Biological order provided by α-helical secondary protein structures is an important resource exploitable by living organisms for increasing the efficiency of energy transport. In particular, self-trapping of amide I energy quanta by the induced phonon deformation of the hydrogen-bonded lattice of peptide groups is capable of generating either pinned or moving solitary waves following the Davydov quasiparticle/soliton model. The effect of applied in-phase Gaussian pulses of amide I energy, however, was found to be strongly dependent on the site of (...) application. Moving solitons were only launched when the amide I energy was applied at one of the α-helix ends, whereas pinned solitons were produced in the α-helix interior. In this paper, we describe a general mechanism that launches moving solitons in the interior of the α-helix through phase-modulated Gaussian pulses of amide I energy. We also compare the predicted soliton velocity based on effective soliton mass and the observed soliton velocity in computer simulations for different parameter values of the isotropy of the exciton-phonon interaction. The presented results demonstrate the capacity for explicit control of soliton velocity in protein α-helices, and further support the plausibility of gradual optimization of quantum dynamics for achieving specialized protein functions through natural selection. (shrink)

Protein α-helices provide an ordered biological environment that is conducive to soliton-assisted energy transport. The nonlinear interaction between amide I excitons and phonon deformations induced in the hydrogen-bonded lattice of peptide groups leads to self-trapping of the amide I energy, thereby creating a localized quasiparticle (soliton) that persists at zero temperature. The presence of thermal noise, however, could destabilize the protein soliton and dissipate its energy within a finite lifetime. In this work, we have computationally solved the system (...) of stochastic differential equations that govern the quantum dynamics of protein solitons at physiological temperature, T=310 K, for either a single isolated α-helix spine of hydrogen bonded peptide groups or the full protein α-helix comprised of three parallel α-helix spines. The simulated stochastic dynamics revealed that although the thermal noise is detrimental for the single isolated α-helix spine, the cooperative action of three amide I exciton quanta in the full protein α-helix ensures soliton lifetime of over 30 ps, during which the amide I energy could be transported along the entire extent of an 18-nm-long α-helix. Thus, macromolecular protein complexes, which are built up of protein α-helices could harness soliton-assisted energy transport at physiological temperature. Because the hydrolysis of a single adenosine triphosphate molecule is able to initiate three amide I exciton quanta, it is feasible that multiquantal protein solitons subserve a variety of specialized physiological functions in living systems. (shrink)

Three apparently unrelated developmental processes – mammalian myogenesis, the choice of neural fate and sex determination in Drosophila – are controlled by a common mechanism. Most of the genes governing these processes encode transcriptional factors that contain the helix‐loop‐helix (HLH) motif. This domain mediates the formation of homo‐ or heterodimers that specifically bind to DNA through a conserved basic region adjacent to the HLH motif. Dimers differ in their affinity for DNA and in their ability to activate transcription (...) from HLH binding‐site containing promoters. In addition, the activity of HLH proteins is inhibited by dimerization with another class of HLH proteins that lack a basic domain entirely or have an altered one. These structural properties provide a molecular mechanism to explain the synergistic and antagonistic functional relations among the HLH encoding genes that control several developmental pathways. (shrink)

ABSTRACT Rosalind Franklin is best known for her informative X-ray diffraction patterns of DNA that provided vital clues for James Watson and Francis Crick's double-stranded helical model. Her scientific career did not end when she left the DNA work at King's College, however. In 1953 Franklin moved to J. D. Bernal's crystallography laboratory at Birkbeck College, where she shifted her focus to the three-dimensional structure of viruses, obtaining diffraction patterns of Tobacco mosaic virus (TMV) of unprecedented detail and clarity. During (...) the next five years, while making significant headway on the structural determination of TMV, Franklin maintained an active correspondence with both Watson and Crick, who were also studying aspects of virus structure. Developments in TMV research during the 1950s illustrate the connections in the emerging field of molecular biology between structural studies of nucleic acids and of proteins and viruses. They also reveal how the protagonists of the “race for the double helix” continued to interact personally and professionally during the years when Watson and Crick's model for the double-helical structure of DNA was debated and confirmed. (shrink)

