In this thesis I examine a number of topics that bear on explanation and understanding in molecular and cell biology, in order to shed new light on explanatory practice in those areas and to find novel angles from which to approach relevant philosophical debates. The topics I look at include mechanism, emergence, cellular complexity, and the informational role of the genome. I develop a perspective that stresses the intimacy of the relations between ontology and epistemology. Whether a phenomenon looks (...) mechanistic, or complex, or indeed emergent, is largely an epistemic matter, yet has an objective basis in features of the world. After reviewing several concepts of mechanism I consider the influential recent account of Machamer, Darden and Craver (MDC). That account makes interesting proposals concerning the relationship between mechanistic explanation and intelligibility, which are consistent with the results of the investigation I undertake into the science surrounding protein folding. In relation to a number of other issues pertaining to biological systems I conclude that the MDC account is insufficiently nuanced, however, leading me to outline an alternative approach to mechanism. This emphasizes the importance of structure—function relations and addresses issues raised by reflection on the nature of cellular complexity. These include the distinction between structure and process and the different possible bases on which system organization may be maintained. The account I give of emergence construes the phenomenon in terms of psychological deficit: phenomena are emergent when we lack the capacity to trace through and model their causal structures using our cognitive schemas. I conclude by developing these ideas into a preliminary and partial account of explanation and understanding. This aspires to cover the significant fraction of work in molecular and cell biology that correlates biological structures, processes and functions by visualizing phenomena and making them imaginable. (shrink)

A new therapeutic strategy could break the stalemate in the war on cancer by targeting not all cancerous cells but the small fraction that lie at the root of cancers. Lucie Laplane offers a comprehensive analysis of cancer stem cell theory, based on an original interdisciplinary approach that combines biology, biomedical history, and philosophy.

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

Many studies of the unification of science focus on the theories of different disciplines. The model for integration is the theory reduction model. This paper argues that the embodiment of theories in scientists, and the institutions in which scientists work and the instruments they employ, are critical to the sort of integration that actually occurs in science. This paper examines the integration of scientific endeavors that emerged in cell biology in the period after World War II when the development (...) of cell fractionation and electron microscopy made serious investigations of cell organelles possible. One surprising feature of such integration is that it generated further disintegration as the new institutions of cell biology separated the practitioners of the new discipline from other, closely related biological disciplines. (shrink)

The demand of many scientific areas for the usage of fractional partial differential equations to explain their real-world systems has been broadly identified. The solutions may portray dynamical behaviors of various particles such as chemicals and cells. The desire of obtaining approximate solutions to treat these equations aims to overcome the mathematical complexity of modeling the relevant phenomena in nature. This research proposes a promising approximate-analytical scheme that is an accurate technique for solving a variety of noninteger partial differential equations. (...) The proposed strategy is based on approximating the derivative of fractional-order and reducing the problem to the corresponding partial differential equation. Afterwards, the approximating PDE is solved by using a separation-variables technique. The method can be simply applied to nonhomogeneous problems and is proficient to diminish the span of computational cost as well as achieving an approximate-analytical solution that is in excellent concurrence with the exact solution of the original problem. In addition and to demonstrate the efficiency of the method, it compares with two finite difference methods including a nonstandard finite difference method and standard finite difference technique, which are popular in the literature for solving engineering problems. (shrink)

There is a growing appreciation of the extent of transcriptome variation across individual cells of the same cell type. While expression variation may be a byproduct of, for example, dynamic or homeostatic processes, here we consider whether single‐cell molecular variation per se might be crucial for population‐level function. Under this hypothesis, molecular variation indicates a diversity of hidden functional capacities within an ensemble of “identical” cells, and this functional diversity facilitates collective behavior that would be inaccessible to a (...) homogenous population. In reviewing this topic, we explore possible functions that might be carried by a heterogeneous ensemble of cells; however, this question has proven difficult to test, both because methods to manipulate molecular variation are limited and because it is complicated to define, and measure, population‐level function. We consider several possible methods to further pursue the hypothesis that “variation is function” through the use of comparative analysis and novel experimental techniques. (shrink)

