sort of people to produce in the hands of individual parents, absent government intervention. I argue that liberal eugenics cannot be justified on the basis of the underlying liberal theory which inspires it. I introduce an alternative to Rawls's social primary goods that might be called natural primary goods: hereditable mental and physical capacities and dispositions that are valued across a (...) range of projects and pursuits. I suggest that reproductive genetic biotechnologies like embryo selection, cellular surgery, and genetic engineering, which aim to enhance ‘general purpose’ traits in offspring are less like childrearing practices a liberal government leaves to the discretion of parents than like practices the state makes compulsory. I argue that if the liberal commitment to autonomy is important enough for the state to mandate childrearing practices such as health care and basic education, that very same interest is important enough for the state to mandate safe, effective, and functionally integrated genetic practices that act on analogous all‐purpose traits such as resistance to disease and general cognitive functioning. I conclude that the liberal case for compulsory eugenics is a reductio against liberal theory. (shrink)

The catch 22 situation in psychiatry is that for precise diagnostic categories/criteria, we need precise investigative tests, and for precise investigative tests, we need precise diagnostic criteria/categories; and precision in both diagnostics and investigative tests is nonexistent at present. The effort to establish clarity often results in a fresh maze of evidence. In finding the way forward, it is tempting to abandon the scientific method, but that is not possible, since we deal with real human psychopathology, not just concepts to (...) speculate over. Search for clear-cut definitions/diagnostic criteria in psychiatry must be relentless. There is a greater need to be ruthless and blunt in this, rather than being accommodative of diverse opinions. Investigative tests - psychological, serum, CSF, or neuroimaging - are only corroborative at present; they need to become definitive. Medicalisation appears most prominent in psychiatry; so, diagnostic proliferation and fuzziness appear inevitable. And yet, the established diagnostic entities need to forward greater and conclusive precision. Also, the need for clarity and precision must outweigh pandering to and mollifying diverse interests, moreso in the upcoming revision of diagnostic manuals. This is specially because the DSM-5, being an Association manual, may need to accommodate powerful member lobbies; and ICD-11 may similarly need to cater to diverse country lobbies. Finding precise biological correlates of psychiatric phenomena, whether through neuroimaging, molecular neurobiology and/or neurogenomics, is the right way forward. It is in the 1.5-kg structure in the cranium that all secrets of psychiatric conditions lie. Social forces, behavioural modification, psychosocial restructuring, study of intrapsychic processes, and philosophical insights are not to be discounted, but they are supplementary to the primary goal - studying and deciphering those brain processes that result in psychiatric malfunction. Experimental breakthroughs, both in psychiatric aetiology and therapeutics, will come mainly from biology and its adjunct, psychopharmacology; while supplementary and complementary breakthroughs will come from the psychosocial, cognitive and behavioural approaches; the support base will come from phenomenology, epidemiology, nosology and diagnostics; while insights and leads can hopefully come from many fields, especially the psychosocial, the behavioural, the cognitive and the philosophical. Major energies must now be marshalled towards finding biomarkers and deciphering the precise phenotype-genotype-endophenotype axis of psychiatric disorders. Energies also need to be focussed on unravelling those critical processes in the brain that tip the scale towards psychiatric disorders. At how those critical processes are set into motion by forces de novo, in utero, in the genes and their expression, by the environment's psychopathological social forces - stress, peer pressure, poverty, deprivation, alienation, malnutrition, discrimination of various types (caste, gender, race, etc.), mass conflicts (war, terror attacks, etc.), disasters (natural and man-made), religious/ideological fascism - or social institutions like marriage, family, work place, political governance, etc. Ultimately, we must decipher how the brain goes into malfunction when such varied forces impinge on it, which precise cortical areas and neuronal cellular and molecular processes are involved in such malfunction and its manifestation, as also which of these are involved when malfunction ceases and health is restored, and the psychosocial processes and institutions which aid such health restoration, as also those which promote well-being and help in primary prevention. Emphasis on the brain and its intimate neurological and molecular mechanisms will not impinge on, or nullify, importance of the 'mind,' wherein subtle and gross brain functions in the form of behaviour, thought and emotions in all their ramifications will continue to be the focus of psychological, cognitive, sociological, psychopharmacological, behavioural and philosophical research. Progress in brain research must move in tandem with progress in 'mind' research. (shrink)