The hardest part of replicating a genome is the beginning. The first step of DNA replication (called “initiation”) mobilizes a large number of specialized proteins (“initiators”) that recognize specific sequences or structural motifs in the DNA, unwind the double helix, protect the exposed ssDNA, and recruit the enzymatic activities required for DNA synthesis, such as helicases, primases and polymerases. All of these components are orderly assembled before the first nucleotide can be incorporated. On the occasion of the 50th anniversary (...) of the discovery of the DNA structure, we review our current knowledge of the molecular mechanisms that control initiation of DNA replication in eukaryotic cells, with particular emphasis on the recent identification of novel initiator proteins. We speculate how these initiators assemble molecular machines capable of performing specific biochemical tasks, such as loading a ring‐shaped helicase onto the DNA double helix. BioEssays 25:1158–1167, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Certain sequences of double‐helical DNA can be recognized and tightly bound by oligonucleotides. The effects of such triple‐helical structures on DNA binding proteins have been studied. Stabilities of DNA triple‐helices at or near physiological conditions are sufficient to inhibit DNA binding proteins directed to overlapping sites. Such proteins include restriction endonucleases, methylases, transcription factors, and RNA polymerases. These and Other results suggest that oligonucleotide‐directed triple‐helix formation could provide the basis for designing artificial gene repressors. The general question of whether (...) biological systems employ RNA molecules for recognition and regulation of double‐helical DNA is discussed. (shrink)

The essential biological processes that sustain life are catalyzed by protein nano-engines, which maintain living systems in far-from-equilibrium ordered states. To investigate energetic processes in proteins, we have analyzed the system of generalized Davydov equations that govern the quantum dynamics of multiple amide I exciton quanta propagating along the hydrogen-bonded peptide groups in α-helices. Computational simulations have confirmed the generation of moving Davydov solitons by applied pulses of amide I energy for protein α-helices of varying length. The stability (...) and mobility of these solitons depended on the uniformity of dipole-dipole coupling between amide I oscillators, and the isotropy of the exciton-phonon interaction. Davydov solitons were also able to quantum tunnel through massive barriers, or to quantum interfere at collision sites. The results presented here support a nontrivial role of quantum effects in biological systems that lies beyond the mechanistic support of covalent bonds as binding agents of macromolecular structures. Quantum tunneling and interference of Davydov solitons provide catalytically active macromolecular protein complexes with a physical mechanism allowing highly efficient transport, delivery, and utilization of free energy, besides the evolutionary mandate of biological order that supports the existence of such genuine quantum phenomena, and may indeed demarcate the quantum boundaries of life. (shrink)

The discovery of conserved protein domains found in many Drosophila and mammalian developmental gene products suggests that fundamental developmental processes are conserved throughout evolution. Our understanding of development has been enhanced by the discovery of the widespread role of the homeodomain (HD). The action of HD‐containing proteins as transcriptional regulators is mediated through a helix‐turn‐helix motif which confers sequence specific DNA binding. Unexpectedly, the well conserved structural homology between the HD and the prokaryotic helix‐turn‐helix proteins (...) contrasts with their divergent types of physical interaction with DNA. A C‐terminal extension of the HD recognition helix has assumed the role that the N‐terminus of the prokaryotic helix plays for specification of DNA binding preference. However, the HD appears also capable of recognizing DNA in an alternative way and its specificity in vivo may be modified by regions outside the helix‐turn‐helix motif. We propose that this intrinsic complexity of the HD, as well as its frequent association with other DNA binding domains, explains the functional specificity achieved by genes encoding highly related HDs. (shrink)

An interplay between DNA‐dependent biological processes appears to be crucial for cell viability. At the molecular level, this interplay relies heavily on the communication between DNA‐bound proteins, which can be facilitated and controlled by the dynamic structure of double‐stranded DNA. Hence, DNA structural alterations are recognized as potential tools to transfer biological information over some distance within a genome. Until recently, however, direct evidence for DNA structural information as a mediator between cellular processes was lacking. This changed when the concept (...) of transient waves of DNA supercoiling, induced by proteins tracking along the right‐handed DNA double helix, came into the limelight. Indeed, a number of observations now suggest that helix tracking‐induced DNA structural information might be exploited to participate in the regulation of a variety of DNA transactions in vivo. (shrink)

