Cytoplasmic protein-tyrosine kinases (PTKs) are enzymes involved in transducing a vast number of signals in metazoans. The importance of the Tec family of kinases was immediately recognized when, in 1993, mutations in the gene encoding Bruton's tyrosine kinase (Btk) were reported to cause the human disease X-linked agammaglobulinemia (XLA).(1,2) Since then, additional kinases belonging to this family have been isolated, and the availability of full genome sequences allows identification of all members in selected species enabling phylogenetic considerations. Tec (...) kinases are endowed with Pleckstrin homology (PH) and Tec homology (TH) domains and are involved in diverse biological processes related to the control of survival and differentiation fate. Membrane translocation resulting in the activation of Tec kinases with subsequent Ca2+ release seems to be a general feature. However, nuclear translocation may also be of importance. The purpose of this essay is to characterize members of the Tec family and discuss their involvement in signaling. The three-dimensional structure, expression pattern and evolutionary aspects will also be considered. BioEssays 23:436–446, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

X‐linked agammaglobulinemia is a heritable immunodeficiency disease caused by a differentiation abnormality, resulting in the virtual absence of B Iymphocytes and plasma cells. The affected gene encodes a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase, designated Btk. Btk and the other family members, Tec, Itk and Bmx, contain five regions, four of which are common structural and functional modules that are found in other signaling proteins. Mutations affect all domains of the gene, but amino acid substitutions (...) seem to be confined to certain regions. More than 150 unique mutations have been identified and are collected in a mutation database, BTKbase. Here we discuss the three‐dimensional structural implications of such mutations and their putative functional role. Of special interest are mutations affecting the pleckstrin homology domain, as Btk is the only disease‐associated protein so far reported to carry mutations in this particular module. (shrink)

Signaling by the Epidermal Growth Factor Receptor (EGFR) and related ErbB family receptor tyrosine kinases can be deregulated in human malignancies as the result of mutations in the genes that encode these receptors. The recent identification of EGFR mutations that correlate with sensitivity and resistance to EGFR tyrosine kinase inhibitors in lung and colon tumors has renewed interest in such activating mutations. Here we review current models for ligand stimulation of receptor dimerization and for activation of (...) receptor signaling by receptor dimerization. In the context of these models, we discuss ErbB receptor mutations that affect ligand binding and those that cause constitutive receptor phosphorylation and signaling as a result of constitutive receptor dimerization. We discuss mutations in the cytoplasmic regions that affect enzymatic activity, substrate specificity and coupling to effectors and downstream signaling pathways. Finally, we discuss how emergent mechanisms of ErbB receptor mutational activation could impact the search for clinically relevant ErbB receptor mutations. BioEssays 29:558–565, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Oncogenes are altered forms of normal cellular genes known as proto‐oncogenes. Several oncogenes encode enzymes that phosphorylate substrate proteins at tyrosine. In most of these cases the oncogene differs from its proto‐oncogene by multiple mutations that alter the structure of the encoded protein product. Here we discuss how structural changes might effect the regulation and substrate specificity of the protein kinase product of a protooncogene so that it gains the potential to transform cells.

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit a variety (...) of effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The classification frameworks for fault diagnosis of rolling element bearings in rotating machinery are mostly based on analysis in a single time-frequency domain, where sensitive features are not completely extracted. To solve this problem, a new fault diagnosis technique is proposed in the mixed domain, based on the crossover-mutation chaotic particle swarm optimization support vector machine. Firstly, fault features are generated using techniques in the time domain, the frequency domain, and the time-frequency domain. Secondly, the (...) weighted maximum relevance minimum redundancy algorithm is adopted to reduce the dimension of the feature set and to establish the representative feature set. Thirdly, a new crossover-mutation strategy is suggested to reduce the local minima in optimization, and an optimization disturbance is added. Finally, the support vector machine is optimized using the improved chaotic particle swarm to improve fault classification diagnosis. The effectiveness of the proposed new bearing fault diagnostic technique is verified by experimental tests under different bearing conditions. Test results showed that the bearing fault classification accuracy of CMCPSO-SVM in the mixed domain was much higher than those in a single feature domain. (shrink)

Intercellular signaling by growth factors, hormones and neurotransmitters produces second messenger molecules such as cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG). Protein Kinase A and Protein Kinase C are the principal effector proteins of these prototypical second messengers in certain cell types. Recently, novel receptors for cAMP and DAG have been identified. These proteins, designated EPAC (Exchange Protein directly Activated by cAMP) or cAMP‐GEF (cAMP regulated Guanine nucleotide Exchange Factor) and CalDAG‐GEF (Calcium and Diacylglycerol regulated Guanine nucleotide Exchange (...) Factor) or RasGRP (Ras Guanine nucleotide Releasing Protein) are able to mediate some of the physiologic effects of the second messengers in a protein‐kinase‐independent fashion. These proteins are exchange factors for Ras family GTPases that operate in pathways that run parallel to the classic kinase‐dependent pathways. The rapidly emerging recognition of the functions of these “non‐kinase” effectors in diverse processes such as insulin secretion, thymocyte development, asthma and malignant transformation creates new opportunities for discovery and identifies potential new therapeutic targets. BioEssays 26:730–738, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Clonal disease is often regarded as almost synonymous with cancer. However, it is becoming increasingly clear that our bodies harbor numerous mutant clones that are not tumors, and mostly give rise to no disease at all. Here we discuss three somatic mutations arising within the hematopoietic system: BCR‐ABL, characteristic of chronic myeloid leukemia; mutations of the PIG‐A gene, characteristic of paroxysmal nocturnal hemoglobinuria; the V617F mutation in the JAK2 gene, characteristic of myeloproliferative diseases. The population frequencies of these (...) three blood disorders fit well with a hierarchical model of hematopoiesis. The fate of any mutant clone will depend on the target cell and on the fitness advantage, if any, that the mutation confers on the cell. In general, we can expect that only a mutation in a hematopoietic stem cell will give long‐term disease; the same mutation taking place in a cell located more downstream may produce just a ripple in the hematopoietic ocean. (shrink)

Depuis une dizaine d'années, des centaines des millions d'internautes ont donné naissance à des édifices informationnels novateurs. Ces dispositifs dits Web 2.0 constituent de nouveaux modèles éditoriaux. Ces changements,qui s'inscrivent dans la continuité de l'histoire des techniques et des usages, accélèrent considérablement les processus historiques en cours. Par la métaphore des frontières, cet article analyse les profondes mutations intervenues dans le domaine des savoirs : question de l'accès, enjeux de la mémoire collective, transformation de la nature des savoirs.

