We apply molecular code theory to a rule-based model of the human inner kinetochore and study how complex formation in general can give rise to molecular codes. We analyze 105 reaction networks generated from the rule-based inner kinetochore model in two variants: with and without dissociation of complexes. Interestingly, we found codes only when some but not all complexes are allowed to dissociate. We show that this is due to the fact that in the kinetochore model proteins can (...) only bind at kinetochores by attaching to already attached proteins and cannot form complexes in free solution. Using a generalized linear mixed model we study which centromere protein can take which role in a molecular code . By this, associations between CENPs and code roles are found. We observed that CenpA is a major risk factor while CenpQ is a major protection factor . Finally we show, using an abstract model of copolymer formation, that molecular codes can also be realized solely by the formation of stable complexes, which do not dissociate. For example, with particular dimers as context a molecular code mapping from two different monomers to two particular trimers can be realized just by non-selective complex formation. We conclude that the formation of protein complexes can be utilized by the cell to implement molecular codes. Living cells thus facilitate a subsystem allowing for an enormous flexibility in the realization of mappings, which can be used for specific regulatory processes, e.g. via the context of a mapping. (shrink)

Biologists and historians often present natural history and molecular biology as distinct, perhaps conflicting, fields in biological research. Such accounts, although supported by abundant evidence, overlook important areas of overlap between these areas. Focusing upon examples drawn particularly from systematics and molecular evolution, I argue that naturalists and molecular biologists often share questions, methods, and forms of explanation. Acknowledging these interdisciplinary efforts provides a more balanced account of the development of biology during the post-World War II era.

The successes of molecular developmental biology over the last ten years have been particularly impressive in those directions favored by its major paradigms. New technologies have both guided and been guided by the progress of the field. I review briefly some of the major insights into embryonic development that have derived from research in four specific areas: early embryogenesis of various forms; “pattern formation”; evolutionary conservation of regulatory elements; and spatial mechanisms of gene regulation. There remain many major problem (...) areas, some of which may require new orientations to solve. (shrink)

We present a molecular model of eukaryotic gene transcription. For the β‐globin locus, we hypothesise that a transcription machine composed of multiple RNA polymerase II (PolII) assembles using the locus control region as a foundation. Transcription and locus remodelling can be achieved by pulling DNA through this multi‐PolII ‘reading head’. Once a transcription complex is formed, it may engage an active gene in several rounds of transcription. Observed intergenic sense and antisense transcripts may be the result of PolII pulling (...) the DNA through the reading head whilst searching for the promoter of a gene. Support for this hypothesis is provided using various data from the literature. In the model, DNA is packed in a 30‐nm chromatin fibre, thus gene regulatory regions separated by kilobases are close in space. This, and the need to store transcription‐induced supercoiling, may explain why functionally interacting regions are often separated by many kilobases. (shrink)

SummaryThe complex relation between molecular ideas and hydrodynamics in midnineteenth-century British science is considered. This relation is presented in the historical literature, almost invariably, in terms of a complete antithesis which signified an ontological commitment on behalf of British scientists to the idea that matter was essentially continuous. However, the analysis will reveal that molecular ideas were scattered within the main body of hydrodynamics and that molecular discourse was intersecting hydrodynamical discussions at specific points. Questions of resistance (...) and complex fluid phenomena were inviting various molecular conceptualizations of fluid matter, although these never took the form of a complete mathematical theory. (shrink)

The practice and development of modern medicine requires large amounts of data, particularly in the domain of cancer. The future of personalized medicine lies neither with “genomic medicine” nor with “precision medicine”, but with “data medicine”. The establishment of this DM has required far-reaching changes, to establish four essential elements connecting patients and doctors: biobanks, databases, bioinformatic platforms and genomic platforms. The “transformation” of scientific research areas, such as genetics, bioinformatics and biostatistics, into clinical specialties has generated a new vision (...) of care. Molecular tumor boards are one response to these changes and are now providing better access to next-generation sequencing and new cancer treatments to patients with inoperable or metastatic cancers, and those for whom the usual treatment has failed. However, MTB face a crucial ethical challenge: maintaining and improving the trust of patients, clinicians, researchers and industry in academic medical centers supported by private or public funding rather than providing genetic data directly to private companies. We believe that, in this era of DM, appropriate modern digital communication networks will be required to maintain this trust and to improve the organization and effectiveness of the system. There is, therefore, a need to reconsider the form and content of informed consent documents at all academic medical centers and to introduce dynamic and electronic informed consent. (shrink)

Although it is now generally acknowledged that new biomedical technologies often produce new definitions and sometimes even new concepts of disease, this observation is rarely used in research that anticipates potential ethical issues in emerging technologies. This article argues that it is useful to start with an analysis of implied concepts of disease when anticipating ethical issues of biomedical technologies. It shows, moreover, that it is possible to do so at an early stage, i.e. when a technology is only just (...) emerging. The specific case analysed here is that of ‘molecular medicine’. This group of emerging technologies combines a ‘cascade model’ of disease processes with a ‘personal pattern’ model of bodily functioning. Whereas the ethical implications of the first are partly familiar from earlier—albeit controversial—forms of preventive and predictive medicine, those of the second are quite novel and potentially far-reaching. (shrink)