Macromolecular protein complexes catalyze essential physiological processes that sustain life. Various interactions between protein subunits could increase the effective mass of certain peptide groups, thereby compartmentalizing protein α-helices. Here, we study the differential effects of applied massive barriers upon the soliton-assisted energy transport within proteins. We demonstrate that excentric barriers, localized onto a single spine in the protein α-helix, reflect or trap three-spine solitons as effectively as concentric barriers with comparable total mass. Furthermore, wider (...) class='Hi'>protein solitons, whose energy is lower, require heavier massive barriers for soliton reflection or trapping. Regulation of energy transport, delivery and utilization at protein active sites could thus be achieved through control of the soliton width, or of the effective mass of the protein subunits. (shrink)

Saethre‐Chotzen syndrome (SCS), a human autosomal dominant condition with limb defects and craniosynostosis, is caused by haploinsufficiency of TWIST1, a basic helix–loop–helix (bHLH) transcription factor. Until recently, the molecular pathogenesis of the limb defects in SCS has not been well understood. Now, Firulli et al.1 show in mouse and chick that ectopic expression of a related bHLH protein, Hand2, results in phenocopies of the limb defects caused by Twist1 loss‐of‐function mutations. These two proteins interact in a dosage‐dependent (...) antagonistic manner, and both can be regulated through phosphorylation at conserved helix I amino acid residues. These findings provide an important link between the misregulation of Twist1 dimerization and the limb phenotypes observed in SCS. BioEssays 27:1102–1106, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Resistance to inhibitors of cholinesterase 8A (Ric‐8A) is a prominent non‐receptor GEF and a chaperone of G protein α‐subunits (Gα). Recent studies shed light on the structure of Ric‐8A, providing insights into the mechanisms underlying its interaction with Gα. Ric‐8A is composed of a core armadillo‐like domain and a flexible C‐terminal tail. Interaction of a conserved concave surface of its core domain with the Gα C‐terminus appears to mediate formation of the initial Ric‐8A/GαGDP intermediate, followed by the formation of (...) a stable nucleotide‐free complex. The latter event involves a large‐scale dislocation of the Gα α5‐helix that produces an extensive primary interface and disrupts the nucleotide‐binding site of Gα. The distal portion of the C‐terminal tail of Ric‐8A forms a smaller secondary interface, which ostensibly binds the switch II region of Gα, facilitating binding of GTP. The two‐site Gα interface of Ric‐8A is distinct from that of GPCRs, and might have evolved to support the chaperone function of Ric‐8A. (shrink)

The structures of protein and DNA were discovered primarily by means of synthesizing component-level information about bond types, lengths, and angles, rather than analyzing X-ray diffraction photographs of these molecules. In this paper, I consider the synthetic and analytic approaches to exemplify alternative heuristics for approaching mid-twentieth-century macromolecular structure determination. I argue that the former was, all else being equal, likeliest to generate the correct structure in the shortest period of time. I begin by characterizing problem solving in these (...) cases as proceeding via the elimination of candidate structures through the successive application of component-level information and interpretations of X-ray diffraction photographs, each of which serves as a kind of constraint on structure. Then, I argue that although each kind of constraint enables the elimination of a considerable proportion of candidate structures, component-level constraints are significantly more likely to do so correctly. Thus, considering them before X-ray diffraction photographs is a better heuristic than one that reverses this order. Because the synthetic approach that resulted in the determination of the protein and DNA structures exemplifies such a heuristic, its use can help account for these discoveries. (shrink)