Sickle cell haemoglobin polymerization reduces erythrocyte deformability, causing deleterous vaso-occlusions. The double-nucleation model states that polymers grow from HbS aggregates, the nuclei, in solution , onto existing polymers . When linearized at initial HbS concentration, this model predicts early polymerization and its characteristic delay-time :591–610, 611–631, 1985). Addressing its relevance for describing complete polymerization, we constructed the full, non-linearized model . Here, we compare the simulated outputs to experimental progress curves . Within 10% from start, average root mean square (...) deviation between simulated and experimental curves is 0.04 ± 0.01 . Conversely, for complete progress curves, averaged rms is 0.48 ± 0.04. This figure is improved to 0.13 ± 0.01 by adjusting heterogeneous pathway parameters : the nucleus stability , and the fraction of polymer surface available for nucleation , from 5e−7, to 13 . Similar results are obtained at 37°C. We conclude that the physico-chemical description of heterogeneous nucleation warrants refinements in order to capture the whole HbS polymerization process. (shrink)

Novel methods such as mass‐spectrometry enable a view of the proteomes of cells in unprecedented detail. Recently, these efforts have culminated in quantitative measurements of the number of copies per cell for most expressed proteins in organisms ranging from bacteria to mammalian cells. Here, we estimate the expected total number of proteins per unit of cell volume using known parameters related to the composition of cells such as the fraction of cell mass that is protein, and the (...) average protein length. Using simple arguments, we estimate a range of 2–4 million proteins per cubic micron (i.e. 1 fL) in bacteria, yeast, and mammalian cells. Interestingly, we find that measured values that are reported for fission yeast and mammalian cells are often about 3–10 times lower. We discuss this apparent discrepancy and how to use the estimate as benchmark to recalibrate proteome‐wide quantitative censuses or to revisit assumptions about cell composition. (shrink)

The rate‐limiting step in the uptake and metabolism of Dglucose by insulin target cells is thought to be glucose transport mediated by glucose transporters (primarily the GLUT4 isoform) localized to the plasma membrane. However, subcellular fractionation, photolabelling and immunocytochemical studies have shown that the pool of GLUT4 present in the plasma membrane is only one of many subcellular pools of this protein. GLUT4 has been found in occluded vesicles at the plasma membrane, clathrin‐coated pits and vesicles, early endosomes, and (...) tubulo‐vesicular structures; the latter are analogous to known specialized secretory compartments. Tracking the movement of GLUT4 through these compartments, and defining the mechanism and site of action of insulin in stimulating this subcellular trafficking, are major topics of current investigation. Recent evidence focuses attention on the exocytosis of GLUT4 as the major site of insulin action. Increased exocytosis may be due to decreased retention of glucose transporters in an intracellular pool, or possibly to increased assembly of a vesicle docking and fusion complex. Although details are unknown, the presence in GLUT4 vesicles of a synaptobrevin homologue leads us to propose that a process analogous to that occurring in synaptic vesicle trafficking is involved in the assembly of GLUT4 vesicles into a form suitable for fusion with the plasma membrane. Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3‐kinase, is discussed. (shrink)

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

Interactions among membrane proteins regulate numerous cellular processes, including cell growth, cell differentiation and apoptosis. We need to understand which proteins interact, where they interact and to which extent they interact. This article describes a set of novel approaches to measure, on the surface of living cells, the number of clusters of proteins, the number of proteins per cluster, the number of clusters or membrane domains that contain pairs of interacting proteins and the fraction of one protein species (...) that interacts with another protein within these domains. These data can then be interpreted in terms of the function of the protein‐protein interactions. BioEssays 26:196–203, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Among emotions, surprise has been extensively studied in psychology. In linguistics, surprise, like other emotions, has mainly been studied through the syntactic patterns involving surprise lexemes. However, little has been done so far to correlate the reaction of surprise investigated in psychological approaches and the effects of surprise on language. This cross-disciplinary volume aims to bridge the gap between emotion, cognition and language by bringing together nine contributions on surprise from different backgrounds - psychology, human-agent interaction, linguistics. Using different methods (...) at different levels of analysis, all contributors concur in defining surprise as a cognitive operation and as a component of emotion rather than as a pure emotion. Surprise results from expectations not being met and is therefore related to epistemicity. Linguistically, there does not exist an unequivocal marker of surprise. Surprise may be either described by surprise lexemes, which are often associated with figurative language, or it may be expressed by grammatical and syntactic constructions. Originally published as a special issue of Review of Cognitive Linguistics 13:2 (2015). (shrink)