The practice and development of modern medicine requires large amounts of data, particularly in the domain of cancer. The future of personalized medicine lies neither with “genomic medicine” nor with “precision medicine”, but with “data medicine”. The establishment of this DM has required far-reaching changes, to establish four essential elements connecting patients and doctors: biobanks, databases, bioinformatic platforms and genomic platforms. The “transformation” of scientific research areas, such as genetics, bioinformatics and biostatistics, into clinical specialties has generated a new vision (...) of care. Molecular tumor boards are one response to these changes and are now providing better access to next-generation sequencing and new cancer treatments to patients with inoperable or metastatic cancers, and those for whom the usual treatment has failed. However, MTB face a crucial ethical challenge: maintaining and improving the trust of patients, clinicians, researchers and industry in academic medical centers supported by private or public funding rather than providing genetic data directly to private companies. We believe that, in this era of DM, appropriate modern digital communication networks will be required to maintain this trust and to improve the organization and effectiveness of the system. There is, therefore, a need to reconsider the form and content of informed consent documents at all academic medical centers and to introduce dynamic and electronic informed consent. (shrink)

Chords are not pure sets of tones or notes. They are mainly characterized by their matrices. A chord matrix is the pattern of all the lengths of intervals given without further context. Chords are well-structured invariants. They show their inner logical form. This opens up the possibility to develop a molecular logic of chords. Chords are our primitive, but, nevertheless, already interrelated expressions. The logical space of internal harmony is our well-known chromatic scale represented by an infinite line (...) of integers. Internal harmony is nothing more than the pure interrelatedness of two or more chords. We consider three cases: chords inferentially related to subchords, pairs of chords in the space of major–minor tonality and arbitrary chords as arguments of unary chord operators in relation to their outputs. One interesting result is that chord negation transforms any pure major chord into its pure minor chord and vice versa. Another one is the fact that the negation of chords with symmetric matrices does not change anything. A molecular logic of chords is mainly characterized by combining general rules for chord operators with the inner logical form of their arguments. (shrink)

I am honored to have been invited to participate in this Workshop on Comparative Studies of Building Molecular Biology, with a discussion of Japanese experiences in constructing a science — in this case, the discipline of molecular biology. As I understand it, the construction of a science must be equivalent to building a new culture. My having given this title to my paper suggests that I have enough knowledge about the subject to perhaps even extrapolate its course into (...) the future — which I do not. What I do have is a sincere admiration of my old friends and colleagues, in Japan and elsewhere, who together tried to build a new science of molecular biology in Japan. (shrink)

Significant progress in the molecular investigation of endogenous bioelectric signals during pattern formation in growing tissues has been enabled by recently developed techniques. Ion flows and voltage gradients produced by ion channels and pumps are key regulators of cell proliferation, migration, and differentiation. Now, instructive roles for bioelectrical gradients in embryogenesis, regeneration, and neoplasm are being revealed through the use of fluorescent voltage reporters and functional experiments using well‐characterized channel mutants. Transmembrane voltage gradients (Vmem) determine anatomical polarity and function (...) as master regulators during appendage regeneration and embryonic left‐right patterning. A state‐of‐the‐art recent study reveals that they can also serve as prepatterns for gene expression domains during craniofacial patterning. Continued development of novel tools and better ways to think about physical controls of cell‐cell interactions will lead to mastery of the morphogenetic information stored in physiological networks. This will enable fundamental advances in basic understanding of growth and form, as well as transformative biomedical applications in regenerative medicine. (shrink)

Mitotic spindles constitute the machinery responsible for equidistribution of the genetic material into each daughter cell during cell division. They are transient and hence quite labile structures, changing their morphology even while performing their function. Biochemical, immunological and genetic analyses of mitotic cells have allowed us to identify a variety of molecules that are recruited to form the spindle at the onset of mitosis. Evaluation of the roles of these molecules in both the formation and in the dynamics of (...) spindle microtubules should be important for understanding the molecular basis of mitosis and its regulation. We have recently identified a novel mitosis‐specific microtubule‐associated protein (MAP) using a monoclonal antibody probe raised against the mitotic spindles isolated from cultured mammalian cells. This 95/105 kDa antigen represents a unique component of the spindle distinct from any of the other MAPs reported so far. Antibody microinjection resulted in mitotic inhibition in a stage‐specific and dosedependent manner, indicating that the protein is an essential spindle component. (shrink)

Neurofilaments and microtubules are important components of the neuronal cytoskeleton. In axons or dendrites, these filaments are aligned in parallel arrays, and separated from one another by nonrandom distances. This distinctive organization has been attributed to cross bridges formed by NF side arms or microtubule‐associated proteins. We recently proposed a polymer‐brush‐based mechanism for regulating interactions between neurofilaments and between microtubules. In this model, the side arms of neurofilaments and the projection domains of microtubule‐associated proteins are highly unstructured and exert long‐range (...) repulsive forces that are largely entropic in origin; these forces then act to organize the cytoskeleton in axons and dendrites. Here, we review the biochemical, biophysical, genetic and cell biological data for the polymer‐brush and cross‐bridging models. We explore how the data traditionally used to support cross bridging may be reconciled with a polymer‐brush mechanism and compare the implications of recent experimental insights into axonal transport and physiology for each model. BioEssays 26:1017–1025, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The heme‐containing cytochromes P‐450 are a ubiquitous family of monooxygenase isozymes responsible for the oxidative metabolism of a wide variety of endogenous as well as exogenous compounds. Many of the compounds metabolized by this enzyme system are effectively detoxified and converted to derivatives more easily eliminated from the organism. However, some compounds can be activated to reactive species capable of eliciting a cascade of toxic lesions, including cancer. Since its discovery nearly 30 years ago, the cytochrome P‐450 enzyme system has (...) received a great deal of attention, particularly in the areas of their mechanisms of metabolism, range of substrate specificity, the purification and characterization of the multiple isozymes and, more recently, the regulation of expression of specific forms. This review will discuss current notions concerning the expression of at least one cytochrome P‐450 isozyme and future directions that should lead to a more complete understanding of cytochrome P‐450 gene expression in general, particularly as it impacts upon biochemical pharmacology. (shrink)