Stomata are microscopic pores on the surface of land plants used for gas and water vapor exchange. A pair of highly specialized guard cells surround the pore and adjust pore size. Studies in Arabidopsis have revealed that cell–cell communication is essential to coordinate the asymmetric cell divisions required for proper stomatal patterning. Initial research in this area identified signaling molecules that negatively regulate stomatal differentiation. However, genes promoting cell‐fate transition leading to mature guard cells remained elusive. Now, three closely related (...) basic helix–loop–helix (bHLH) proteins, SPEECHLESS, MUTE and FAMA have been identified as positive regulators that direct three consecutive cell‐fate decisions during stomatal development. The identification of these genes opens a new direction to investigate the evolution of stomatal development and the conserved functions of bHLH proteins in cell type differentiation adopted by plants and animals. BioEssays 29:861–870, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Helix–loop–helix (HLH) genes encode for transcription factors affecting a whole variety of developmental programs, including neurogenesis. At least seven functional classes (denoted I to VII) of HLH genes exist,1 with subclass members exhibiting homo‐ and heterodimerisation for proper DNA binding and transcriptional regulation of downstream target genes. In the developing nervous system, members of class II, V and VI have been most extensively studied concerning their roles in neural programming. In contrast, the function of class I proteins (such (...) as E12 and E47) is poorly defined and the orthodox view relegates them to general dimerisation duties that are necessary for the activity of the other classes. However, closer scrutiny of the spatiotemporal expression patterns of class I factors, combined with recent biochemical evidence, would suggest that class I proteins possess specific functions during early neural differentiation. This essay supports this possibility, in addition to putting forward the hypothesis that, outside their general dimerisation activity, class I genes have independent roles in regulating neurogenesis. BioEssays 25:709–716, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

DNA–protein interactions are fundamental to many biological processes, including the regulation of gene expression. Determining the binding affinities of transcription factors (TFs) to different DNA sequences allows the quantitative modeling of transcriptional regulatory networks and has been a significant technical challenge in molecular biology for many years. A recent paper by Maerkl and Quake1 demonstrated the use of microfluidic technology for the analysis of DNA–protein interactions. An array of short DNA sequences was spotted onto a glass slide, which (...) was then covered with a microfluidic device allowing each spot to be within a chamber into which the flow of materials was controlled by valves. By trapping the DNA–protein complexes on the surface and measuring their concentrations microscopically, they could determine the binding affinity to a large number of DNA sequences that were varied systematically. They studied four TFs from the basic helix–loop–helix family of proteins, all of which bind to E‐box sites with the consensus CAnnTG (where “n” can be any base), and showed that variations in affinity for different sites allows each TF to regulate different genes. BioEssays 29:717–721, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Ets proteins are a family of transcription factors that regulate the expression of a myriad of genes in a variety of tissues and cell types. This functional versatility emerges from their interactions with other structurally unrelated transcription factors. Indeed, combinatorial control is a characteristic property of Ets family members, involving interactions between Ets and other key transcriptional factors such as AP1, SRF, and Pax family members. Intriguingly, recent molecular modeling and crystallographic data suggest that not only the ETS DNA-binding domain, (...) but also the DNA recognition helix α3, are often directly required for Ets partner's selection. Indeed, while most DNA-binding proteins appear to exploit differences within their DNA recognition helices for sites selection, the Ets proteins exploit differences in their surfaces that interact with other transcription factors, which in turn may modify their DNA-binding properties in a promoter-specific fashion. Taken together, the gene-specific architecture of these unique complexes can mediate the selective control of transcriptional activity. BioEssays 24:362–370, 2002. ©2002 Wiley Periodicals, Inc. (shrink)

Sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b), a member of the SERCA family, is expressed ubiquitously and transports Ca2+ into the sarco/endoplasmic reticulum using the energy provided by ATP binding and hydrolysis. The crystal structure of SERCA2b in its Ca2+‐ and ATP‐bound (E1∙2Ca2+‐ATP) state and cryo‐electron microscopy (cryo‐EM) structures of the protein in its E1∙2Ca2+‐ATP and Ca2+‐unbound phosphorylated (E2P) states have provided essential insights into how the overall conformation and ATPase activity of SERCA2b is regulated by the transmembrane helix (...) 11 and the subsequent luminal extension loop, both of which are specific to this isoform. More recently, our cryo‐EM analysis has revealed that SERCA2b likely adopts open and closed conformations of the cytosolic domains in the Ca2+‐bound but ATP‐free (E1∙2Ca2+) state, and that the closed conformation represents a state immediately prior to ATP binding. This review article summarizes the unique mechanisms underlying the conformational and functional regulation of SERCA2b. (shrink)