Focal adhesion kinase (FAK) is a nonreceptor protein‐tyrosine kinase implicated in controlling cellular responses to the engagement of cell‐surface integrins, including cell spreading and migration, survival and proliferation. Aberrant FAK signaling may contribute to the process of cell transformation by certain oncoproteins, including v‐Src. Progress toward elucidating the events leading to FAK activation following integrin‐mediated cell adhesion, as well as events downstream of FAK, has come through the identification of FAK phosphorylation sites and interacting proteins. A signaling partnership (...) is formed between FAK and Src‐family kinases, leading to tyrosine phosphorylation of FAK and associated ‘docking’ proteins Cas and paxillin. Subsequent recruitment of proteins containing Src homology 2 domains, including Grb2 and c‐Crk, to the complex is likely to trigger adhesion‐induced cellular responses, including changes to the actin cytoskeleton and activation of the Ras‐MAP kinase pathway. (shrink)

Class I PI 3‐kinases signal by producing the signaling lipid phosphatidylinositol(3,4,5) trisphosphate, which in turn acts by recruiting downstream effectors that contain specific lipid‐binding domains. The class I PI 3‐kinases comprise four distinct catalytic subunits linked to one of seven different regulatory subunits. All the class I PI 3‐kinases produce the same signaling lipid, PIP3, and the different isoforms have overlapping expression patterns and are coupled to overlapping sets of upstream activators. Nonetheless, studies in cultured cells and in animals have (...) demonstrated that the different isoforms are coupled to distinct ranges of downstream responses. This review focuses on the mechanisms by which the production of a common product, PIP3, can produce isoform‐specific signaling by PI 3‐kinases.Editor's suggested further reading in BioEssays: Phosphatidylinositol 4,5‐bisphosphate: Targeted production and signaling AbstractHow does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? Abstract. (shrink)

The muscle-specific kinase MuSK is part of an agrin receptor complex which stimulates tyrosine phosphorylation and drives clustering of acetylcholine receptors (AChRs) in the postsynaptic membrane at the vertebrate neuromuscular junction. MuSK also regulates synaptic gene transcription in subsynaptic nuclei. Over the past few years decisive progress has been made in the identification of MuSK effectors, helping at understanding its function in the formation of the NMJ. Alike AChR, MuSK and several of its partners are the target of (...) class='Hi'>mutations responsible for diseases of the NMJ, such as congenital myasthenic syndromes. This minireview will focus on the multiple MuSK effectors so far identified that place MuSK at the center of a multifunctional signaling complex involved in the organization of the NMJ and associated disorders. (shrink)

The DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP (...) class='Hi'>kinase family members are involved in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352–358, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Small gaseous molecules play important roles in biological signaling in both animal and plant physiology. The hydrocarbon gas ethylene has long been known to regulate diverse aspects of plant growth and development, including fruit ripening, leaf senescence and flower abscission. Recent progress has been made toward identifying components involved in ethylene signal transduction in the plant Arabidopsis thaliana. Ethylene is perceived by five receptors that have similarity to two‐component signaling proteins. The hydrophobic amino‐terminus of the receptors binds ethylene, and (...) class='Hi'>mutations in this domain both prevent ethylene binding and confer ethylene insensitivity to the plant; the carboxyl‐terminal portion of the receptors has similarity to bacterial his tidine protein kinases. Genetic data suggest a model in which ethylene binding inhibits receptor signaling, yet precisely how these receptors function is unclear. Two of the receptors have been found to associate with a negative regulator of ethylene responses called CTR1, which appears to be a mitogen‐activated protein kinase (MAPK) kinase kinase. BioEssays 23:619–627, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double‐strand‐break‐inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA‐strand breaks trigger widespread activation of ATM through changes in chromatin structure.1 This review discusses a checkpoint activation model in which chromatin perturbations (...) lead to the conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells. BioEssays 25:627–630, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Huxley coined the phrase, the “evolutionary synthesis” to refer to the acceptance by a vast majority of biologists in the mid-20th Century of a “synthetic” view of evolution. According to this view, natural selection acting on minor hereditary variation was the primary cause of both adaptive change within populations and major changes, such as speciation and the evolution of higher taxa, such as families and genera. This was, roughly, a synthesis of Mendelian genetics and Darwinian evolutionary theory; it was a (...) demonstration that prior barriers to understanding between various subdisciplines in the life sciences could be removed. The relevance of different domains in biology to one another was established under a common research program. The evolutionary synthesis may be broken down into two periods, the “early” synthesis from 1918 through 1932, and what is more often called the “modern synthesis” from 1936-1947. The authors most commonly associated with the early synthesis are J.B.S. Haldane, R.A. Fisher, and S. Wright. These three figures authored a number of important synthetic advances; first, they demonstrated the compatibility of a Mendelian, particulate theory of inheritance with the results of Biometry, a study of the correlations of measures of traits between relatives. Second, they developed the theoretical framework for evolutionary biology, classical population genetics. This is a family of mathematical models representing evolution as change in genotype frequencies, from one generation to the next, as a product of selection, mutation, migration, and drift, or chance. Third, there was a broader synthesis of population genetics with cytology, genetics, and biochemistry, as well as both empirical and mathematical demonstrations to the effect that very small selective forces acting over a relatively long time were able to generate substantial evolutionary change, a novel and surprising result to many skeptics of Darwinian gradualist views. The later “modern” synthesis is most often identified with the work of Mayr, Dobzhansky and Simpson. There was a major institutional change in biology at this stage, insofar as different subdisciplines formerly housed in different departments, and with different methodologies were united under the same institutional umbrella of “evolutionary biology.” Mayr played an important role as a community architect, in founding the Society for the Study of Evolution, and the journal Evolution, which drew together work in systematics, biogeography, paleontology, and theoretical population genetics. (shrink)

The recent discovery and structure determination of a novel ubiquitin‐like dimerization domain in protein kinase D (PKD) has significant implications for its activation. PKD is a serine/threonine kinase activated by the lipid second messenger diacylglycerol (DAG). It is an essential and highly conserved protein that is implicated in plasma membrane directed trafficking processes from the trans‐Golgi network. However, many open questions surround its mechanism of activation, its localization, and its role in the biogenesis of cargo transport carriers. (...) In reviewing this field, the focus is primarily on the mechanisms that control the activation of PKD at precise locations in the cell. In light of the new structural findings, the understanding of the mechanisms underlying PKD activation is critically evaluated, with particular emphasis on the role of dimerization in PKD autophosphorylation, and the provenance and recognition of the DAG that activates PKD. (shrink)

Mutations in DNA topoisomerase II are often correlated with drug‐resistance in tumor cell lines. Studies of topoisomerase II‐mediated drug‐resistance in various model systems, as well as the sequencing of such mutations from drug‐resistant tumors, have shed light on the functional domains of topoisomerase II, on how it interacts with inhibitors, and on the different mechanisms by which cells avoid the toxic effects of many clinically important anti‐tumor drugs.