Nous étudions dans cet article les différentes formes de prédication seconde détachée en position initiale dans un corpus comparable composé de textes d’économie en anglais et en français. Ce corpus a été annoté sous le logiciel Analec. L’enjeu est de montrer en quoi un même phénomène syntaxique est exploité, sur le plan discursif, de façon divergente dans chacune des deux langues. Une étude qualitative et quantitative des prédications secondes du corpus montre que la prédication seconde prend le plus souvent la (...) forme d’une participiale en –ing en anglais, où elle se spécialise dans un rôle méta-énonciatif de balise textuelle pour le lecteur, ce qui n’est pas le cas en français. (shrink)

This study presents a sociological profile of Peruvian female industrialists and some narratives of their struggle for personal independence and entrepreneurial success within the context of global restructuring and local deindustrialization. The study adopts the classical definition of woman's economic independence as a result of women's participation in the world of paid labor.

Surprise is treated as an affect in Aristotelian philosophy as well as in Cartesian philosophy. In experimental psychology, surprise is considered to be an emotion. In phenomenology, it is only addressed indirectly (Husserl, Heidegger, Levinas), with the important exception of Ricoeur and Maldiney; it is reduced to a break in cognition by cognitivists (Dennett). Only recently was it broached in linguistics, with a focus on lexico-syntactic categories. As for the expression of surprise, it has been studied in connection with evidentiality (...) in languages that encode surprise morphosyntactically. However, how surprise is encoded in languages that lack an evidential morphosyntactic system has been largely unexplored. This book provides new insights into the dynamics of surprise based on a heuristic hypothesis tested against the investigation of time, language and emotion. It is intended to arouse the interest of a multidisciplinary audience keen on crossing the disciplinary borders of phenomenology, cognitive sciences, and pragmatics. The theoretical approaches adopted in this collection of articles rely on experiments and corpus data. They advance knowledge by building on robust empirical results coming from psychology, microphenomenology, linguistics and physiology. (shrink)

The production of evidence for scientific hypotheses and theories often depends upon complex instruments and techniques for employing them. An important epistemological question arises as to how the reliability of these instruments and techniques is assessed. To address that question, this paper examines the introduction of electron microscopy and cell fractionation in cell biology. One important claim is that scientists often arrive at their techniques for employing instruments like the electron microscope and the ultracentrifuge by tinkering and (...) that they evaluate the resulting techniques in part by whether they produce plausible data given developing theories. (shrink)

ZusammenfassungDer Elementarbaustein aller Lebewesen ist die Zelle. Sie besitzt eine reiche innere Struktur mit einer Vielzahl von Organellen fur verschiedene Stoffwechselfunktionen.Zur Analyse der Funktionen dieser Organelle wird die Methode der Zellfraktionierung einge‐setzt. Die Zellen werden dabei aufgebrochen und – meist mit Zentrifugations‐Techniken – in verschiedene Fraktionen aufgetrennt. Mit Hilfe von Markern, d.h. von charakteristischen bio‐chemischen oder morphologischen Merkmalen der einzelnen Organelle werden die Fraktionen identifiziert und dann im Hinblick auf ihre Stoffwechselfunktionen analysiert.Eine prinzipielle Schwierigkeit dieser Analyse besteht in der Tatsache, (...) dass es umso wahr‐scheinlicher ist, dass sich die Funktionen der isolierten Organelle verandern, je sorgfältiger sie gereinigt werden.SummaryThe elementary building block of all living organisms is the cell. It has a rich inner structure with a multitude of organelles for various metabolic functions.The analysis of these functions is made possible by the method of cell fractionation. Cells are homogenized and separated, mainly by centrifugation techniques, into a number of fractions. With the aid of markers, i.e. of characteristic biochemical or morphological properties of individual organelles, the fractions are identified and then analyzed for their metabolic functions.A principal difficulty of this analysis consists in the fact that an alteration of the functions of isolated organelles is the more probable, the more extensively they are purified.RésuméĽélément fondamental de tout être vivant est la cellule. Elle a une riche structure interieure avec une multitude ?on;organelles pour différentes fonctions metaboliques.Ľanalyse de leurs fonctions repose sur la méthode du fractionnement des cellules. Les cellules sont broyées et séparées en différentes fractions, le plus souvent par des techniques de centrifugation. Les fractions sont identifyérs àľaide de marqueurs, c'est‐à‐dire de propriétés biochimiques ou morphologiques charactéristiques pour une organelle individuelle, puis elles sont analysées quant a leurs fonctions métaboliques.Ľune des principales difficultés provient du fait que plus on purifie une organelle, plus on risque ?on;altérer sa fonction. (shrink)