The ArgumentThis paper focuses on the opening of a discursive space: the emergence of informational and scriptural representations of life and their self-negating consequences for the construction of biological meaning. It probes the notion of writing and the book of life and shows how molecular biology's claims to a status of language and texuality undermines its own objective of control. These textual significations were historically contingent. The informational representations of heredity and life were not an outcome of the internal cognitive (...) momentum of molecular biology; they were not a logical necessity of the unravelling of the base-pairing of the DNA double-helix. They were transported into molecular biology still within the protein paradigm of the gene in the 1940s and permeated nearly every discipline in the life and social sciences. These information-based models, metaphors, linguistic, and semiotic tools which were central to the formulation of the genetic code were transported into molecular biology from cybernetics, information theory, electronic computing, and control and communication systems — technosciences that were deeply embedded with the military experiences of world war II and the Cold War. The information discourse thus became fixed in molecular biology not because it worked in the narrow epistemic sense (it did not), but because it positioned molecular biology within postwar discourse and culture, perhaps within the transition to a post-modern information-based society. (shrink)

In this paper, I discuss the discovery of the DNA structure by Francis Crick and James Watson, which has provoked a large historical literature but has yet not found entry into philosophical debates. I want to redress this imbalance. In contrast to the available historical literature, a strong emphasis will be placed upon analysing the roles played by theory, model, and evidence and the relationship between them. In particular, I am going to discuss not only Crick and Watson's well-known model (...) and Franklin's x-ray diffraction pictures (the evidence) but also the less well known theory of helical diffraction, which was absolutely crucial to Crick and Watson's discovery. The insights into this groundbreaking historical episode will have consequences for the ‘new’ received view of scientific models and their function and relationship to theory and world. The received view, dominated by works by Cartwright and Morgan and Morrison ([1999]), rather than trying to put forth a ‘theory of models’, is interested in questions to do with (i) the function of models in scientific practice and (ii) the construction of models. In regard to (i), the received view locates the model (as an idealized, simplified version of the real system under investigation) between theory and the world and sees the model as allowing the application of the former to the latter. As to (ii) Cartwright has argued for a phenomenologically driven view and Morgan and Morrison ([1999]) for the ‘autonomy’ of models in the construction process: models are determined neither by theory nor by the world. The present case study of the discovery of the DNA structure strongly challenges both (i) and (ii). In contrast to claim (i) of the received view, it was not Crick and Watson's model but rather the helical diffraction theory which served a mediating purpose between the model and the x-ray diffraction pictures. In particular, Cartwright's take on (ii) is refuted by a comparison of Franklin's bottom-up approach with Crick and Watson's top-down approach in constructing the model. The former led to difficulties, which only a strong confidence in the structure incorporated in the model could circumvent. How to Get to the Structure 1.1 X-ray diffraction and its synthesis 1.2 Model building and Pauling's panache 1.3 The structure of proteins 1.3.1 A failed inference to the best explanation 1.3.2 The misleading 5.1 Å spot in proteins and how to get rid of it 1.3.3 Derived predictions from Pauling's alpha-helix of protein molecules The CCV Theory of Helical X-Ray Diffraction 2.1 The role of the CCV theory in the discovery of the DNA structure Killing the Helix 3.1 Appreciating all evidence—in vain Conclusion Epilogue: Chargaff's Ratios CiteULike Connotea Del.icio.us What's this? (shrink)