Specimens of Lamellibrachia (Annelida: Siboglinidae) were recently discovered at cold seeps in the eastern Mediterranean. In this study, we have investigated the phylogeny and function of intracellular bacterial symbionts inhabiting the trophosome of specimens of Lamellibrachia sp. from the Amon mud volcano, as well as the bacterial assemblages associated with their tube. The dominant intracellular symbiont of Lamellibrachia sp. is a gammaproteobacterium closely related to other sulfide-oxidizing tubeworm symbionts. In vivo uptake experiments show that the tubeworm relies on sulfide for (...) its metabolism, and does not utilize methane. Bacterial communities associated with the tube form biofilms and occur from the anterior to the posterior end of the tube. The diversity of 16S rRNA gene phylotypes includes representatives from the same divisions previously identified from the tube of the vent species Riftia pachyptila, and others commonly found at seeps and vents. (shrink)

Raunig develops a philosophy of dividuality as a way of addressing contemporary modes of production and forms of life. The animal of the molecular revolution will be neither mole nor snake, but a drone-animal-thing that is solid, liquid, and a gas. —from Dividuum As the philosophical, religious, and historical systems that have produced the “individual” (and its counterparts, society and community) over the years continue to break down, the age of “dividuality” is now upon us. The roots of the (...) concept of the “dividuum” can be traced back to Latin philosophy, when Cicero used the term to translate the “divisible” in the writings of Epicurus and Plato; later, medieval scholars utilized the term in theological discussions on the unity of the trinity. Grounding himself in the writings of the medieval bishop Gilbert de Poitiers and his extensive commentaries on Boethius, Gerald Raunig charts a genealogy of the concept and develops a philosophy of dividuality as a way of addressing contemporary modes of production and forms of life. Through its components of dispersion, subsistence, and similarity, dividuality becomes a hidden principle of obedience and conformity, but it also brings with it the potential to realize disobedience and noncompliant con/dividualities. Raunig's bad news is that dividuality is responsible for much of the intensified exploitation and enslavement taking place under contemporary machinic capitalism. Algorithms, derivatives, big data, and social media technology all contribute to the rampant expansion of divisive management strategies and desires for self-division. The good news, however, is that this same terrain of dividuality presents an opportunity for a new kind of resistance, one that can be realized in the form of con/division. (shrink)

This article summarizes the study of anion exchange mechanisms in bacteria. Along with defining at least two different families of anion exchange, an examination of such carrier‐mediated antiport reactions has led to techniques that considerably broaden the scope of biochemical methods for examining membrane proteins. Such advances have been exploited to show that anion exchange itself forms the mechanistic base of an entirely new kind of proton pump, one which may shed light on a variety of bacterial events, including methanogenesis. (...) Perhaps most important, the study of exchange provided the final link in a chain of evidence pointing to a structural [rhythm] that seems to characterize membrane carriers. These three issues ‐ a biochemical tool, a new proton pump, and a common structural rhythm ‐ are briefly examined in the context of their origins in the analysis of bacterial anion exchange. (shrink)

One important aspect of biological explanation is detailed causal modeling of particular phenomena in limited experimental background conditions. Recognising this allows one to appreciate that a sufficient condition for a reduction in biology is a molecular model of (1) only the demonstrated causal parameters of a biological model and (2) only within a replicable experimental background. These identities—which are ubiquitous in biology and form the basis of ruthless reductions (Bickle, Philosophy and neuroscience: a ruthlessly reductive account, 2003)—are criticised (...) as merely “local” (Sullivan, Synthese 167:511–539, 2009) or “fragmentary” (Schaffner, Synthese, 151(3):377–402, 2006). However, in an instructive case, a biological model is preserved in molecular terms, demonstrating a complex phenomenon that has been successfully reduced. (shrink)

Traditionally, phylogenetic relations among living and extinct species have been estimated from their morphology, particularly that of the bones and teeth. During the past two decades, molecular comparisons of DNA, RNA and proteins have increasingly influenced the taxonomy of living forms. Recently, radio‐immunoassay (RIA) has been applied to the resolution of phylogenetic disputes by testing the relationships of residual fossil proteins with those of living organisms.