Cultures of Experiment. – It is generally accepted that the development of modern science is rooted in experiment. Yet for a long time, experimentation did not occupy a prominent role in history of science. With the practical turn in science studies, this has begun to change. This paper is concerned with cultures of experiment. In the first part, a suggestion is made as to how the concept of experimental culture can be used to go beyond a history of disciplines. In (...) the second part, a particular experimental culture in the life sciences is looked at more closely. A survey is given on the changing forms of in vitro experimentation, that is, on analyzing biological functions in a test tube. (shrink)

Modern cells present no signs of a putative prebiotic RNA world. However, RNA coding is not a sine qua non for the accumulation of catalytic polypeptides. Thus, cellular proteins spontaneously fold into active structures that are resistant to proteolysis. The law of mass action suggests that binding domains are stabilized by specific interactions with their substrates. Random polypeptide synthesis in a prebiotic world has the potential to initially produce only a very small fraction of polypeptides that can fold spontaneously into (...) catalytic domains. However, that fraction can be enriched by proteolytic activities that destroy the unfolded polypeptides and regenerate amino acids that can be recycled into polypeptides. In this open system scenario the stable domains that accumulate and the chemical environment in which they are accumulated are linked through self coding of polypeptide structure. Such open polypeptide systems may have been the precursors to the cellular ribonucleoprotein (RNP) world that evolved subsequently. (shrink)

The scientific knowledge needed to engage with policy issues like climate change, vaccination, and stem cell research often conflicts with our intuitive theories of the world. How resilient are our intuitive theories in the face of contradictory scientific knowledge? Here, we present evidence that intuitive theories in 10 domains of knowledge—astronomy, evolution, fractions, genetics, germs, matter, mechanics, physiology, thermodynamics, and waves—persist more than four decades beyond the acquisition of a mutually exclusive scientific theory. Participants were asked to verify two (...) types of scientific statements as quickly as possible: those that are consistent with intuition and those that involve the same conceptual relations but are inconsistent with intuition. Older adults were as accurate as younger adults at verifying both types of statements, but the lag in response times between intuition-consistent and intuition-inconsistent statements was significantly larger for older adults than for younger adults. This lag persisted even among professional scientists. Overall, these results suggest that the scientific literacy needed to engage with topics of global importance may be constrained by patterns of reasoning that emerge in childhood but persist long thereafter. (shrink)

This work is intended to illustrate how gravity is a major factor in shaping life as we know it. It will be argued here that gravity has an influence at all levels, from particles to planets. Moreover, that any change in gravitational acceleration will have a direct and inevitable impact upon the form of any organism. From a fresh perspective some of the mysteries of evolution will be examined in light of gravity and its ubiquity. The creatures of the Earth, (...) past and present, have taken on many forms but why is it that all the terrestrial mega fauna have become extinct? Why is it that reptiles today are only a fraction of the size of their ancestors? Why is it that an insect never reaches the size of a large mammal? What is Tensegrity and how does it influence the structure of the cell, the protein and the larger body of an organism? Many of the considerations here are taken from novel scientific thinkers; these will be outlined and discussed. Many of the ideas may seem controversial and provocative but the author makes no apology for their inclusion. Indeed the purpose here is to stimulate a debate that hopefully leads to a better understanding of life and its evolution. (shrink)