Recent debates over the use of sham surgery as a control for studies of fetal tissue transplantation for Parkinson’s disease have focused primarily on rival interpretations of the US federal regulations governing human-subjects research. Using the core ethical and methodological considerations that underwrite the equipoise requirement, we nd strong prima facie reasons against using sham surgery as a control in studies of cellular-based therapies for Parkinson’s disease and more broadly in clinical research. Additionally, we believe that these reasons can (...) be generalized to apply to the use of other placebo controls that carry signi cant risks of positive harms in and of themselves. As a result, our arguments are centrally relevant to the emerging drive to subject therapies with a surgical component to the same rigorous standards of evaluation as those governing the approval of new pharmaceuticals. (shrink)

I have developed an informational interpretation of Leibniz’s metaphysics and dynamics, but in this paper I will concentrate on his theory of time. According to my interpretation, each monad is an incorporeal automaton programed by God, and likewise each organized group of monads is a cellular automaton governed by a single dominant monad. The activities of these produce phenomena, which must be “coded appearances” of these activities; God determines this coding. A crucially important point here is that we have (...) to distinguish the phenomena for a monad from its states. Both are a kind of representation: a state represents the whole world of monads, and phenomena for a monad “result” from the activities of monads. But the coding for each must be different; R for the first, Ph for the second, where W is a state of the monadic world. The reason for this is that no monadic state is in space and time, but phenomena occur in space and time. Now, the basis of the phenomenal time must be in the timeless realm of monads. This basis is the order of state-transition of each monads. All the changes of these states are given at once by God, and these do not presuppose time. The coded appearances of this order occur in time, and its metric must depend on God’s coding for phenomena. For humans, in particular, this metric time is derived from spatial distance via the laws of dynamics. Thus there may well be an interrelation between spatial and temporal metric. This means that the Leibnizian frame allows relativistic metric of space-time. I will show this after outlining Leibniz’s scenario. (shrink)

Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human serotonergic neurons in vitro. Remarkably, serotonergic neurons derived from each method robustly produce serotonin, express raphe genes, are electrically active, and respond to selective serotonin reuptake inhibitors in vitro. Two of the methods utilize transdifferentiation technology by overexpressing key serotonergic transcription factors. The third and most recent (...) method involves differentiating induced pluripotent stem cells (iPSCs) to serotonergic neurons using developmental patterning cues. In this mini‐review, we briefly describe the developmental programs governing serotonergic specification in vivo and how they have been harnessed to achieve serotonergic differentiation in vitro. We discuss the distinct and overlapping features of the recently published methodologies and their value in the context of in vitro disease modeling.Also see the video abstract here. (shrink)

In 1926, Haldane published an essay titled 'On Being the Right Size' in which he argued that the structure, function, and behavior of an organism are strongly conditioned by the physical forces that exert the greatest impact at the scale at which it exists. This chapter puts Haldane’s insight to work in the context of contemporary cell and molecular biology. Owing to their minuscule size, cells and molecules are subject to very different forces than macroscopic organisms. In a sense, macroscopic (...) and microscopic entities inhabit different “worlds”: the former is ruled by gravity and inertia, whereas the latter is governed by Brownian motion. One implication is that we should be extremely skeptical of models and analogies that seek to explain properties of microscopic entities by appealing to properties of macroscopic ones. Unfortunately, this is precisely what the appeal to engineering metaphors in molecular biology attempts to do. Molecular biologists routinely resort to such metaphors because they are familiar and intuitively intelligible. But if our machines were the size of molecules it would be impossible for them to function the way they do. It follows that we should avoid distorting biological reality by construing it in engineering terms. In this chapter I examine four key metaphors in molecular biology – “genetic program,” “cellular circuitry,” “molecular machine,” and “molecular motor” – and I argue that their deficiencies derive from their neglect of scale. I also try to explain why many biologists today appear to have forgotten the importance of scale that Haldane drew attention to in his essay. I suggest that the reason has to do with the influence of Schrödinger’s argument in 'What is Life?' regarding the stability of the gene. (shrink)