Ductin is the highest conserved membrane protein yet found in eukaryotes. It is multifunctional, being the subunit c or proteolipid component of the vacuolar H+‐ATPase and at the same time the protein component of a form of gap junction in metazoan animals. Analysis of its structure shows it to be a tandem repeat of two 8‐kDa domains derived from the subunit c of the F0 proton pore from the F1F0 ATPase. Each domain contains two transmembrane α‐helices, which together (...) may form a four‐helix bundle. In both the V‐ATPase and gap junction channel, ductin is probably arranged as a hexamer of subunits forming a central channel of gap junction‐like proportions. The two functions appear to be seggregated by ductin having two orientations in the bilayer. Ductin is also the major component of the mediatophore, a protein complex which may aid in the release of neurotransmitters across the pre‐synaptic membrane. It is also a target for a class of poorly understood viral polypeptides. These polypeptides are small and highly hydrophobic and some have oncogenic activity. Ductin thus appears to be at the crossroads of a number of biological processes. (shrink)

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

The centromere is a specialized chromosomal structure that dictates kinetochore assembly and, thus, is essential for accurate chromosome segregation. Centromere identity is determined epigenetically by the presence of a centromere‐specific histone H3 variant, CENP‐A, that replaces canonical H3 in centromeric chromatin. Here, we discuss recent work by Roulland et al. that identifies structural elements of the nucleosome as essential determinants of centromere function. In particular, CENP‐A nucleosomes have flexible DNA ends due to the short αN helix of CENP‐A. The (...) higher flexibility of the DNA ends of centromeric nucleosomes impairs binding of linker histones H1, while it facilitates binding of other essential centromeric proteins, such as CENP‐C, and is required for mitotic fidelity. This work extends previous observations indicating that the differential structural properties of CENP‐A nucleosomes are on the basis of its contribution to centromere identity and function. Here, we discuss the implications of this work and the questions arising from it. (shrink)

Skeletal myoblasts have their origin early in embryogenesis within specific somites. Determined myoblasts are committed to a myogenic fate; however, they only differentiate and express a muscle‐specific phenotype after they have received the appropriate environmental signals. Once proliferating myoblasts enter the differentiation programme they withdraw from the cell cycle and form post‐mitotic multinucleated myofibres (myogenesis); this transformation is accompanied by muscle‐specific gene expression. Muscle development is associated with complex and diverse protein isoform transitions, generated by differential gene expression and (...) mRNA splicing. The myofibres are in a state of dynamic adaptation in response to hormones, mechanical activity and motor innervation, which modulate differential gene expression and splicing during this functional acclimatisation. This review will focus on the profound effects of thyroid hormone on skeletal muscle, which produce alterations in gene and isoform expression, biochemical properties and morphological features that precipitate in modified contractile/mechanical characteristics. Insight into the molecular events that control these events was provided by the recent characterisation of the MyoD gene family, which encodes helix‐loop‐helix proteins; these activate muscle‐specific transcription and serve as targets for a variety of physiological stimuli. The current hypothesis on hormonal regulation of myogenesis is that thyroid hormones (1) directly regulate the myoD and contractile protein gene families, and (2) induce thyroid hormone receptor‐transcription factor interactions critical to gene expression. (shrink)

SCL (TAL1/TCL5) is a member of the helix‐loop‐helix family of transcription factors. Originally identified because of its involvement in a tumour‐specific chromosomal translocation, overexpression of the SCL gene is the most common molecular abnormality found in human T cell leukaemia. Transgenic models have now formally demonstrated that overexpression of SCL within the T cell lineage is capable of causing malignant transformation. Gene targeting experiments have revealed that the SCL gene is crucial for the development of primitive haematopoiesis in (...) the mouse and is also required for the generation of all adult haematopoietic lineages. Biochemical studies have indicated some of the proteins which interact with SCL and this has refined the hypotheses concerning the mechanisms by which SCL plays a role in leukaemogenesis and haematopoietic development. (shrink)