Short-term or working memory provides temporary storage of information in the brain after an experience and is associated with conscious awareness. Neurons sensitive to the multiple stimulus attributes comprising an experience are distributed within many brain regions. Such distributed cell assemblies, activated by an event, are the most plausible system to represent the WM of that event. Studies with a variety of imaging technologies have implicated widespread brain regions in the mediation of WM for different categories of information. Each (...) kind of WM may thus be expected to involve many brain regions rather than a local, uniquely dedicated set of cells. Neurons in a distributed “cell assembly” may be self-selected by their temporally coherent activations. The process by which this fragmented representation of the recent past is reassembled to accomplish essentially automatic and reliable recognition of a recurrent event constitutes an important problem. One plausible mechanism to achieve the identification of past with previous events would require that the representational system mediating WM must coexist in spatial extent and somehow overlap in temporal activation with cell ensembles registering input from subsequent events. The detection of such a postulated mechanism required an experimental approach which would focus upon spatial patterns of coherent activation while information about different events was stored in WM and retrieved, rather than focusing upon the temporal sequences of activation in localized regions of interest. For this purpose, the familiar delayed matching from sample task was modified. A series of information-free flashes, or “noncontingent probes,” was presented before an initial series of visual information items, the Priming Sample, which were to be held in WM during a Delay Period. A second series of visual information items were then presented, the Matching Sample. The task required detection of any item in the second series which had beenabsentfrom the initial series. Thirty such trials with a particular category of visual information constituted a single task. Several DMS tasks with this standardized design, but with different categories of visual information, were presented within each test session. The information categories included letters of the alphabet, single digit numbers, or faces from a school yearbook. Event-related potentials , were computed from 21 standardized electrode placements, separately for information-free probes and for information items in each interval of the trials within a task. Because each electrode is particularly sensitive to coherent activation of neurons in the immediately underlying brain regions, topographic maps were constructed and interpolated across the surface of the scalp. The momentary fluctuations of the resulting voltage “landscapes” throughout the task were then subjected to quantitative analysis. Distinctive landscapes sometimes persisted for prolonged periods, implying sustained engagement of very large populations of neurons. “Difference landscapes” were constructed by subtraction of topographic maps evoked by noncontingent probes during the Delay Period from maps of probe ERPs before the presentation of the initial information in the Priming Sample. Such probe difference landscapes displayed recurrent high similarity to momentary landscapes elicited during subsequent presentation of the information items in the Matching Sample. It seemed as if the distributed cell assembly continuously engaged by mediation of WM of the diverse attributes of the initial stimuli was being dynamically compared to the ensembles engaged by registration of the subsequent stimuli. Spatial Principal Component Analysis was applied to the sequences of momentary voltage landscapes observed throughout trials of each task. This method sought a small number of spatial patterns with which these large sets of inhomogeneous spatial distributions of voltage could be reconstructed. This is the spatial analog of the reconstruction of local ERPs by temporal principal components, as often described previously. Five Spatial Principal Components were found which accounted for about 90% of the total variance of voltage across the surface of the scalp throughout every task. Theloadings,or distinguishing topographic features, of these SPCs, were highly similar during every cognitive task for every subject. However,factor scores,or relative average contribution to the overall voltage distributions, of the different SPCs varied substantially among subjects between the tasks and momentarily within successive intervals of each task. These five SPCs may reflect coherent activation of huge distributed ensembles of neurons which comprise independent but interacting functional brain subsystems. These subsystems may correspond to basic resources available to individuals for allocation to mediate conscious evaluation of information during cognitive activity, providing a filter to bind together fractionated representations of the past to evaluate the present. (shrink)

Plasmodium falciparum is the most deadly human malarial parasite, responsible for an estimated 207 million cases of disease and 627,000 deaths in 2012. Recent studies reveal that the parasite actively regulates a large fraction of its genes throughout its replicative cycle inside human red blood cells and that epigenetics plays an important role in this precise gene regulation. Here, we discuss recent advances in our understanding of three aspects of epigenetic regulation in P. falciparum: changes in histone modifications, nucleosome occupancy (...) and the three‐dimensional genome structure. We compare these three aspects of the P. falciparum epigenome to those of other eukaryotes, and show that large‐scale compartmentalization is particularly important in determining histone decomposition and gene regulation in P. falciparum. We conclude by presenting a gene regulation model for P. falciparum that combines the described epigenetic factors, and by discussing the implications of this model for the future of malaria research. (shrink)

There is increasing evidence that dynamic changes to chromatin, chromosomes and nuclear architecture are regulated by RNA signalling. Although the precise molecular mechanisms are not well understood, they appear to involve the differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. A significant fraction of the genome-wide transcription of non-protein coding RNAs may be involved in this process, comprising a previously hidden layer of intermediary genetic information that (...) underpins developmental ontogeny and the differences between species, ecotypes and individuals. It is also evident that RNA editing is a primary means by which hardwired genetic information in animals can be altered by environmental signals, especially in the brain, indicating a dynamic RNA-mediated interplay between the transcriptome, the environment and the epigenome. Moreover, RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as across generations. (shrink)