Between 1905 and 1913, French physicist Jean Perrin's experiments on Brownian motion ostensibly put a definitive end to the long debate regarding the real existence of molecules, proving the atomic theory of matter. While Perrin's results had a significant impact at the time, later examination of his experiments questioned whether he really gained experimental access to the molecular realm. The experiments were successful in determining the mean kinetic energy of the granules of Brownian motion; however, the values for (...) class='Hi'>molecular magnitudes Perrin inferred from them simply presupposed that the granule mean kinetic energy was the same as the mean molecular kinetic energy in the fluid in which the granules move. This stipulation became increasingly questionable in the years between 1908 and 1913, as significantly lower values for these magnitudes were obtained from other experimental results like alpha-particle emissions, ionization, and Planck's blackbody radiation equation. In this case study in the history and philosophy of science, George E. Smith and Raghav Seth here argue that despite doubts, Perrin's measurements were nevertheless exemplars of theory-mediated measurement-the practice of obtaining values for an inaccessible quantity by inferring them from an accessible proxy via theoretical relationships between them. They argue that it was actually Perrin more than any of his contemporaries who championed this approach during the years in question. The practice of theory-mediated measurement in physics had a long history before 1900, but the concerted efforts of Perrin, Rutherford, Millikan, Planck, and their colleagues led to the central role this form of evidence has had in microphysical research ever since. Seth and Smith's study thus replaces an untenable legend with an account that is not only tenable, but more instructive about what the evidence did and did not show. (shrink)

Microscopy has revealed tremendous diversity of bacterial and eukaryotic forms. Recent molecular analyses show discordance in estimates of biodiversity between morphological and molecular analyses. Moreover, phylogenetic analyses of the diversity of microbial forms reveal evidence of convergence at scales as deep as interdomain: morphologies shared between bacteria and eukaryotes. Here, we highlight examples of such discordance, focusing on exemplary lineages such as testate amoebae, ciliates, and cyanobacteria. These have long histories of morphological study, enabling deeper analyses on both (...) the molecular and morphological sides. We discuss examples in two main categories: (i) morphologically identical (or highly similar) individuals that are genetically distinct and (ii) morphologically distinct individuals that are genetically the same. We argue that hypotheses about discordance can be tested using the concept of neutral morphologies, or more broadly neutral phenotypes, as a null hypothesis. -/- . (shrink)

Taking reduction in the traditional deductive sense, the programmatic claim that most of genetics can be reduced by molecular genetics is defended as feasible and significant. Arguments by Ruse and Hull that either the relationship is replacement or at best a weaker form of reduction are shown to rest on a mixture of historical and logical confusions about the nature of the theories involved.

In a number of membrane-bound viruses, ion channels are formed by integral membrane proteins. These channel proteins include M2 from influenza A, NB from influenza B, and, possibly, Vpu from HIV-1. M2 is important in facilitating uncoating of the influenza A viral genome and is the target of amantadine, an anti-influenza drug. The biological roles of NB and Vpu are less certain. In all cases, the protein contains a single transmembrane α-helix close to its N-terminus. Channels can be formed by (...) homo-oligomerization of these proteins, yielding bundles of transmembrane helices that span the membrane and surround a central ion-permeable pore. Molecular modeling may be used to integrate and interpret available experimental data concerning the structure of such transmembrane pores. This has proved successful for the M2 channel domain, where two independently derived models are in agreement with one another, and with solid-state nuclear magnetic resonance (NMR) data. Simulations based on channel models may yield insights into possible ion conduction and selectivity mechanisms. BioEssays 20:992–1000, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

This paper examines processes of translation through which molecular genetic technologies and practices are incorporated into environmental health research and regulation. Specifically, it considers how scientists, risk assessors, and regulators have used genetically modified mouse models to translate across scientific disciplines, articulate emergent molecular forms, standards, and practices with the extant? gold standard,? and establish roles for molecular knowledge in risk assessment and regulation. Noting variation both within and between regulatory agencies in responses to data from these (...) models, the article describes also the role of public-private networks and their effects on professional and institutional imperatives which shape regulators? responses to the potential applications of these models. The conclusions address the importance of translation for understanding the wider implications of the molecularization of environmental health science. (shrink)

The aim of this dissertation is to provide an analysis of central concepts in philosophy of science from the perspective of current molecular and developmental research. Each chapter explores the ways in which particular phenomena or discoveries in molecular biology influences our philosophical understanding of the nature of scientific knowledge. The introductory prologue draws some general connections between the various threads, which revolve around two central themes: causation and explanation. Chapter Two identifies a particular type of causal relation (...) which is widespread across the sciences, but cannot be straightforwardly accommodated by extant accounts of causation and causal explanation. Chapter Three explores how the form of redundant causality identified in the previous chapter plays an important role in causal explanation, by making the effect stable and robust. Chapter Four offers a novel perspective on the debate over biological reductionism by distinguishing between different paradigms of molecular explanation. Chapter Five provides a philosophical analysis of the so-called "Developmental Synthesis" of evolutionary and developmental biology, and suggests a general account of scientific unification grounded in the notion of explanatory relevance. Chapter Six offers an account of dispositional properties inspired by mechanisms of gene regulation, according to which dispositions are not properties of entities, but properties that describe the behavior of abstract idealized models. Finally, Chapter Seven scrutinizes the concept of the molecular ecosystem, a metaphor frequently employed by biologists to describe cellular interactions, but seldom articulated in detail. (shrink)