Cell proliferation in response to growth factors is mediated by specific high affinity receptors. Ligand‐binding by receptors of the protein tyrosine kinase family results in the stimulation of several intracellular signal transduction pathways. Key signalling enzymes are recruited to the plasma membrane through the formation of stable complexes with activated receptors. These interactions are mediated by the conserved, non‐catalytic SH2 domains present in the signalling molecules, which bind with high affinity and specificity to tyrosine‐phosphorylated sequences on the receptors. The (...) assembly of enzyme complexes is emerging as a major mechanism of signal transduction and may regulate the pleiotropic effects of growth factors. (shrink)

According to the somatic mutation theory (SMT), cancer begins with a genetic change in a single cell that passes it on to its progeny, thereby generating a clone of malignant cells. It is strongly supported by observations of leukemias that bear specific chromosome translocations, such as Burkitt's lymphoma, in which a translocation activates the c‐myc gene, and chronic myeloid leukemia (CML), in which the Philadelphia chromosome causes production of the BCR‐ABL oncoprotein. Although the SMT has been modified and extended to (...) encompass tumor suppressor genes, epigenetic inheritance, and tumor progression through accumulation of further mutations, perhaps the strongest validation comes from the successful treatment of certain malignancies with drugs that directly target the product of the mutant gene.magnified imageDavid Vaux is at the Walter and Eliza Hall Institute and La Trobe Institute for Molecular Science, Melbourne, Australia. (shrink)

Superoxide is produced by a NADPH oxidase of phagocytic cells and contributes to their microbicidal activities. The oxidase is activated when receptors in the neutrophil plasma membrane bind to the target microbe. These receptors recognise antibodies and complement fragments which coat the target cell. The oxidase electron transport chain, located in the plasma membrane, comprises a low potential cytochrome b heterodimer (gp 91‐phox and p22‐phox) associated with FAD. It is non‐functional until at least three proteins, p67‐phox, p47‐phox and p21rac (and (...) possibly others), move from the cytosol to dock on the cytochrome b. The docking involves the interaction of SH3 domains may become exposed follwoing phosphorylation of p47‐phox by protein kinase C or, in model systems, by addition of arachidonic acid to reconstitution mixtures. Following the docking process the electron‐transporting component is able to transfer electrons from NADPH to oxygen. This electrogenic event is charge‐compensated by the opening of a prton channel. Components of the oxidase are expressed in non‐phagocytes, where their function is uncretain but could be related to some signal function of superoxide. (shrink)

PDZ (also called DHR or GLGF) domains are found in diverse membraneassociated proteins including members of the MAGUK family of guanylate kinase homologues, several protein phosphatases and kinases, neuronal nitric oxide synthase, and several dystrophin‐associated proteins, collectively known as syntrophins. Many PDZ domain‐containing proteins appear to be localised to highly specialised submembranous sites, suggesting their participation in cellular junction formation, receptor or channel clustering, and intracellular signalling events. PDZ domains of several MAGUKs interact with the C‐terminal polypeptides of (...) a subset of NMDA receptor subunits and/or with Shaker‐type K+ channels. Other PDZ domains have been shown to bind similar ligands of other transmembrane receptors. Recently, the crystal structures of PDZ domains, with and without ligand, have been determined. These demonstrate the mode of ligand‐binding and the structural bases for sequence conservation among diverse PDZ domains. (shrink)

Cytokine receptors fall into two basic classes: those with their own intrinsic protein tyrosine kinase (PTK) domain, and those lacking a PTK domain. Nonetheless, PTK activity plays a fundamental role in the signal transduction processes lying downstream of both classes of receptor. It now seems likely that many of those cytokine receptors that lack their own PTK domain use members of the JAK family of PTKs to propagate their intracellular signals. Moreover, the involvement of the JAK (...) kinases in a newly defined pathway which links membrane receptors directly to the activation of nuclear genes, via latent cytoplasmic transcription factors known as STATs (for Signal Transducers and Activators of Transcription), appears to be a theme common to cytokine receptors of both classes. (shrink)

Adaptors are proteins of multi‐modular structure without enzymatic activity. Their capacity to organise large, temporary protein complexes by linking proteins together in a regulated and selective fashion makes them of outstanding importance in the establishment and maintenance of specificity and efficiency in all known signal transduction pathways. This review focuses on the structural and functional characterisation of adaptors involved in tyrosine kinase (TK) signalling. TK‐linked adaptors can be distinguished by their domain composition and binding specificities. However, such structural (...) classifications have proven inadequate as indicators of functional roles. A better way to understand the logic of signalling networks might be to look at functional aspects of adaptor proteins such as signalling specificity, negative versus positive contribution to signal propagation, or their position in the signalling hierarchy. All of these functions are dynamic, suggesting that adaptors have important regulatory roles rather than acting only as stable linkers in signal transduction. BioEssays 28: 465–479, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The vav proto‐oncogene encodes a 95 kDa protein which is expressed exclusively in hematopoietic cells. Analysis of the deduced amino acid sequence has revealed the presence of a src‐homology 2 (SH2) domain, 2 SH3 domains, a cysteine‐rich region with similarity to protein kinase C, and a region highly similar to proteins with guanine nucleotide exchange activity on ras‐like GTPases. Recent work has shown that vav is tyrosine phosphorylated in response to stimulation of surface membrane receptors in a variety (...) of hematopoietic cell lines. Vav may play a role in hematopoietic cell signaling by coupling tyrosine kinase pathways to ras‐like GTPases through the regulation of guanine nucleotide exchange. (shrink)