The ArgumentThis paper argues that science and technology studies need to adopt a much wider view of what counts as a laboratory. The factory, it is suggested, is as much a site of invention and intervention as the laboratory. As a site for the government of economic life, the factory is a laboratorypar excellence. One particular factory is studied — the Decatur, Illinois, plant of Caterpillar Inc. — as it is rethought and remade in accordance with ideals of (...) class='Hi'>cellular manufacturing, Just-In-Time systems, customer-driven manufacturing, and competitor benchmarking. But it is not just the changes at the factory itself that are studied. The paper analyzes the linkages and relays between the redesign of a particular manufacturing plant and the plethora of calls for a revitalization of North American manufacturing industry and a new form of economic citizenship. The paper examines the remaking of a factory as anassemblage, a historically specific and temporarily stabilized complex of relations among ways of problematizing the factory in a multiplicity of locales. There are four steps to the changes analyzed here: a problematizing of the factory at the level of North American manufacturing as a whole in the 1980s; a problematizing of the notion of competitiveness at Caterpillar Inc, through the calculative practices of competitor benchmarking and related expertises; a diagraming of the ideal factory in systems terms; and the embedding of notions of the product, of competitiveness, and of a new economic citizenship in the “Assembly Highway” at the Decatur plant. Rethinking the factory took place within this assemblage of relations, rether than at any one site. (shrink)

Membranous organelles allow sub‐compartmentalization of biological processes. However, additional subcellular structures create dynamic reaction spaces without the need for membranes. Such membrane‐less organelles (MLOs) are physiologically relevant and impact development, gene expression regulation, and cellular stress responses. The phenomenon resulting in the formation of MLOs is called liquid–liquid phase separation (LLPS), and is primarily governed by the interactions of multi‐domain proteins or proteins harboring intrinsically disordered regions as well as RNA‐binding domains. Although the presence of RNAs affects the formation (...) and dissolution of MLOs, it remains unclear how the properties of RNAs exactly contribute to these effects. Here, the authors review this emerging field, and explore how particular RNA properties can affect LLPS and the behavior of MLOs. It is suggested that post‐transcriptional RNA modification systems could be contributors for dynamically modulating the assembly and dissolution of MLOs. (shrink)

The progress of the molecular biosciences has been so enormous that a discipline studying how cellular functioning emerges out of the behaviors of their molecular constituents has become reality. Systems biology studies cells as spatiotemporal networks of interacting molecules using an integrative approach of theory , experimental biology , and quantitative network-wide analytical measurement . Its aim is to understand how molecules jointly bring about life. Systems biology is rapidly discovering principles governing the functioning of molecular networks and methods (...) to model and measure them. The application of the conceptual strength of systems sciences such as physics and engineering are opening up new ways of experimentally studying the design and functioning of molecular networks. Typically, in such studies models are used to highlight principles, design experiments, or to act in a predictive mode to specifically modify cellular behavior. In this trend article, theoretical approaches being applied in systems biology will be discussed. A number of books have recently appeared that deal with theoretical aspects of systems biology. In this article they are highlighted to facilitate the communication of systems biology to a broader audience. (shrink)

Cell and tissue-based products, such as autologous adult stem cells, are being prescribed by physicians across the world for diseases and illnesses that they have neither been approved for or been demonstrated as safe and effective in formal clinical trials. These doctors often form part of informal transnational networks that exploit differences and similarities in the regulatory systems across geographical contexts. In this paper, we examine the regulatory infrastructure of five geographically diverse but socio-economically comparable countries with the aim of (...) identifying similarities and differences in how these products are regulated and governed within clinical contexts. We find that while there are many subtle technical differences in how these regulations are implemented, they are sufficiently similar that it is difficult to explain why these practices appear more prevalent in some countries and not in others. We conclude with suggestions for how international governance frameworks might be improved to discourage the exploitation of vulnerable patient populations while enabling innovation in the clinical application of cellular therapies. (shrink)