Recently a number of complex electrophysiological responses to neurotransmitters have been observed that cannot be described as simple excitation or inhibition. These responses are often characterized as modulatory, although there is no consensus on what defines modulation. Morphological studies reveal certain neurotransmitters stored in what might be release sites without synaptic contact. There is no direct evidence for nonsynaptic release from CNS sites, although such release does occur in the periphery and in invertebrates. Nonsynaptic release might provide a basis for (...) diffuse one-cell-to-many communication, but it might also simply be a means of sending the transmitter to a broader area of a single neuron than occurs in typical synapses. Several kinds of macromolecules have been found to be transported in a retrograde direction – and in some cases transsynaptically. There have been suggestions that some neurons may release more than one type of transmitter. Particularly intriguing is the possibility of release of substances that modulate actions of a primary transmitter. Taken together this range of evidence suggests that neurons may use a variety of forms of molecular communication in addition to traditionally described synaptic transmission.Several authors have suggested modes of communication distinct from classical synaptic transmission and have classified released substances using terms such as neurohumor, neurohormone, neuroregulator, and modulator. These suggestions have the heuristic value of drawing together diverse kinds of data, but it remains to be established that the pieces fit together in that fashion – for example, that complex electrophysiological effects are associated with substances released nonsynaptically. In order to reduce confusion, a flexible, generic approach to nomenclature for substances released from neurons and for hypothetical modes of communication is recommended. Some behavioral implications of nonconventional transmission are considered. (shrink)

Fibril‐forming (fibrillar) collagens are extracellular matrix proteins conserved in all multicellular animals. Vertebrate members of the fibrillar collagen family are essential for the formation of bone and teeth, tissues that characterise vertebrates. The potential role played by fibrillar collagens in vertebrate evolution has not been considered previously largely because the family has been around since the sponge and it was unclear precisely how and when those particular members now found in vertebrates first arose. We present evidence that the classical vertebrate (...) fibrillar collagens share a single common ancestor that arose at the very dawn of the vertebrate world and prior to the associated genome duplication events. Furthermore, we present a model, ‘molecular incest’, that not only accounts for the characteristics of the modern day vertebrate fibrillar collagen family but demonstrates the specific effects genome or gene duplications may have on the evolution of multimeric proteins in general. BioEssays 25:142–151, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The Neo‐Darwinian concept of natural selection is plausible when one assumes a straightforward causation of phenotype by genotype. However, such simple 1:1 mapping must now give place to the modern concepts of gene regulatory networks and gene expression noise. Both can, in the absence of genetic mutations, jointly generate a diversity of inheritable randomly occupied phenotypic states that could also serve as a substrate for natural selection. This form of epigenetic dynamics challenges Neo‐Darwinism. It needs to incorporate the non‐linear, (...) stochastic dynamics of gene networks. A first step is to consider the mathematical correspondence between gene regulatory networks and Waddington's metaphoric ‘epigenetic landscape’, which actually represents the quasi‐potential function of global network dynamics. It explains the coexistence of multiple stable phenotypes within one genotype. The landscape's topography with its attractors is shaped by evolution through mutational re‐wiring of regulatory interactions – offering a link between genetic mutation and sudden, broad evolutionary changes. (shrink)

Background The emergence of molecular HIV surveillance (MHS) and cluster detection and response (CDR) programs as key features of the United States (US) HIV strategy since 2018 has caused major controversies. HIV surveillance programs that re-use individuals’ routinely collected clinical HIV data do not require consent on the basis that the public benefit of these programs outweighs individuals’ rights to opt out. However, criticisms of MHS/CDR have questioned whether expanded uses of HIV genetic sequence data for prevention reach beyond (...) traditional public health ethics frameworks. This study aimed to explore views on consent within MHS/CDR among critical stakeholders.Methods In 2021 we interviewed 26 US HIV stakeholders who identified as being critical or concerned about the rollout of MHS/CDR. Stakeholders included participants belonging to networks of people living with HIV, other advocates, academics, and public health professionals. This analysis focused on identifying the range of positions among critical and concerned stakeholders on consent affordances, opt-outs, how to best inform people living with HIV about how data about them are used in public health programs, and related ethical issues.Results Participants were broadly supportive of introducing some forms of consent into MHS/CDR. However, they differed on the specifics of implementing consent. While some participants did not support introducing consent affordances, all supported the idea that people living with HIV should be informed about how HIV surveillance and prevention is conducted and how individuals’ data are used.Conclusions MHS/CDR has caused sustained controversy. Among critical stakeholders, consent is generally desirable but contested, although the right for people living with HIV to be informed was centrally supported. In an era of big data-driven public health interventions and routine uses of HIV genetic sequence data in surveillance and prevention, CDC and other agencies should revisit public health ethics frameworks and consider the possibility of consent processes. (shrink)

On the basis of certain tensions between Jacques Rancière’s aesthetics and his political philosophy, the article tries to trace new modes of subjectivation in contemporary activism and art. It explores how the actors of the overlapping terrains of aesthetic and political practices organize ‘different forms, different spaces of expression and distribution of ideas’ in Rancière’s sense. Yet, analysing the practices of the Occupy movement, the Spanish M15 movement, and the dOCUMENTA (13) ‘agents’ AND AND AND as radically inclusive, polyvocal and (...) transversal, it proposes a position that differs from Rancière’s rejection of activist art, a non-totalizing political aesthetics as a component of molecular revolution. (shrink)