Rho, a member of the Ras superfamily of small GTPases, has multiple biological roles: it regulates signal trasduction pathways linking extracellular growth factors to the assembly of actin stress fibres and focal adhesion complexes; it is required for G1 progression and activates the SRF transcription factor when quiescent fibroblasts are stimulated to grow; and it plays a role later in the cell cycle during cytokinesis. Two groups have recently succeeded in identifying downstream effectors of Rho that may mediate some of (...) these biological effects. One protein identified by both groups is protein kinase N (PKN), a serine/threonine kinase whose catalytic domain is closely related to that of protein kinase C(1,2). (shrink)

Tumor suppressor genes represent a broad class of genes that normally function in the negative regulation of cell proliferation. Loss‐of‐function mutations in these genes lead to unrestrained cell proliferation and tumor formation. A fundamental understanding of how tumor suppressor genes regulate cell proliferation and differentiation should reveal important aspects of signalling pathways and cell cycle control. A recent report describing the Drosophila tumor suppressor gene warts has implications in the study of the human myotonic dystrophy gene(1). These genes encode (...) members of a cyclic AMP‐dependent protein kinase subfamily that includes other plant and animal orthologues. (shrink)

The mechanisms by which most receptor protein‐tyrosine kinases (RTKs) transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. This tidy picture has, however, some strange characters lurking around the edges. Cases have now been identified in which RTKs lack kinase activity, but, despite being “dead” appear to have roles in signal transduction. Even stranger are the cases in which genes (...) encoding RTKs produce protein products consisting of only a portion of the kinase domain. At least one such “fractured” RTK appears to be involved in signal transduction. Here we describe how these strange molecules might function and discuss the questions associated with their evolution. BioEssays 23:69–76, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