The formation of blood vessels within the vascular system entails a variety of cellular processes, including proliferation, migration and differentiation. In many cases, these diverse processes need to be finely coordinated among neighbouring endothelial cells in order to establish a functional vascular network. For instance, during angiogenic sprouting specialized endothelial tip cells follow guidance cues and migrate extensively into avascular tissues while trailing stalk cells must stay connected to the patent blood vessel. The vascular endothelial growth factor (VEGF) and (...) Notch signalling pathways have emerged as the major players in governing these different cellular behaviours. In particular, recent work indicates an important role for Notch signalling in determining how an endothelial cell responds to VEGF. In this review, we provide an overview of these biochemically distinct pathways and discuss how they may interact during endothelial cell differentiation and angiogenesis. BioEssays 30:303–313, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Hydra are remarkable because they are immortal. Much of immortality can be ascribed to the asexual mode of reproduction by budding, which requires a tissue consisting of stem cells with continuous self‐renewal capacity. Emerging novel technologies and the availability of genomic resources enable for the first time to analyse these cells in vivo. Stem cell differentiation in Hydra is governed through the coordinated actions of conserved signaling pathways. Studies of stem cells in Hydra, therefore, promise critical insights of general relevance (...) into stem cell biology including cellular senescence, lineage programming and reprogramming, the role of extrinsic signals in fate determination and tissue homeostasis, and the evolutionary origin of these cells. With these new facts as a backdrop, this review traces the history of studying stem cells in Hydra and offers a view of what the future may hold. (shrink)

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more difficult to study at a mechanistic (...) level. We consider the relatively well‐understood mechanisms by which mating‐type switching and the pheromone‐induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse. BioEssays 25:856–867, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Much progress has been made recently towards uncovering the mechanisms that control the size to which organisms and their organs grow, and identifying some of the genes responsible. Size control, however, is only half of the equation. In growing to the right size, tissues must also grow to the right shape. A recent paper1 suggests that a hitherto overlooked cellular behaviour governs the size and shape of a growing tissue, and issues a challenge to developmental biologists to identify the (...) molecular mechanisms involved. BioEssays 25:5–8, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Kennedy Institute of Ethics Journal 10.3 (2000) 265-281 [Access article in PDF] Scope Note 39 Genes, Patents, and Bioethics-Will History Repeat Itself? Susan Cartier Poland Gene patenting--the very notion sounds absurd! How can anyone claim to have invented the genes with which one is born? To make matters worse, genetic makeup precedes birth, meaning the existence of the invention predates the existence of the inventor. So, do we really (...) own our genes, or do they belong to our parents, or our governments, or a Supreme Being? Ownership is only one bioethical issue involved in gene patenting. But before looking at the issues, some essential and basic terms must be understood, namely genes and patents. Genes In his book On the Origin of Species, published in 1859, the biologist Charles Darwin proposed a theory called "natural selection," whereby living things changed over time or evolved through generations due to competition and variation. By experimenting with the garden pea in the 1860s, Gregor Mendel, a monk and accomplished horticulturalist, provided the mechanism of inheritance supporting the natural selection theory of his contemporary Darwin. That mechanism is the gene, or, as Mendel described it, a discrete "factor." The gene has also been defined as "the fundamental unit of heredity" (United States 1987, p. 157). Each individual has two copies of a gene, one from each parent, but that individual passes down to offspring only one of the two copies. Because of Mendel, the gene has become a scientific concept and the basis of a new scientific field: genetics.David C. Page (2000) of the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology explained today's terms for genetics structures using an analogy taken from the home. In his view, the cell is a kitchen, the genome is a shelf in the kitchen, the chromosome is a cookbook on the shelf, the gene is a recipe in the cookbook, and a base-pair (either adenine with thymine or guanine with cytosine) is a single letter in the recipe. A protein, the [End Page 265] working molecule blueprinted by a gene, is a dish ready to eat, and an ingredient in the dish is an amino acid, which is a building block of the protein as specified by a string of base-pairs.Colin Tudge (1993), a British science journalist, would disagree with Page's description of the gene as a recipe. A recipe is like a blueprint: both are directions that precede the work. But a gene is not passive according to Tudge; it actively administers the cell's work, and it also responds to cellular events (Aldridge 1996).The current focus of scientific research and funding is on the gene and the completion of the sequencing of all the genes that comprise the human genome, portrayed in the press as a race between the U.S. government's Human Genome Project and the private corporation Celera Genomics. The real action, however, is at the protein level. The gene only holds the information to produce a protein; it is the three-dimensional shaped protein that does the work. In order to produce energy, eliminate waste, and perform other functions specific to a cell or tissue, proteins must bind, thus creating "biological pathways." Proteins bind (or not) and detach as a function of their shapes, which are determined by their precise chemical composition as spelled out in their genetic code. IBM will spend the next five years making one computer, Blue Gene, that will then take an entire year to come up with the chemical map for only one protein (Gillis 2000). It is estimated that there are about 40,000 proteins in the human body.Despite these overwhelming numbers, modern biology has been able to achieve significant results within the Human Genome Project's 15-year time frame, from 1990 to 2005. The genetic map was completed in 1993; the physical map was completed in 1995; and the genetic sequence is expected to be completed in 2002, with 97 to 99 percent completed as of 26 June 2000. This... (shrink)