Fanconi anaemia (FA) comprises a group of autosomal recessive disorders resulting from mutations in one of eight genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF and FANCG). Although caused by relatively simple mutations, the disease shows a complex phenotype, with a variety of features including developmental abnormalities and ultimately severe anaemia and/or leukemia leading to death in the mid teens. Since 1992 all but two of the genes have been identified, and molecular analysis of their products has revealed a (...) complex mode of action. Many of the proteins form a nuclear multisubunit complex that appears to be involved in the repair of double‐strand DNA breaks. Additionally, at least one of the proteins, FANCC, influences apoptotic pathways in response to oxidative damage. Further analysis of the FANC proteins will provide vital information on normal cell responses to damage and allow therapeutic strategies to be developed that will hopefully supplant bone marrow transplantation. BioEssays 24:439–448, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Understanding how scientific activities use naming stories to achieve disciplinary status is important not only for insight into the past, but for evaluating current claims that new disciplines are emerging. In order to gain a historical understanding of how new disciplines develop in relation to these baptismal narratives, we compare two recently formed disciplines, systems biology and genomics, with two earlier related life sciences, genetics and molecular biology. These four disciplines span the twentieth century, a period in which the (...) processes of disciplinary demarcation fundamentally changed from those characteristic of the nineteenth century. We outline how the establishment of each discipline relies upon an interplay of factors that include paradigmatic achievements, technological innovation, and social formations. Our focus, however, is the baptism stories that give the new discipline a founding narrative and articulate core problems, general approaches and constitutive methods. The highly plastic process of achieving disciplinary identity is further marked by the openness of disciplinary definition, tension between technological possibilities and the ways in which scientific issues are conceived and approached, synthesis of reductive and integrative strategies, and complex social interactions. The importance – albeit highly variable – of naming stories in these four cases indicates the scope for future studies that focus on failed disciplines or competing names. Further attention to disciplinary histories could, we suggest, give us richer insight into scientific development. (shrink)

In recent times, the exponential growth of sequenced genomes and structural knowledge of proteins, as well as the development of computational tools and controlled vocabularies to deal with this growth, has fueled a demand for conceptual clarification regarding the concept of function in molecular biology. In this article, we will attempt to develop an account of function fit to deal with the conceptual/philosophical problems in that domain, but which can be extended to other areas of biology. To provide this (...) account, we will argue for three theses: (1) some authors have confused metatheoretical issues (about the meaning and application criteria of terms) with metaphysical ones (about teleology); this led them to (2) look for explicit definitions of “function”, in terms of necessary and sufficient criteria of application, in order to make the concept of function eliminable; however, (3) if one leaves metaphysical worries aside and focuses on functional attribution practices, it is more adequate to say that the concept of function has an open texture. That is, that a multiplicity of application criteria is available, none of which is sufficient nor necessary to attribute a function to a trait, and which only in concert form a clear picture. We distinguish this thesis from some usual forms of pluralism. Finally, we will illustrate this account with a historical reconstruction of the ascription of a water transport function to aquaporins. (shrink)

The phenomenon of ‘canalization’ ‐ the genetic capacity to buffer developmental pathways against mutational or environmental perturbations ‐ was first characterized in the late 1930s and early 1940s. Despite enormous subsequent progress in understanding the nature of the genetic material and the molecular basis of gene expression, there have been few attempts to interpret the classical work on canalization in molecular genetic terms. Some recent findings, however, bear on one form of canalization, ‘genetic canalization’, the stabilization of (...) development against mutational effects. These data indicate that co‐expressed paralogous genes can function as mutual ‘back‐up’ elements in developmental processes. Paralogues, however, are far from the only basis of canalization: other genetic sources can be readily envisaged and some of these are described here. The evolutionary questions about genetic canalization and the mechanistic questions about developmental instability that still need to be addressed are also briefly discussed. (shrink)

In a number of membrane-bound viruses, ion channels are formed by integral membrane proteins. These channel proteins include M2 from influenza A, NB from influenza B, and, possibly, Vpu from HIV-1. M2 is important in facilitating uncoating of the influenza A viral genome and is the target of amantadine, an anti-influenza drug. The biological roles of NB and Vpu are less certain. In all cases, the protein contains a single transmembrane α-helix close to its N-terminus. Channels can be formed by (...) homo-oligomerization of these proteins, yielding bundles of transmembrane helices that span the membrane and surround a central ion-permeable pore. Molecular modeling may be used to integrate and interpret available experimental data concerning the structure of such transmembrane pores. This has proved successful for the M2 channel domain, where two independently derived models are in agreement with one another, and with solid-state nuclear magnetic resonance (NMR) data. Simulations based on channel models may yield insights into possible ion conduction and selectivity mechanisms. BioEssays 20:992–1000, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms (...) of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

MacDonald and Kreitman (1991) propose a test of the neutral mutationrandom drift (NM-RD) hypothesis, the central claim of the neutral theory of molecular evolution. The test involves generating predictions from the NM-RD hypothesis about patterns of molecular substitutions. Alternative selection hypotheses predict that the data will deviate from the predictions of the NM-RD hypothesis in specifiable ways. To conduct the test Mac- Donald and Kreitman examine the evolutionary dynamics of the alcohol dehydrogenase (Adh) gene in three species of (...) Drosophila. The test compares the number of DNA sequence changes between species and within species. The number of DNA differences is an indicator of the evolutionary rate of the Adh gene. Based on the test they conclude that there is strong evidence for adaptive protein evolution at particular sites in the gene. Understanding the test requires some basic knowledge about molecular terms and the predictions of neutral theory. The two important terms are fixed differences and polymorphisms. These are determined by comparing DNA sequences made up of thousands of individual nucleotide sites. A site that is unchanged within a species but different from a related species counts as a fixed difference. These are mutations that occur in some common ancestor of the lineage such that all descendants inherit the change. A site that differs within a species counts as a polymorphism. Determining the number of fixed differences and polymorphisms requires placing 1 each individual gene sequence onto a phylogenetic tree. A coalescent tree charts the ancestral relationships for a set of individual gene sequences. Sequences sampled from within a species form a within-species tree. The common ancestors of each within-species tree form a between-species tree. A detected difference counts as a polymorphism or a fixed difference depending on where it occurs in the phylogenetic tree (cf. Table 1). The test uses the numbers of polymorphisms and fixed differences as indicators of evolutionary rates.. (shrink)