continent. 2.2 (2012): 155–158 Michel Serres. Biogea . Trans. Randolph Burks. Minneapolis: Univocal Publishing. 2012. 200 pp. | ISBN 9781937561086 | $22.95 Conveying to potential readers the significance of a book puts me at risk of glad handing. It’s not in my interest to laud the undeserving, especially on the pages of this journal. This is not a sales pitch, but rather an affirmation of a necessary work on very troubled terms: human, earth, nature, and the problematic world we made. (...) It is this world that aspirates the silence (so to speak), and therefore the subject which, along with the development of the “made world” exports the excess augmentation of the cosmically missing, this silence of the natural, et cetera. Had we learned from Locke that lesson of “labor,” to consume what we need… but perhaps we need more than what matters? Serres’ Biogea has several functions on this manner, if it is indeed a book to be consumed. First, readers searching for novelistic entertainment have a place to dwell. Biogea deserves a place in your back pocket; biographical generosity and poetic fluidity should satisfy most textual fetishes. For lay philosophers who want to refresh their acumen, Biogea deserves a place on the book shelf, one already reads a sorely needed postmodern tune-up here. Serres’ style is clearly French; he leaves few cheese crumbs on his words, rather preciseness and breathing in the work give way to a sweeping manner that breaks the narrative line of sight. A circular narrative and anachronistic fragmentation of terms allows an abyssal atmosphere to swell, if only to pump into the book the externality of its broader text. Biogea aspires to a higher standard and the book, at times, is thinking this negentropic problem too. Univocal, the publisher, has crafted a book appropriate for the hands to hold and the translations are an achievement of an otherwise difficult writer to translate. Terms are the conditions of a broader text. It is important to note that Serres’ content is as much a thinking of terminal ports. There is a regard for the transportation technology of the written word. For me, this is the mark of genius, a craftiness that tells of a book device that I may trust. Serres is an accomplished thinker and a necessary voice to check the putative trendiness of anti-postmodernist and market-driven theory of endless cultural liquidation. Offering interventions on subjectivity as an open system we are given a chance to affirm the human, not merely to discard it, but to engage its poetic image emotion, the calibratory silent sense of the analogic world; the terms on which we base our efforts. 1 The human is the center of its own negation, constantly mediating it. Something deeper at stake appears in the work then, and it is quite obvious from the onset. Certainly, a book is an intensification of possible text and those who brought this actual book into existence have captured a rarity in regards to the subject matter and artistic accomplishment. I mentioned terms as conditions, so let us understand Biogea as bio-yea, a yes to bios . An affirmation of living and accepting presence for all of its defiance of images, words, and things temporal. Therefore Serres’ existence and its existants plays parts; out of linearity and still like a porous bone pumping blood it manufactures into the fleshy life it becomes. Starting from a man named silence chaos emerges, or the man “Old Taciturn” takes up a journey anticipating a great flood. In other words, a development akin to the one in Genesis. In dealing with this ancestral occupation, fusing Genesis with contemporary philosophical terms, Serres initiates this anachronistic fragmentation under the forming subjectivity of his own autobiography. This mutation in the open system is precisely one of Serres’ terms. There an abyss is at work, stated, but also measured by heels on the ground—the abyss dispatching earthen tensions, that which plays our tunes, that which we abide by and recognize in volcanoes, rivers, oceans, earthquakes and weaponry in the battles of the world. Set in later stages of the book, such tensions are harnessed through scientific principles in an attempt to unify the terms of natural force if only to terminate the world. Thus the elevation of the earth into the world is clearly set forth. Here already, and few pages in, a resonance is set forth under appellations such as the river Garonne, a subjectivity as much as it is inhuman, the river is the inhuman that makes us human. I get the sense that Serres is taking up a challenge issued by Wallace Stevens; namely, that the great poems of heaven and hell have been written, but that only the poem of the earth has resisted composition. 2 On this level we cannot avoid the killing factor of silence, given that our cognition blocks its pure, radical obliteration. Thus a silence of attunement to the earth is in a novel dialectic of the rithmic and rhythm. A technological world, a triumph of termination is set forth. If a text imposes its will given the reader who authorizes it, it is made to convey or convect a presupposition to a reader or its inhabitant(s). Text is therefore both, in-content, contenting, contentedness, and in reading it, a way to navigate self-destruction (dis-content). Here then would one note that the “inhuman” reveals itself, “an aperiodic rhythm of lovers and beloved…the sea as our friend…but as our enemy…maternal vivifying sea.” The sea is an open book, or vaginal birth canal, where the engagement of text comes forth: “…woman sea, open vulva.” One sees like the sea, but only after it, when the uninhabitable truth of inhabiting it switches the polarity of the sailors soul: “I was seeing like the sea” (9-11). In other words, we are invited to embrace the nonsense of the visible. At this point I am taken to Jean-François Lyotard’s work The Inhuman , specifically the first entry on negentropy that would be congruent with Serres’ thematic. 3 The human being exports, deports, or transplants its relation through text, through the system— and this is its sense or relation to silence, to music. Unaware of Serres’ proximity to this work, the concept of gender interrelation as regards a solar catastrophe runs clear. It would be, on this basis, that Serres references his peers, the other texts that, as mentioned above, are discarded in philosophy today. For students of philosophy what we have here is perhaps a gift, a needed project. If silence and death are at work, there is a political valence to deal with, and here, much like the domain of the text and the dominion of the reader, we confront the world of natural, fluid violence. The anti-postmodernist critique is in part based on a weak idea that the loss of ideology, of a world vision, motivates the “correlationist” project. 4 Serres seems to offer another way to view this when he notes that whereas persons “sometimes kill,” it is clearly “the collective” that “always kills” (17). What is the collective today, if not an organizing function we never see yet acts in its favor in the name of truth? One feels a sense of enigma here, if only to link to what Stevens remarked of communism as a “grubby faith,” providing this applies for capitalism as well, namely any ideology of progress overly interested in absolutes. Here we get the sense that the inhuman, silence, this type of killing, always killing, could not be matched by human-made, political dynamos. Or that if it comes to an equilibrium, a catastrophe is never too far from us to read with our heels. We are left to note that the forces of nature presuppose and permeate political systems, the more these systems obtain force, the more the system takes upon itself the proper name of nature that motivates its dissemination, albeit falsely. This note, that in an age of ecocide and technological captivity (sustainability and transparency) political regimes won’t grow our soul-learning ears any larger than our tongues, stands clear to us. The promise of technological desubjectification is here pushed aside. Regarding politics, Serres illustrates this fact: Where did this corpse come from? Who was it? Who killed it? I don’t know. I won’t try to find out. I refuse to get vengeance for it. And I only see Garonne. For our victims, today, are the rivers, too. Their waters have irrigated my life, enchanted my thought, invigorated my body; I’ve known them to be threatening, untamable, as dangerous as the sea when it rages. Yes, murderous. They decided to control their courses; dams, sometimes senseless, destroying sites and valleys, reduced entire populations to servile displacements; programs for the irrigation of thirsty farmland, often beneficial of course, completed their drying up.(22) Serres enters into his idea concerning the captivity of language from the natural into a world system: For thousands of years, we have been licking things with our tongues, covering and daubing them so as to appropriate things for ourselves. If language boils down to a convention, this convention took place between the speakers without consulting the thing named, become as a result the property of those who covered it in this way with their drawn or voiced productions. Malfeasance analyzes these acts of appropriation. Thus every inert object, every living thing as well, sleeps under the covers of signs, a little in the way that, today, a thousand posters shouting messages and ugly riots of color drown, with their filthy flood, the landscapes, or better, exclude them from perception because the meaning, almost nil, of this false language and these base images forms an irresistible source of attraction to our neurons and eyes. This appropriation covers the world’s beauty with ugliness. (38-39) Technological concealment coming to bear, we begin to get a sense of another commentary on the condition of sensing, driving home the necessity of a text dealing with such subject matter to be what its terms insist. Thus toward new openings: The new opening. As low beneath our feet as you like, the Biogea opens us to another space, high enough for us to be able to acquire a wisdom there, that of redeveloping this same place differently from our fathers, this place that’s still politically cut up by old hatreds, beneath the flood of tears and blood that we call history. Without this soft place, spiritually very old, but newly conceived in this way, without the juridical construction of a common good, opposed to our filthy ownership, I don’t see how our planet, hard, will survive. Hardness that depends on a softness, material belonging that depends on this temporary rented location (51). Serres enters into a summit on the content and the structure of his work. Archimedes is brought in with the concept of three volcanoes. Meaning fire, but as well earth, water, air. For it was Archimedes’ war machines that sought to lift the earth, thus bringing in the question of principles of science: “can a principle be invented while controlling its consequences?” (66-7). May the earth be put in a sentence, terminated by terminology, appellations, gone wild? By means of these element-dominating laws, this old physicist began to tear nature away from the ancient myths; by a strange return, today we’re plunging our successes back into the anxieties and terrors from which that ancient physics was born. Yes, our new history of science and technology is plunging, today, as though in a loop, into the fundamental human myths from which Empedocles’ first laws came. A major progression and a regression on the nether side of the origins. Consequently, the contemporary time requires that we try to return to that unity in which the principles of hate and love are at the same time human, living, inert and global. We will never attain a deontology of our knowledge and actions without thinking the subjective, the objective, the collective, and the cognitive all together simultaneously. Here, hate and love are the result of these four components.(71) Working then on the concept of fire-starting mirrors to the atomic annihilation of the Second War, Serres works into the subjectivity in question on the matter of rhythm—say rithmic— precisely at that point: Knowledge is changing today. The all-political is dying; the monarchy of the sciences said to be hard is coming to a close. The science of the things of the world will have to communicate just as much as the things of the world do, which do it much better than humans do, who don’t always want to do it. Let’s celebrate two changes this morning. The first one strikes a new blow to our narcissism. No, knowledge and the world don’t resemble our analytical enjoyments of refined cutting up, of endless debates and of exclusions full of hate. They, on the contrary, form a bloc and a sum, alliance and alloys. Uniting the fields of knowledge among themselves the way the things are connected among themselves, the second newness puts into place sets united by interlacing, webs and simplexes that combine with the things of the world, themselves combined, the combined knowledge that understands them.(130-1) Biogea closes on its opening flood thematic, approaching the initial telos of Genesis. Here the trees are brought into a position with atmosphere, the opaque abyssal reservoir, the tomb of the sun, sea in the polarity of the earthen heaven and hell. The poem of the earth then is silent but deadly, indeed, as funny as that phrase is, mainly a tomb gas. The meaning of the living and the non-meaning of things converge in the muteness of the world; this meaning and non-meaning plunge there and come out, the ultimate eddy. Mundus patet: through a fissure, through an opening, a fault, a cleft come noises, calls as small as these apertures. I’m listening, attentive, I’m translating, I’m advancing in the scaled-down meaning and science. Mundus patet: should the world open greatly, it will launch me into its silence. The totality remains silent. Knowledge expanded in elation. White origin of meaning, fountain of joy. (198) Final Remarks One test of a review is the long term trajectory the referee thinks the book will have. I see Serres’ text lending greatly into the vision of Biogea . In fact, in the vision of the novel inquiries of Stephen Jay Gould’s work there is something to be thought on the level of the individual and the species; namely, that humanity and its uniqueness is in its deferral, its thinking and naming, a thinking surrounded by silence that filters into everything, that pulls us through the world, the kinetic pulse we recognize, and all of that we cleave away in the base philosophical maxim of difference itself. Unique individuals are spatial creatures: we dwell, and we ought to get good at it. Yet this is an imaginative space that, if you are crazy enough to believe it, de-term-ine the conditions of its own terms. That is why we are not merely creating spaces on the acceleration of time, or so this ignoramus thinks, to accidentally transcend. Imagination already has this insatiable silence that we drink up and fail to manifest. Space is timeless. The imagination itself, shared by humans for themselves, their objects, and the species as a whole, is a non-defined space of relation; a whole human trajectory as part of nature, and part of worlds that are the other side of thinking nature, the consequence of it, at least our attempt to do so. Our survival is based on our deliberation, our caution, our natural deconstructive sense toward this silence that is already part of the song, sung, singing of this century without end. Good books will let us inhabit this space and recognize a form of life. Serres’ text moves toward dwelling, as noted, in masterful and accessible ways. The pitched battles are the falling replays of anemic and dead politics. As soon as we realize there is humanity, we may be able to enjoy the end of it, our inhuman capability of listening to silence. NOTES 1. See Michel Serres. The Parasite . Minneapolis: University of Minnesota Press. 2007. 2. Wallace Stevens, “Imagination as Value” [ca. 1945], in Collected Poetry and Prose . New York: The Library of America. 1997. 724-39. 3. Jean-François Lyotard. The Inhuman: Reflections on Time . Trans. Geoffrey Bennington & Rachel Bowlby. Stanford, CA: Stanford University Press. 1992. 4. See the introduction: Quentin Melliassoux. After Finitude: An Essay on the Necessity of Contingency . Trans. Ray Brassier. New York: Continuum. 2008. EDITOR'S NOTE: This review was updated on August 8, 2012. Substantial edits include block quotes from the book under review as well as the inclusion of comments from the author. (shrink)