Ultradian rhythms are those that cycle many times in a day and are therefore measured in hours, minutes, seconds or even fractions of a second. In yeasts and protists, a temperature‐compensated clock with a period of about an hour (30–90 minutes) provides the time base upon which all central processes are synchronized. A 40‐minute clock in yeast times metabolic, respiratory and transcriptional processes, and controls cell division cycle progression. This system has at its core a redox cycle involving NAD(P)H (...) and dithiol–disulfide interconversions. It provides an archetype for biological time keeping on longer time scales (e.g. the daily cycles driven by circadian clocks) and underpins these rhythms, which cannot be understood in isolation. Ultradian rhythms are the foundation upon which the coherent functioning of the organism depends. BioEssays 29:465–473, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Souvent considérée comme un point aveugle de son œuvre, la question du parti constitue pourtant une composante centrale de la pensée de Marx. En prenant en compte l’expérience militante qui fut la sienne tout au long de sa vie, cet article entreprend de montrer que Marx a développé non pas une mais deux théories du parti bien distinctes. La thèse décisive formulée à la fin des années 1840 dans le Manifeste du parti communiste – celle d’un parti communiste conçu comme (...) fraction éclairée d’un parti ouvrier plus large – disparaît en effet de l’horizon stratégique de Marx au cours des années 1860, cédant la place à une réflexion centrée sur la construction du parti de classe, dans laquelle l’idée même d’une distinction fonctionnelle entre parti ouvrier et parti communiste perd son sens. Opposant alors de façon systématique le parti à la secte, Marx cherche à penser les conditions de possibilité d’une activité politique autonome de la classe ouvrière plutôt qu’une organisation fondée sur une doctrine pré-constituée. (shrink)

AMBIS is a complete identification system which includes (1) a highly reproducible electrophoresis unit; (2) a beta‐scanner with the ability to rapidly locate and measure beta particle emission data from a variety of isotopes and surfaces; and (3) an IBM computer with a massive data storage capacity for the emission data plus subsequent manipulation of that data. Hence it provides a rapid facility for (1) classification of all types of micro‐organisms, (2) examination of cells of multicellular plants and animals, (3) (...) routine determination of molecular weights of one or more proteins in a complex mixture, (4) quantification of single or mixed compounds in a band, (5) scanning and quantification of dot and other blots, immunodiffusion precipitates and probes, (6) direct counting of radioactive solutions from RIA, column fractions, etc., without the need of expensive scintillation fluids with their consequent hazards, (7) circumventing the need of much time‐consuming auto‐radiography, and (8) setting up databases plus exchange and transference of data between AMBIS systems in different locations via floppy disk, modem or other forms of rapid transmission. (shrink)

Diseases causing inherited retinal degeneration in humans, such as retinitis pigmentosa and macular dystrophy, are genetically heterogeneous and clinically diverse. More than 40 genes causing retinal degeneration have been mapped to specific chromosomal sites; of these, at least 10 have been cloned and characterized. Mutations in two proteins, rhodopsin and peripherin/RDS, account for approximately 35% of all cases of autosomal dominant retinitis pigmentosa and a lesser fraction of other retinal conditions. This target article reviews the genes and mutations causing retinal (...) degeneration and proposes mechanisms whereby specific mutations lead to particular clinical consequences, that is, the relationship between genotype and phenotype. Retinitis pigmentosa and macular dystrophy are genetically heterogeneous diseases that cause retinal degeneration in humans and often result in severe visual impairment or blindness. Although many of the genes causing these diseases have not been identified, three photoreceptor-specific proteins have been implicated: rhodopsin, peripherin/RDS, and the P-subunit of rod phosphodiesterase. Mutations in the genes for these three proteins can cause either dominant retinitis pigmentosa, recessive retinitis pigmentosa, dominant congenital stationary night blindness, or dominant macular degeneration. Why this multiplicity of clinical phenotypes? Our target article summarizes the genetic and biochemical background to this question and proposes a number of possible explanations. Discussion focuses mainly on 73 distinct disease-causing mutations of rhodopsin. We feel that rhodopsin and other photoreceptor proteins can serve as model systems for unraveling the connection between genotype and phenotype, not only for inherited retinal diseases but for other degenerative disorders as well. (shrink)