The human blood coagulation system comprises a series of linked glycoproteins that upon activation induce the generation of downstream enzymes ultimately forming fibrin. This process is primarily important to arrest bleeding (hemostasis). Hemostasis is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation. Excess, pathological, coagulation activity occurs in “thrombosis”, the formation of an intravascular clot, which in the most dramatic (...) form precipitates in the microvasculature as disseminated intravascular coagulation. Thrombosis occurs according to a biochemical machine model in the case of atherothrombosis on a ruptured atherosclerotic plaque, but may develop at a slower rate in venous thrombosis, illustrating that the coagulation machinery can act at different velocities. The separate coagulation enzymes are also important in other biological processes, including inflammation for which the rapid conversion of one coagulation factor by the other is not a prerequisite. The latter role of coagulation enzymes may be related to the old and probably maintained function of the coagulation machine in innate immunity. BioEssays 25:1220–1228, 2003. © 2003 Wiley Perioicals, Inc. (shrink)

The most interesting biological molecules are long polymers. In analogy with human alphabetic languages, they can be called texts and analysed, as to the primary structure, as sequences of letters or of words . It is considered that the study of words, in a linguistic approach, may contribute positively to the understanding of molecular interactions . The molecular and human languages and dialects are contrasted. The molecular one is peculiarly distinct from the human, for instance, by its (...) use of a tridimensional morphology, temporal dynamics, absence of spacings and punctuation, and overlapping messages. A mathematical method is presented, for discovering words in texts. The word AAA was studied in the evolution of the 5S ribosomal RNA. It was shown that this word is more frequent in less complex organisms and less frequent in the more complex ones, in the fungi, plants, and vertebrates lineages. In the two latter ones, the degree of genie variability was also reduced. To the contrary, a moderate degree of usage of this word persisted in the whole invertebrates lineage, where a high degree of genie variability was maintained. In mitochondria, plastids and mycoplasmas, the frequency of the word AAA was increased, consistently with their need for interactions with a wider range of variation. These behaviors indicate that the monotonous AAA word allows for ambiguity in interactions. With the evolution of organic complexity and of greater molecular specificity, ambiguous words were progressively avoided.As moléculas biológicas mais interessantes são longos polímeros. Em analogia com a linguagem humana alfabética, estes podem ser chamados de textos, e analisados, quanto à estrutura primária, como sequência de letras ou de palavras . Considera-se que o estudo das palavras, em abordagem de tipo lingüístico, possa contribuir para o entendimento das interações moleculares. As linguagens e dialetos, moleculares e humanos, são contrastados. A linguagem molecular se distingue peculiarmente da humana, por exemplo, por utilizar forma tridimensional, dinâmica temporal, ausência de espaçamento e pontuação, e sobreposição de significados. Apresenta-se um método matemático para descoberta, de palavras em textos. A palavra AAA foi estudada na evolução do RNA ribossômico 5S. Observou-se que esta palavra é mais freqüente em organismos menos complexos e menos freqüente nos mais complexos, das linhagens de fungos, plantas e vertebrados. Nas duas últimas, reduziu-se também o grau de variabilidade gênica. Pelo contrário, grau moderado de freqüência da palavra persistiu em toda a linhagem dos invertebrados, com manutenção paralela de alto nível de variabilidade gênica. Nas mitocôndrias, plastídeos e micoplasmas, a freqüência da palavra AAA foi aumentada, de acordo com sua necessidade de interações com maior amplitude de variação. Esses comportamentos indicam que a palavra monótona AAA permite ambigüidade de interações. Com a evolução da complexidade orgânica e da maior especificidade molecular, as palavras ambíguas foram progressivamente evitadas. (shrink)

This article addresses the issue of units of analysis and atomistic models in psychology taking creativity research as a case study. A classic typology in this area, initially proposed by Rhodes, distinguishes between the four P's of creativity: person, process, product, and press. Continuing an effort to rewrite this basic language of the discipline from a cultural psychological perspective in the form of five A's, the discussion here focuses on bringing relationships to the fore within this framework and problematising (...) strict distinctions between each of the five elements. A closer look at the five A's of creativity, drawing on theoretical considerations and illustrated by interviews with creators working in different domains, reveals the permeable borders surrounding these units and challenges clear divisions between actors and audiences, action and artefacts, actors and artefacts. In the end, it is argued that creative phenomena cannot be properly understood and studied outside of their integrated and dynamic totality defined as a creativity complex. Implications of adopting this “molecular” perspective for theory and methodology are discussed. (shrink)