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

Stomata, the most influential components in gas exchange with the atmosphere, represent a revealing system for studying cell fate determination. Studies in Arabidopsis thaliana have demonstrated that many of the components, functioning in a signaling cascade, guide numerous cell fate transitions that occur during stomatal development. The signaling cascade is initiated at the cell surface through the activation of the membrane receptors TOO MANY MOUTHS (TMM) and/or ERECTA (ER) family members by the secretory peptide EPIDERMAL PATTERNING FACTOR1 (EPF1) and/or a (...) substrate processed proteolytically by the subtilase STOMATAL DENSITY AND DISTRIBUTION1 (SDD1) and transduced through cytoplasmic MAP kinases (YODA (YDA), MKK4/MKK5, and MPK3/MPK6) towards the nucleus. In the nucleus, these MAP kinases regulate the activity of the basic helix‐loop‐helix (bHLH) proteins SPEECHLESS (SPCH), MUTE, and FAMA, which act in concert with the bHLH‐Leu zipper protein SCREAM (SCRM) (and/or its closely related paralog, SCREAM2). This article reviews current insights into the role of this signaling cascade during stomatal development. (shrink)

DNA glycosylases remove aberrant DNA nucleobases as the first enzymatic step of the base excision repair (BER) pathway. The alkyl‐DNA glycosylases AlkC and AlkD adopt a unique structure based on α‐helical HEAT repeats. Both enzymes identify and excise their substrates without a base‐flipping mechanism used by other glycosylases and nucleic acid processing proteins to access nucleobases that are otherwise stacked inside the double‐helix. Consequently, these glycosylases act on a variety of cationic nucleobase modifications, including bulky adducts, not previously associated (...) with BER. The related non‐enzymatic HEAT‐like repeat (HLR) proteins, AlkD2, and AlkF, have unique nucleic acid binding properties that expand the functions of this relatively new protein superfamily beyond DNA repair. Here, we review the phylogeny, biochemistry, and structures of the HLR proteins, which have helped broaden our understanding of the mechanisms by which DNA glycosylases locate and excise chemically modified DNA nucleobases. (shrink)

The assembly of intermediate filaments is a fundamental property of the central rod domain of the individual subunit proteins. This rod domain, with its high propensity for α‐helix formation, is the common and identifying feature of this family of proteins. Assembly occurs in vitro in the absence of other proteins or exogenous sources of energy; in vivo, it appears as if other factors, as yet poorly understood, modulate the assembly of intermediate filaments. Parallel, in‐register dimers form via coiled‐coil interactions (...) of the rod domain. Tetramers may form from staggered arrays of parallel or antiparallel arrangements of dimers. Higher‐order polymerization, which occurs spontaneously if the ionic strength of a mixture of dimers and tetramers is raised, proceeds rapidly through poorly described intermediates to the final 10 nm filament. This process is dependent on and modulated by the non‐α‐helical end domains, as well as those amino acids present at the very beginning and end of the rod domain. The interactions governing tetramer formation are most probably the same ones that are responsible for the lateral and longitudinal associations within intermediate filaments. (shrink)

DNA is an important agent not only in chemistry and biology but also in technology and modern culture. A number of books approach the double helix from different angles. These perspectives include (1) the science of DNA and genetics; (2) genetic engineering; (3) the ethics of manipulating genetic material; and (4) DNA in culture and religion. Various views of DNAprovide insights into human nature beyond its molecular composition.

This essay introduces this special issue on virtue ethics in relation to military AI. It describes the current situation of military AI ethics as following that of AI ethics in general, caught between consequentialism and deontology. Virtue ethics serves as an alternative that can address some of the weaknesses of these dominant forms of ethics. The essay describes how the articles in the issue exemplify the value of virtue-related approaches for these questions, before ending with thoughts for further research.

Interaction between sciences has always been an optimum. Within this frame of interdisciplinary approach, an attempt is made to apply a method, a mathematical model, used in the Hyperstructure Theory, in teaching and research procedure. More specifically, when dealing with a great amount of data arranged in a ‘linear’ disposal, it is quite difficult to teach. This is the case when the Helix Model is suggested to be used. With the Helix Model, every single piece of data is (...) present and every element maintains its independence. (shrink)