La grande majorité des Églises protestantes de tradition luthérienne et réformée admettent aujourd’hui, sans restriction, les femmes au pastorat. La proportion des femmes parmi les pasteurs augmente au fil des ans ; elle est de 15 % en France aujourd’hui. Sur la base des premiers résultats d’une enquête qualitative et quantitative effectuée auprès des pasteures, en 1995-1998, cet article montre que la féminisation du pastorat représente une étape supplémentaire dans un processus de sécularisation et de professionnalisation du rôle du clerc. (...) Cette étape se traduit par une évolution du pastorat dans deux domaines : le passage d’un rôle didactique et d’autorité à un rôle d’accompagnement et d’écoute et, d’autre part, la plus grande distinction entre vie professionnelle et vie privée. (shrink)

Harmony Search Algorithm (HSA) is an evolutionary algorithm which mimics the process of music improvisation to obtain a nice harmony. The algorithm has been successfully applied to solve optimization problems in different domains. A significant shortcoming of the algorithm is inadequate exploitation when trying to solve complex problems. The algorithm relies on three operators for performing improvisation: memory consideration, pitch adjustment, and random consideration. In order to improve algorithm efficiency, we use roulette wheel and tournament selection in memory consideration, replace (...) the pitch adjustment and random consideration with a modified polynomial mutation, and enhance the obtained new harmony with a modified β-hill climbing algorithm. Such modification can help to maintain the diversity and enhance the convergence speed of the modified HS algorithm. β-hill climbing is a recently introduced local search algorithm that is able to effectively solve different optimization problems. β-hill climbing is utilized in the modified HS algorithm as a local search technique to improve the generated solution by HS. Two algorithms are proposed: the first one is called PHSβ–HC and the second one is called Imp. PHSβ–HC. The two algorithms are evaluated using 13 global optimization classical benchmark function with various ranges and complexities. The proposed algorithms are compared against five other HSA using the same test functions. Using Friedman test, the two proposed algorithms ranked 2nd (Imp. PHSβ–HC) and 3rd (PHSβ–HC). Furthermore, the two proposed algorithms are compared against four versions of particle swarm optimization (PSO). The results show that the proposed PHSβ–HC algorithm generates the best results for three test functions. In addition, the proposed Imp. PHSβ–HC algorithm is able to overcome the other algorithms for two test functions. Finally, the two proposed algorithms are compared with four variations of differential evolution (DE). The proposed PHSβ–HC algorithm produces the best results for three test functions, and the proposed Imp. PHSβ–HC algorithm outperforms the other algorithms for two test functions. In a nutshell, the two modified HSA are considered as an efficient extension to HSA which can be used to solve several optimization applications in the future. (shrink)

There is increasing evidence to suggest that cytoplasmic tyrosine kinases of the Src family have a pivotal role in the regulation of a number of cellular processes. Members of this family have been implicated in cellular responses to a variety of extracellular signals, such as those arising from growth factors and cell‐cell interactions, as well as in differentiative and developmental processes in both vertebrates and invertebrates. A better understanding of the regulation and of the structure‐function relationships of these enzymes might (...) aid in the development of specific ways to interfere with their action, as well as serving as a paradigm for regulation of other protein tyrosine kinases that have SH2 and SH3 domains. In this review we will first discuss the regulation of Src family protein tyrosine kinases, with particular emphasis on their SH2 and SH3 domains. We will then briefly review other non‐receptor protein tyrosine kinases that have SH2 and SH3 domains. (shrink)

La notion d’expérimentation, initialement réservée au domaine des sciences expérimentales, est employée aujourd’hui pour qualifier de multiples pratiques sociopolitiques : gouvernementales, activistes ou artistiques. Cette extension des usages du terme manifeste l’influence de l’imaginaire des pratiques de recherche expérimentale sur les conceptions contemporaines du politique. Elle accompagne des mutations du parler et de l’agir politiques qu’il importe de mieux caractériser, au confluent de la raison scientifique et technique et des transformations de l’espace public.Experimentation, which initially concerned only the experimental (...) sciences field, is a term now used to describe a great many forms of socio-political practice, for example among governments, activists or artists. This extension of the term’s usage illustrates the influence of imagination in experimental research on contemporary conceptions of politics. It is supporting changes in the patterns of political speech and action that need to be better characterised, as they are occurring at the point where scientific and technical reason meets the transformation of the public sphere. (shrink)