Gooddy, a British neurologist, argues that our sense of time, and relativity in general, is a function of the nervous system. Written for the general reader, the 10 essays discuss atomic, cellular, and glandular "clocks," age, government time vs. personal time, and time disorders (such as being in love). Annotation copyrighted by Book News, Inc., Portland, OR.

Over the past decade, research has revealed biomolecular condensates' relevance in diverse cellular functions. Through a phase separation process, they concentrate macromolecules in subcompartments shaping the cellular organization and physiology. In the nucleus, biomolecular condensates assemble relevant biomolecules that orchestrate gene expression. We here hypothesize that chromatin condensates can also modulate the nongenetic functions of the genome, including the nuclear mechanical properties. The importance of chromatin condensates is supported by the genetic evidence indicating that mutations in their members (...) are causative of a group of rare Mendelian diseases named chromatinopathies (CPs). Despite a broad spectrum of clinical features and the perturbations of the epigenetic machinery characterizing the CPs, recent findings highlighted negligible changes in gene expression. These data argue in favor of possible noncanonical functions of chromatin condensates in regulating the genome's spatial organization and, consequently, the nuclear mechanics. In this review, we discuss how condensates may impact nuclear mechanical properties, thus affecting the cellular response to mechanical cues and, eventually, cell fate and identity.Chromatin condensates organize macromolecules in the nucleus orchestrating the transcription regulation and mutations in their members are responsible for rare diseases named chromatinopathies. We argue that chromatin condensates, in concert with the nuclear lamina, may also govern the nuclear mechanical properties affecting the cellular response to external cues. (shrink)

Regulation of microtubule (MT) dynamics is essential for many cellular processes, but the machinery that controls MT dynamics remains poorly understood. MT plus‐end tracking proteins (+TIPs) are a set of MT‐associated proteins that dynamically track growing MT ends and are uniquely positioned to govern MT dynamics. +TIPs associate with each other in a complex array of inter‐ and intra‐molecular interactions known as the “+TIP network.” Why do so many +TIPs bind to other +TIPs? Typical answers include the ideas that (...) these interactions localize proteins where they are needed, deliver proteins to the cortex, and/or create regulatory pathways. We propose an additional and more mechanistic hypothesis: that +TIPs bind each other to create a superstructure that promotes MT assembly by constraining the structural fluctuations of the MT tip, thus acting as a polymerization chaperone. (shrink)