Two posttranslational lipid modifications present on all Hedgehog (Hh) morphogens—an N‐terminal palmitate and a C‐terminal cholesterol—are established and essential regulators of Hh biofunction. Yet, for several decades, the question of exactly how both lipids contribute to Hh signaling remained obscure. Recently, cryogenic electron microscopy revealed different modes by which one or both lipids may contribute directly to Hh binding and signaling to its receptor Patched1 (Ptc). Some of these modes demand that the established release factor Dispatched1 (Disp) extracts dual‐lipidated Hh (...) from the cell surface, and that another known upstream signaling modulator called Scube2 chaperones the dual‐lipidated morphogen to Ptc. By mechanistically and biochemically aligning this concept with established in vivo and recent in vitro findings, this reflection identifies remaining questions in lipidated Hh transport and evaluates additional mechanisms of Disp‐ and Scube2‐regulated release of a second bioactive Hh fraction that has one or both lipids removed. (shrink)

How do common and rare genetic polymorphisms contribute to quantitative traits or disease risk and progression? Multiple human traits have been extensively characterized at the genomic level, revealing their complex genetic architecture. However, it is difficult to resolve the mechanisms by which specific variants contribute to a phenotype. Recently, analyses of variant effects on molecular traits have uncovered intermediate mechanisms that link sequence variation to phenotypic changes. Yet, these methods only capture a fraction of genetic contributions to phenotype. Here, in (...) reviewing the field, it is proposed that complex traits can be understood by characterizing the dynamics of biochemical networks within living cells, and that the effects of genetic variation can be captured on these networks by using protein–protein interaction (PPI) methodologies. This synergy between PPI methodologies and the genetics of complex traits opens new avenues to investigate the molecular etiology of human diseases and to facilitate their prevention or treatment. (shrink)

Dans cet entretien consacré à leur livre Managerial Capitalism : Ownership, management and the coming new mode of production (Pluto Press, 2018), G. Duménil et D. Lévy reviennent sur les implications de leur analyse du capitalisme managérial pour l’étude du capitalisme historique, de ses structures de classes fondamentales, et de ses alliances de pouvoirs variables. La thèse du marxisme traditionnel identifiant les managers à une fraction de classe capitaliste s’en trouve critiquée, de même que les présupposés véhiculés par le concept (...) de « capitalisme d’État ». Invités à revenir plus précisément sur leur distinction entre modes de production et « ordres sociaux », comme configurations variables de hiérarchies de pouvoirs et d’alliances de classe, les auteurs clarifient les raisons pour lesquelles ils introduisent une nouvelle catégorie de mode de production managérial qui impose de repenser le mode de production capitaliste lui-même suivant une logique de « l’hybridité ». Celle-ci permet de complexifier les tendances du capitalisme historique sur la longue durée, d’approfondir l’analyse de classe du capitalisme managérial, et d’y spécifier différentiellement, par rapport au « compromis » d’après-guerre (caractérisé par une alliance entre managers et classes populaires sous la direction des premiers), le dernier ordre social en date caractérisé par une alliance « au sommet » entre managers et capitalistes (au détriment des classes populaires) : le néolibéralisme. (shrink)

Baculovirus vectors have proven useful in producing high levels of biologically active eukaryotic proteins and providing cellular fractions which are enriched in the protein of interest. Expression occurs in infected insect cells which also provide a suitable environment for posttranslational modification and folding of the protein product. Stable baculovirus vectors can be constructed rapidly with a minimum of viral manipulation.