As an alternative dispute resolution procedure, Domain Name Arbitration addresses not only contentions regarding the ownership of web pages, but also infringements of the Intellectual Property law such as cyber squatting or Internet piracy. In this spirit, panelists of the World Intellectual Property Organization enact law in accordance with what the involved parties provide them as burden of proof. Following this line of thought, we can assume that one party may remain unrepresented when it is not able to accomplish (...) legal procedures successfully. Nevertheless, does this kind of asymmetry always function in the way that we presume? This paper sets out to study how WIPO panelists tackle knowledge asymmetries when being manifested in Domain Name Arbitration. In particular, this paper concentrates on comparing two Domain Name Arbitration processes in which knowledge asymmetries play a significant role in the panelist’s final-and legally binding- decision. This analysis also examines how specific text-internal features give us a hint of unbalanced relationships between the Complainant and the Respondent of a Domain Name Arbitration process. It endeavors, thus, to understand how lexical, rhetorical-grammatical and discursive features work within discourse and may reach to influence the communicative act itself. Following Vijay K. Bhatia’s critical discourse analysis as main theoretical framework, this paper tries to comprehend the role asymmetries play in enacting Domain Name law. (shrink)

Hermeneutic rationality arises from the idea that experience is a cumulative process, in which differences are not eliminated but preserved. The universality which derives from this process is an “intensional universality”, which follows a law of direct proportionality between extension and intension: the more an educated individual enriches her experiences, the more she is able to universalize her understanding of others. Experience is then inevitably open and never closed, that is, free for other experiences. If we use the word “ (...) class='Hi'>domain” to describe the condition of a closed and predetermined system or ontology, the entities of which are pre-assumed, we can therefore call this open universality a “universality without domain”.This description of hermeneutical experience leads to a question about its logical and ontological presuppositions. In the second part of the paper I refer to a particular practice which is central for hermeneutical theory in order to show how I understand these presuppositions: the practice of translation. In translation we experience the impossibility of rendering completely the sense of the source language in a target language, that is, we experience a difference which cannot be suppressed. I compare this experience to the discovery of the incommensurable magnitudes in ancient Greek mathematics, a discovery that shook Parmenidean and Pythagorean ontology: in my opinion, philosophical hermeneutics more or less implicitly develops the consequences of this incredible discovery, which marks the passage to a differential, comparative and integrative rationality and ontology. (shrink)

The protein tyrosine kinase activity of the v‐abl oncogene has been demonstrated to subvert the normal second messenger systems used by lymphoid cells for growth and differentiation. Transformation of bone marrow with the Abelson murine leukemia virus results in the appearance of B cell lineage cells arrested at the pre‐B cell stage. Recent reports have characterized these cells expressing high v‐abl kinase activity as deficient in detectable NF‐kB DNA binding activity and low level RAG gene expression. These observations (...) suggest that v‐abl may be inhibiting the differentiation of B cells by blocking these two crucial elements in the maturation pathway. (shrink)

James Franklin has argued that the formal, mathematical sciences of complexity — network theory, information theory, game theory, control theory, etc. — have a methodology that is different from the methodology of the natural sciences, and which can result in a knowledge of physical systems that has the epistemic character of deductive mathematical knowledge. I evaluate Franklin’s arguments in light of realistic examples of mathematical modelling and conclude that, in general, the formal sciences are no more able to guarantee certainty (...) than the natural sciences. Yet the formal sciences are characterized by a ‘domain-independence’ that is philosophically interesting, and I argue that it is this property that Franklin actually employs to distinguish the formal from the natural sciences. I use Einstein’s ‘principle’/‘constructive’ theory distinction to contrast the domain-independence of physical theories with the domain-independence of formal mathematical theories, and show how both kinds of domain-independence function to generate the domain-independence that is observed in the complex systems sciences. © 1999 Elsevier Science Ltd. All rights reserved. (shrink)

Bacteria are able to induce defense and DNA repair systems that specifically counteract the toxic effects of some important natural agents. «Adaptive responses» to alkylation and oxidation damage have revealed novel strategies for escape from certain kinds of genetic damage.

At this time when the development of synthetic biology and artificial intelligence are changing the world around us, philosophers and scientists, first of all, must converge to analyze the present and predict the ethical-social consequences and biological dangers associated with new “living entities” that are not the result of the natural evolutionary process. As synthetic/artificial life forms (xenobots, robots, transgenic organisms, etc.) become more and more abundant and sophisticated, it seems first of all necessary to bring some order to all (...) this new biodiversity, establishing what is alive and what is not, and analyzing the consequences of this incessant creative activity. Here I intend to organize all these human-made entities and clarify their status as living beings or artificial elements, leaving the door open to an uncertain future in which we will be able to see how “the artificial” and “the natural” could merge to originate something different from everything known. Accordingly, I propose the creation of a new domain, Lithbea, which includes all synthetic and artificial entities within a new kingdom called Humade (derived from human-made). I have also included viruses in a new realm, the Viral kingdom, because they were excluded from the classical three-domain tree of life despite playing a fundamental role in the evolution of biodiversity on Earth. Finally, I make a brief comment on the unpredictability of the unknown, the implications of this new landscape of biodiversity, and the uncertain future of all these advances. (shrink)

Aphrodite, tout en présidant à la sexualité et à l’éros, est une puissance divine aux multiples facettes exerçant aussi son action dans d’autres domaines. Depuis l’époque archaïque, Aphrodite et Arès constituent un couple bien établi au sein du panthéon de la Grèce ancienne. Cette association avec le dieu guerrier, attestée à la fois dans les récits mythiques et dans les cultes, se révèle solidaire d’autres données concernant les prérogatives politiques et militaires d’Aphrodite. L’examen de ce dossier nous invite à remettre (...) en question le portrait canonique d’Aphrodite en tant que « déesse de l’amour » et à repenser son rapport avec le dieu de la guerre autrement qu’en termes d’opposition complémentaire. Aphrodite, loin d’être exclue de l’univers de la guerre, y contribue efficacement et peut susciter elle-même « le désir de la bataille ». Aussi, à l’intersection du domaine d’Aphrodite avec celui d’Arès, des liens se nouent entre l’éros et la fureur guerrière.Aphrodite in the world of Ares. Elements for a dialogue between myth and cult. Aphrodite, the goddess governing sexuality and eros, is a deity with a large and multi-facetted sphere of action. Since archaic times, Aphrodite and Ares have constituted a well-established couple within the pantheon of ancient Greece. The association with the warrior god, attested both in myth and cult, is consistent with other evidence regarding Aphrodite’s political and military prerogatives. All of this prompts us to question Aphrodite’s canonical portrait as the “goddess of love” and to rethink her relationship with the “god of war” in terms other than those of complementary opposition. Aphrodite, far from being excluded from the world of war, contributes to it effectively in many different ways and is able to arouse “the desire for battle”. At the intersection of Aphrodite’s realm with that of Ares, links are woven between eros and fighting fervour. (shrink)