The eyespot organelle of the green alga Chlamydomonas allows the cell to phototax toward (or away) from light to maximize the light intensity for photosynthesis and minimize photo‐damage. At cytokinesis, the eyespot is resorbed at the cleavage furrow and two new eyespots form in the daughter cells 180° from each other. The eyespots are positioned asymmetrically with respect to the microtubule cytoskeleton. Eyespots are assembled from all three chloroplast membranes and carotenoid‐filled granules, which form a sandwich structure overlaid by the (...) tightly apposed plasma membrane. This review describes (1) my interest in cellular asymmetry and organelle biology, (2) isolation of mutations that describe four genes governing eyespot placement and assembly, (3) the characterization of the EYE2 gene, which encodes a thioredoxin superfamily member, and (4) the characterization of the MIN1 gene, which is required for the layered organization of granules and membranes in the eyespot. BioEssays 25:410–416, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A stereospecific binding site is not the only determinant governing the selectivity of transport proteins. An understanding of transport across cellular membranes requires a description of the different compartments within a transmembrane channel; evidence for the existence of these compartments comes from the selectivity properties of genetically modified maltoporin. Such compartments may also be of significance in determining the specificity of other transport proteins.

The aim is to investigate the Information Communication Technology on GDP growth in Western Balkan countries from 2000 - 2019. Different econometric techniques were used such as pooled OLS, fixed effects, random effects, and the Hausman Taylor model with instrumental variables. The findings indicate that fixed telephone subscriptions and individuals using the internet have a positive effect on GDP growth, while the fixed broadband subscriptions and mobile cellular subscriptions have a negative effect on GDP growth. The results also show (...) general government final consumption has a negative effect on GDP growth, whereas foreign direct investment has a positive effect on GDP growth, but the coefficient is statistically insignificant. The study will serve for policy makers to invest more in ICT since this will contribute to the economic growth and welfare benefits. There is no study that has been analyzed about ICT in Western Balkan countries, thus findings will be valuable to the government. (shrink)

How does your mind work? How does your brain give rise to your mind? These are questions that all of us have wondered about at some point in our lives, if only because everything that we know is experienced in our minds. They are also very hard questions to answer. After all, how can a mind understand itself? How can you understand something as complex as the tool that is being used to understand it? This book provides an introductory and (...) self-contained description of some of the exciting answers to these questions that modern theories of mind and brain have recently proposed. Stephen Grossberg is broadly acknowledged to be the most important pioneer and current research leader who has, for the past 50 years, modelled how brains give rise to minds, notably how neural circuits in multiple brain regions interact together to generate psychological functions. This research has led to a unified understanding of how, where, and why our brains can consciously see, hear, feel, and know about the world, and effectively plan and act within it. The work embodies revolutionary Principia of Mind that clarify how autonomous adaptive intelligence is achieved. It provides mechanistic explanations of multiple mental disorders, including symptoms of Alzheimer's disease, autism, amnesia, and sleep disorders; biological bases of morality and religion, including why our brains are biased towards the good so that values are not purely relative; perplexing aspects of the human condition, including why many decisions are irrational and self-defeating despite evolution's selection of adaptive behaviors; and solutions to large-scale problems in machine learning, technology, and Artificial Intelligence that provide a blueprint for autonomously intelligent algorithms and robots. Because brains embody a universal developmental code, unifying insights also emerge about shared laws that are found in all living cellular tissues, from the most primitive to the most advanced, notably how the laws governing networks of interacting cells support developmental and learning processes in all species. The fundamental brain design principles of complementarity, uncertainty, and resonance that Grossberg has discovered also reflect laws of the physical world with which our brains ceaselessly interact, and which enable our brains to incrementally learn to understand those laws, thereby enabling humans to understand the world scientifically. Accessibly written, and lavishly illustrated, Conscious Mind/Resonant Brain is the magnum opus of one of the most influential scientists of the past 50 years, and will appeal to a broad readership across the sciences and humanities. (shrink)

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, (...) elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. (shrink)