The Aristotelian axiom that function follows form was beautifully instantiated in molecular biology by the discovery of DNA’s structure that immediately suggested how DNA might work as depository and vehicle for genetic information. However, later on molecular biology became infatuated with the gene that became the center of the universe. This gene-centered viewpoint is an obstacle for the emerging field of evo-devo aiming at finding the causal connections between evolution and biological development. Here it is argued that (...) molecular biology must reject the narrow-minded causality associated with the gene-centered view and so it must recover to the spirit of Aristotelian natural history and its four types of causation in order to foster the evo-devo field of research. (shrink)

Of the many genes mutated on the road to tumor formation, few have received as much attention as p53. The gene has come to occupy center stage for the simple reason that it is more frequently altered in human tumors than any other known gene, undergoing mutation at a significant rate in almost every tumor type in which it has been studied. This association between p53 mutation and tumorigenesis has spurred a flurry of research attempting to delineate the normal function (...) of p53 and, by extension, the role of p53 mutation in tumor formation. At the cellular level, p53 has been shown to suppress growth. Recent efforts to further discern the function of p53 have centered on the underlying molecular basis for this growth suppression. In particular, research has focused on the identification of cellular molecules (specifically DNA and proteins) with which the p53 protein associates. p53 has now been shown to bind DNA in a sequence‐specific manner, and mounting evidence suggests that p53 acts as a transcription factor, perhaps regulating the expression levels of genes involved in the inhibition of cell growth. The logical next step in understanding p53 function involves the resolution of two questions: (1) what are the physiological transcriptional targets of p53, and (2) what cellular proteins regulate or mediate the ability of p53 to modulate transcription? Some initial clues to these puzzles are now emerging, and these form the subject of this review. (shrink)

Interleukin 5 (IL‐5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL‐5 acts on committed B cells to induce differentiation into Ig‐producing cells and on common progenitors for CD5+ pre‐B cells and CD5+ macrophages to support their survival. (...) The antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL‐5 receptor (IL‐5R) consists of two different polypeptide chains; αL chain and β chain. The IL‐5R α chain is 60 kDa protein that binds IL‐5 with low affinity. The IL‐5R β chain is a 130 kDa protein which does not bind IL‐5 by itself but is necessary to form the high affinity IL‐5R. The β chain was identified by using one of the anti‐IL‐5R mAb and anti‐IL‐3R mAb as the IL‐3R homologue. This β chain is also used as the β chain of GM‐CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes. (shrink)

Central nervous system (CNS)Abbreviations: CNS=central nervous system; PNS=peripheral nervous system; MS=multiple sclerosis; MBP=myelin basic protein; MHC=major histocompatibility complex; EAE=experimental allergic encephalomyelitis; O‐2A=oligodendrocyte‐type 2 astrocyte; GC=galactocerebroside; GFAP=glial fibrillary acidic protein; FGF=fibroblast growth factor; IGF1=insulin‐like growth factor. regeneration is a subject of great interest, particularly in diseases causing a dramatic loss of neurons. However, some CNS diseases do not affect neurons but damage other cells, such as the myelin‐forming cells — called oligodendrocytes — which are also crucial to the harmonious function of (...) the nervous system. Diseases in which oligodendrocytes and myelin are attacked can cause devastating neurological dysfunction which is sometimes followed by recovery and myelin repair or remyelination. The question of the regeneration potential of oligodendrocytes in experimental and human demyelinating diseases such as multiple sclerosis has been debated for a long time. Present evidence suggests that oligodendrocyte precursor cells persist in the adult CNS and that oligodendrocyte regeneration can occur but may be limited by ongoing disease processes. Here we will briefly review recent advances which have broadened our understanding of the cellular and molecular events of CNS remyelination. (shrink)

It is now clear that two prominent nuclear domains, interchromatin granule clusters (IGCs) and Cajal bodies (CBs), contribute to the highly ordered organization of the extrachromosomal space of the cell nucleus. These functional domains represent structurally stable but highly dynamic nuclear organelles enriched in factors that are required for different nuclear activities, especially RNA biogenesis. IGCs are considered to be the main sites for storage, assembly, and/or recycling of the essential spliceosome components. CBs are involved in the biogenesis of several (...) classes of small RNPs as well as the modification of newly assembled small nuclear RNA. We have summarized data on the molecular composition, structure, and functional roles of IGCs and CBs in the nuclei of mammalian somatic cells and oocytes of some animals with a special focus on insects. We have focused on similarities and differences between the IGCs and CBs of oocytes and the well‐studied CBs and IGCs of cultured mammalian somatic cells. We have shown the heterogeneous character of oocyte IGCs and CBs, both in structure and molecular content. We have also demonstrated the unique capacity of oocytes to form close structural interactions between IGC and CB components. We proposed to consider these joint structures as integrated entities, sharing the features of both IGCs and CBs. (shrink)

We claim that in contemporary studies in molecular biology and biomedicine, the nature of ‘manipulation’ and ‘intervention’ has changed. Traditionally, molecular biology and molecular studies in medicine are considered experimental sciences, whereas experiments take the form of material manipulation and intervention. On the contrary “big science” projects in biology focus on the practice of data mining of biological databases. We argue that the practice of data mining is a form of intervention although it does not (...) require material manipulation. We also suggest that material manipulation, although still present in in the practice of data mining, fulfill a different epistemic role. (shrink)