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and function. The latter point (...) is of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

Birds produce different types of sounds in different contexts such as begging for food in youngsters, alerting to a danger, defending a territory or attracting a sexual partner. About half of the bird species are able to transform their vocalizations through imitation, improvisation or invention of sounds. Here we review the different experimental procedures that have been used to study the learning capacities of birds in the vocal domain and in the auditory domain, with a particular emphasis on (...) recent technological developments. Nowadays, it is possible to record individual vocalizations of birds living in social groups or to record continuously the vocal ontogeny of birdsong. In conditioning experiments, new paradigms have successfully replaced food rewards with a socio-sexual reward. It is possible to engage in vocal interactions with a bird using dedicated computer systems. In both the laboratory and more recently in the field, different techniques have been used to train young oscine songbirds to learn from acoustic models. The use of virtual social environments and robots as social agents are also promising avenues. All together, these new techniques will permit researchers to explore more deeply the umwelt of bird species. (shrink)

During the fifteenth century the organic body politic metaphor was gradually associated or superseded by a physiological paradigm built on the ancient humoral theory. The new body politic, based on humours rather than on organs, eventually became a dynamic and fluid entity. Authors such as Nicole Oresme or Jean Gerson alleged that the etiology of humoral imbalance had its origins in growing social inequalities; Claude de Seyssel subsequently urged that the cure to restore the humoral balance should focus on creating (...) new hope and bridges for the gifted. Seyssel was able to draw up his pioneering manifesto for social mobility thanks to the new physiological image of the civic body. The present study argues that such a physiological conception transformed anxiety about motion and disarray into a belief that social fluidity was indispensable to the well-being and health of the whole body, but the idea that (social) order and movements are not conflicting, was soon eradicated by new perspectives on nobility constructed on race and blood. (shrink)

Protein–protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein–protein recognition mechanism, mediated by disordered regions longer than 20–30 residues. Bioinformatics predictions and well‐characterized examples, such as the kinase‐inhibitory domain of Cdk inhibitors and the Wiskott–Aldrich syndrome protein (WASP)‐homology (...) domain 2 of actin‐binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains. (shrink)

Protein–protein interactions are thought to be mediated by domains, which are autonomous folding units of proteins. Recently, a second type of interaction has been suggested, mediated by short segments termed linear motifs, which are related to recognition elements of intrinsically disordered regions. Here, we propose a third kind of protein–protein recognition mechanism, mediated by disordered regions longer than 20–30 residues. Bioinformatics predictions and well‐characterized examples, such as the kinase‐inhibitory domain of Cdk inhibitors and the Wiskott–Aldrich syndrome protein (WASP)‐homology (...) domain 2 of actin‐binding proteins, show that these disordered regions conform to the definition of domains rather than motifs, i.e., they represent functional, evolutionary, and structural units. Their functions are distinct from those of short motifs and ordered domains, and establish a third kind of interaction principle. With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains. (shrink)

The article investigates the sociocultural implications of the changing modern workplace and of pharmacological cognitive enhancement as a potential adaptive tool from the viewpoint of social niche construction. We will attempt to elucidate some of the sociocultural and technological trends that drive and influence the characteristics of this specific niche, and especially to identify the kind of capabilities and adaptations that are being promoted, and to ascertain the capabilities and potentialities that might become diminished as a result. In this context, (...) we will examine what PCE is, and how and why it might be desirable as a tool for adaptation within the workplace. As human beings are, or at least should be allowed to be, more than merely productive, able-bodied and able-minded workers, we will further examine how adaptation to the workplace niche could result in problems in other domains of modern societal life that require the same or other cognitive capabilities. In this context we will also focus on the concept of responsibility and how it pertains to PCE and the modern workplace niche. This will shed some light on the kind of trends related to workplace niche construction, PCE and capability promotion that we can expect in the future, and on the contexts in which this might be either beneficial or detrimental to the individual as a well-rounded human being, and to other members of society. (shrink)

Confronted with problems or situations that do not yield toknown theories and world views, scientists and students are alike. Theyare rarely able to directly build a model or a theory thereof. Rather,they must find ways to make sense of the circumstances using theircurrent knowledge and adjusting what is recognized in the process. Thisway of thinking, using past ways of perceiving the physical world tobuild new ones does not follow a logical path and cannot be described astheory revision. Likewise, in many (...) situations it is awkward, indeedoften impossible, to resort to analogical reasoning to account for it.This paper presents a new mechanism, called `tunnel effect', that mayexplain, in part, how scientists and students reason while constructinga new conceptual domain. `Tunnel effect' is also contrasted withanalogical reasoning. (shrink)

Within critical realist circles, the development of knowledge in the natural and social domains has thus far been much stronger by comparison with its respective development within the personal domain. What I want to explore here is how knowledge can be positively used to have emancipatory effects at the level of the individual. The way in which we are able to achieve this is by coming to have what Spinoza calls more adequate ideas of ourselves, other beings, and our (...) place in nature through strengthening the explanatory power and minimizing the fallibility of the knowledge we use in our judgements and progressive articulations of personal situations by making use of explanatory critique and cause-object matching techniques. This article explains what an explanatory critique actually is and does before turning to explain why it interests us in relation to Spinoza’s thought and then how it is specifically useful in connection with emotional revision and control. (shrink)

Global health is by definition and necessity a collaborative field; one that requires diverse professionals to address the clinical, biological, social, and political factors that contribute to the health of communities, regions, and nations. While much work has been done in recent years to define the field of global health and set forth discipline-specific global health competencies, less has been done in the area of interprofessional global health education. This paper documents the results of a roundtable that was convened to (...) study the need for an interprofessional team skills competency domain for global health students. The paper sets forth a preliminary set of team competencies based on existing scholarship and the results of the roundtable. Once an agreed upon set of competencies is defined, a valuable next task will be development of a model curriculum to teach team skills to students in global health. The preliminary competencies offered in this paper represent a good first step toward ensuring that global health professionals are able to collaborate effectively to make the field as cohesive and collaborative as the mighty task of global health demands. (shrink)