Managing Complexity in Healthcare introduces the ComEntEth (Complex Entropic Ethical) model as an integrated bio-medical and philosophical approach to understanding how people get things done in healthcare. Drawing on the complexity sciences, studies of entropy in living organisms, and the ethics of Emmanuel Levinas, healthcare is theorised as energetic relational exchanges between people as entropic and ethical entities that unfold around a central attractor: Reduction in elevated entropy or suffering in patients. Living entities are engaged in a continuous struggle against (...) the tendency to produce entropy. From the cellular to the collective of human endeavours, the tendency of complex systems is to disorder and decay. Yet in the micro-activity of healthcare enterprise, people resist this tendency by expending energy to create order and sustain life. Making sense of how this miraculous work is made possible is the foundation of this book. Through practical examples - from analysis of practitioner burnout, rural and remote healthcare, the functioning of emergency departments, to government, social and institutional responses to the COVID-19 pandemic -this new integral philosophy provides practitioners, managers, policy designers, and scholars an effective way to understand the dynamics of daily processes and practices that link the micro of everyday interactions with the macro-trends of healthcare. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An age‐related (...) decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

A number of conditioning experiments utilize food as a reward. Hunger is considered to be a critical factor governing the animal's behavior in these experiments. Despite its significance, most theories of animal conditioning fail to take hunger into consideration while analyzing the behavioral data. In this paper, we analyze the neuroscientific data supporting the hypothesis that hunger and food consumption affect the brain's dopamine system, which in turn governs the animal's behavior. According to this hypothesis, chronic hunger results in a (...) decrease in the extra-cellular dopamine levels in the animal's brain. This decrease is believed to trigger a series of reactions that increase the responsivity of the phasic dopamine system. A direct consequence of this is an increased vigor of all dopamine-dependent behaviors. The level of extra-cellular dopamine is also modulated by the process of food consumption via the neurotransmitter Acetylcholine. Food consumption raises the dopamine above the baseline level. This rise depends on the animals' hunger, which when satisfied increases the level of Acetylcholine, which causes the dopamine level to fall back to the baseline. Thus, extra-cellular dopamine governs the response vigor, with an increase in dopamine resulting in a more vigorous response. This paper makes two primary contributions. Firstly, we present an abstract mathematical model based on the above hypothesis. Our mathematical model is able to provide a simple explanation for a number of behavioral findings. Another contribution of this paper is the development of a neurocomputational Leabra model of dopamine and acetylcholine activity in the basal ganglia to incorporate hunger and satiation. The experimental results obtained from this neural model are also largely in agreement with behavioral findings. (shrink)

This article explores the critical limitations of the now decades-long shift toward digital culture in the material and cultural constitution of biotechnology. It does this by telling the story of three contemporary efforts to reimagine the logic of life on the logic of the digital and the struggles attendant to building the infrastructures needed to actualize that re-imagination and make it profitable. In tracing these stories, it lifts out how biotechnologists, once caught in the spell of the digital sublime, are (...) having to confront the ways in which dreams of a data-driven and automated biology, far from eliciting an exalted future of health, wealth, and security, are simply reinforcing at the level of the organism a world already boxed in by algorithmic modes of reason and governed by imperatives of optimization. In the midst of these binds, this article points to a pathos which is beginning to stir at the bench as blue-collar technologists seek to activate an older feel for craftwork, and how this pathos signals a familiar but vital reciprocity between the maker and the made. It concludes that, in the end, breakdowns in the digital sublime make space for a more interesting biotechnical proposition, one in which the living thing being crafted has to be accommodated rather than rendered algorithmic: the cellular targets of biotechnical intervention must be coerced, cajoled, and enticed into playing along with our biotechnical imaginations. To act differently proves to be the real source of our trouble. The stories in this article draw on fieldwork conducted by the author through multiple experiments in collaborative anthropology. These experiments began in connection to a then-emerging brand of biotechnology called synthetic biology, were carried forward in view of a “post-engineering” approach to systems biology, and are currently (as of the writing of this essay) being conducted among biologists and technologists working to build “digital infrastructures” for the life sciences (i.e., digital tools for assembling, mediating, and synthesizing post-genomic biology). (shrink)