Although chemotherapy is one of the most common treatments for cancer, it can be only partially successful. Drug resistance is the main cause of the failure of chemotherapy. In this work, we present a mathematical model to study the impact of both intrinsic and acquired resistances on chemotherapy effectiveness. Our simulations show that intrinsic resistance could be as dangerous as acquired resistance. In particular, our simulations suggest that tumors composed by even a small fraction of intrinsically resistant cells may lead (...) to an unsuccessful therapy very quickly. Our results emphasize the importance of monitoring both intrinsic and acquired resistances during treatment in order to succeed and the importance of doing more experimental and genetic research in order to develop a pretreatment clinical test to avoid intrinsic resistance. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this (...) debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

We understand the workings of the human body as a series of interdependent physiological relationships: muscle interacts with bone as the heart responds to hormones secreted by the brain, all the way down to the inner workings of every cell. To make an organism function, no one component can work alone. In light of this, why is it that the accepted understanding that the physical phenomenon of the mind is attributed only to the brain? In The Embodied Mind, internationally (...) renowned psychiatrist Dr. Thomas R. Verny sets out to redefine our concept of the mind and consciousness. He brilliantly compiles new research that points to the mind's ties to every part of the body. The Embodied Mind collects disparate findings in physiology, genetics, and quantum physics in order to illustrate the mounting evidence that somatic cells, not just neural cells, store memory, inform genetic coding, and adapt to environmental changes-all behaviors that contribute to the mind and consciousness. Cellular memory, Verny shows, is not just an abstraction, but a well-documented scientific fact that will shift our understanding of memory. Verny describes single-celled organisms with no brains demonstrating memory, and points to the remarkable case of a French man who, despite having a brain just a fraction of the typical size, leads a normal life with a family and a job. The Embodied Mind shows how intelligence and consciousness-traits traditionally attributed to the brain alone-also permeate our entire being. Bodily cells and tissues use the same molecular mechanisms for memory as our brain, making our mind more fluid and adaptable than we could have ever imaged. (shrink)

L’article étudie la naissance et le développement du calendrier ecclésiastique chrétien, i. e. le comput, depuis les premiers témoignages de la célébration annuelle de la résurrection de Jésus jusqu’aux traductions des tables astronomiques arabes au xiie siècle. Il privilégie les procédures qui aboutissent à la détermination des dates pascales et à leur mise en forme tabulaire. Les analyses sont conduites à partir d’un double point de vue. L’un est scientifique. Il s’appuie sur les données astronomiques retenues par Ptolémée et sur (...) l’apport de la tradition mathématique grecque au calcul par approximations. Les cycles soli-lunaires sont posés à partir des fractions continues et le cycle soli-hebdomadaire à partir du plus petit commun multiple. Le second point de vue est social : l’unification du comput participe à celle de la chrétienté comprise comme une configuration politico-religieuse. Deux conclusions s’imposent. Quelle que soit l’importance que la civilisation médiévale a attribuée au comput, il reste que : 1 / les Pâques sont porteuses de significations irréductibles aux techniques chronométriques qui inscrivent cette fête dans le déroulement de l’année ; 2 / ces techniques ont toutefois marqué profondément les curiosités intellectuelles des Latins et les ont préparé à accueillir avec ferveur les zīj et la numération de position. (shrink)

Secretory proteins and membranes move in transfer vesicles from the rough endoplasmic reticulum through the transitional region to the outer saccule of the Golgi complex. In both arthropod and vertebrate cells, the GC beads are a characteristic structural component of the transitional region. The beads are particles about half the size of ribosomes arranged equidistantly from one another and the smooth face of the ER. In an active GC, the beads are in rings through which the ER membrane emerges to (...) form transfer vesicles. The beads may be part of the energy‐dependent step required for the movement of proteins along the secretory pathway, since they lose their ring arrangement under conditions that lower cellular ATP. The beads are organizers for Golgi complexes in the sense that they are the first recognizable components of new GCs as they arise from ER. Arthropod GC beads, but not those of vertebrates, can be visualized through their reaction with bismuth in vivo and in fixed tissue. Useful paradigms for traffic between the ER and the GC need to combine structural and biochemical information. Insect fat body, with its readily resolvable bismuth‐stained beads and easily fractionated cell components may have particular value for this problem. (shrink)

Edward Titchener, one of the great champions of introspectionist psychology, declared that 'the term Introspection, as we find it used today, is highly equivocal, and that the procedure which it connotes may be scientifically illegitimate, or even wholly imaginary' . He made the point because he wanted to insulate his preferred method of doing psychological research from criticisms that were directed against forms of introspection that he conceded to be unreliable. The point, however, is not just that we can introspect (...) more or less carefully. It is that there are 'gross differences in the meaning of the word' . 'Introspection' is Janus-faced. It splinters into several different species, involving different underlying mechanisms. (shrink)