Until recently, cardiotoxicity in the setting of a malignant disease was attributed solely to the detrimental effects of chemo‐ and/or radio‐therapy to the heart. On this account, the focus was on the evaluation of well‐established cardiac biomarkers for the early detection of myocardial damage. Currently, this view has been revised. Cardiotoxicity is not restricted to a single organ but instead affects the endothelium as a whole. Indeed, it has come into light that not only cancer therapy but also malignant cells (...) per se can impair the cardiovascular system, through a paracrine and endocrine mode of action. Even more intriguingly, a clear interplay between molecular pathways involved in cancer and cardiovascular disease has become prevalent, suggesting a common nominator that governs the pathophysiology of these two entities. Taken together, our strategy in the quest of novel biomarkers in the emerging field of cardio‐oncology should be critically reshaped. (shrink)

This article discusses the manipulation and measurement of levels of situational self-focus, which is generally labeled ''self-awareness.'' A new scale was developed to quantify levels of public and private self-awareness. Five studies were conducted to assess the psychometric properties, reliability, and validity of the Situational Self-Awareness Scale (SSAS). The SSAS was found to have a reliable factor structure, to detect differences in public and private self-awareness produced by laboratory manipulations, and to be sensitive to changes in self-awareness within individuals over (...) time and across situations. The SSAS can be used as a manipulation check of laboratory self-awareness manipulations and as a means of assessing naturally occurring fluctuations in public and private self-awareness in order to clarify the relation between self-awareness and other variables (e.g., mood and memory). (shrink)

The defects of any form of government may be either negative or positive. It is negatively defective if it does not concentrate in the hands of the authorities power sufficient to fulfil the necessary offices of a government; or if it does not sufficiently develop by exercise the active capacities and social feelings of the individual citizens. On neither of these points is it necessary that much should be said at this stage of our inquiry.

An exciting and highly original examination of the practices of truth-telling and speaking out freely (parr?sia) in ancient Greek tragedy and philosophy. Foucault discusses the difficult and changing practices of truth-telling in ancient democracies and tyrannies and offers a new perspective on the specific relationship of philosophy to politics.

Sovereign is he who provides the exception.…The exception is more interesting than the rule. The rule proves nothing; the exception proves everything. In the exception the power of real life breaks through the crust of a mechanism that has become torpid by repetition.In spring 2020, in response to the COVID-19 crisis, world leaders imposed severe restrictions on citizens’ civil, political, and economic liberties. These restrictions went beyond less controversial and less demanding social distancing measures seen in past epidemics. Many states (...) and countries imposed universal lockdowns. Lockdowns, as we define them here, require people to stay home; in some countries and places, citizens must have ad hoc licenses to... (shrink)

There is a long-running debate as to whether privacy is a matter of control or access. This has become more important following revelations made by Edward Snowden in 2013 regarding the collection of vast swathes of data from the Internet by signals intelligence agencies such as NSA and GCHQ. The nature of this collection is such that if the control account is correct then there has been a significant invasion of people's privacy. If, though, the access account is correct then (...) there has not been an invasion of privacy on the scale suggested by the control account. I argue that the control account of privacy is mistaken. However, the consequences of this are not that the seizing control of personal information is unproblematic. I argue that the control account, while mistaken, seems plausible for two reasons. The first is that a loss of control over my information entails harm to the rights and interests that privacy protects. The second is that a loss of control over my information increases the risk that my information will be accessed and that my privacy will be violated. Seizing control of another's information is therefore harmful, even though it may not entail a violation of privacy. Indeed, seizing control of another's information may be more harmful than actually violating their privacy. (shrink)

In most liberal democracies for example, the central bank is as independent as the supreme court, yet deals with a wide range of economic, social, and political issues. How do these public servants make these policy decisions? What normative principles inform their judgments? In The Machinery of Government, Joseph Heath attempts to answer these questions. He looks to the actual practice of public administration to see how normative questions are addressed. More broadly, he attempts to provide the outlines of (...) a "philosophy of the executive" by taking seriously the claim to political authority of the most neglected of the three branches of the state. (shrink)