One of our most brilliant evolutionary biologists, Richard Lewontin has also been a leading critic of those--scientists and non-scientists alike--who would misuse the science to which he has contributed so much. In The Triple Helix, Lewontin the scientist and Lewontin the critic come together to provide a concise, accessible account of what his work has taught him about biology and about its relevance to human affairs. In the process, he exposes some of the common and troubling misconceptions that misdirect (...) and stall our understanding of biology and evolution.The central message of this book is that we will never fully understand living things if we continue to think of genes, organisms, and environments as separate entities, each with its distinct role to play in the history and operation of organic processes. Here Lewontin shows that an organism is a unique consequence of both genes and environment, of both internal and external features. Rejecting the notion that genes determine the organism, which then adapts to the environment, he explains that organisms, influenced in their development by their circumstances, in turn create, modify, and choose the environment in which they live.The Triple Helix is vintage Lewontin: brilliant, eloquent, passionate, and deeply critical. But it is neither a manifesto for a radical new methodology nor a brief for a new theory. It is instead a primer on the complexity of biological processes, a reminder to all of us that living things are never as simple as they may seem. (shrink)

Changes in knowledge production, increasing interaction between government, universities and industry, and changes in labor markets for doctoral degree holders are forces that have spurred a debate about the organization of doctoral education and the competencies graduates need to master to work as scientists and researchers in a triple helix research context. Recent policy also has supported a redefinition of researcher training with increasing focus on broader skills and relevance for careers outside the university sector. Consequently, it is pertinent (...) to investigate current changes in doctoral education and researcher training. Particularly further knowledge about university–industry collaboration as a context for researcher training is required. With this in mind, this study provides empirical illustrations of how research training carried out in collaborative research contexts is experienced by doctoral students, and offers some insight into antecedent and process factors that are central in shaping PhD students’ research and training experience in collaborative research contexts. Based on the empirical data and a review of existing literature, suggestions for further research are made. (shrink)

While the Triple Helix and Quadruple Helix models are popular in innovation studies, the relations between them have not been addressed extensively in the literature. There are diverse interpretations of helix models in empirical studies that apply them, but these sometimes deviate from the original theses of the models. Such a situation can confuse newcomers to the field in terms of which helix model to apply in their empirical research. We discern that the cause of this (...) research challenge is a lack of systematic comparison of the two models. To bridge the research gap, this paper compares the models from the perspectives of how they were introduced and discussed in the literature and improved and how useful they are in addressing the innovation processes in contemporary society. Our major findings are as follows: First, reviewing the extant literature applying the two helix models for identifying research gaps, we discover that these studies were influenced by three views on the relations between the two models that were located on a continuum between two extreme ends—namely, isolation versus integration of the two models. Second, we provide a systematic comparison of both the advantages and weaknesses of the two models, and this may help researchers choose suitable helix models as conceptual/analytical tools in their empirical innovation studies. Third, our comparison of the two models shows that they are largely supplementary to each other when analysing innovation processes in contemporary society, providing a ground for potential synergy building between the two helix models. (shrink)

In this article, we propose four modifications to the standard Triple Helix innovation model, which consists of the three strands: university, government, industry. First, in view of recent economic, cultural, organizational and ideological changes in many countries, it is now important to introduce a fourth strand to the standard model, namely society. Second, we observe that strands occur in doublets which we refer to as binomials. Examples of doublets include university/society, university/industry, industry/society, etc. Third, the binomials are organized in (...) a hierarchic mode; for example in the university/society binomial, university may be dominant and the society secondary. The hierarchy arrangement proves decisive. Fourth, Helix-driven innovation processes take the form of temporary segmented phases. Using the case study of Dip-Pen nanolithography, we identify four phases where each phase is characterised by specific binomials accompanied by a hierarchy: academic instrument research (university/society); from instrument to tool; company start-up (university/industry); the mature firm and commercialization (industry/society); confirming the societal strand nanofication (society/industry). The government strand operates as a recessive component in phases one and four. (shrink)

The author discusses B.G. Yudin's image technoscience as having two contours, the external one dealing with science, business and society, and the internal one represented by laboratories. Together these two contours present a multidimensional net of relations between science and technology in conducting experiments, development of instruments (e.g. visualization tools), etc. The author argues that, in such a system, coordinated activity of the internal and the external contours is provided by a synergy of regulatory principles of truth, good and usefulness. (...) He discusses a case of synthetic biology which, as he argues, demonstrates that the internal and external contours of technoscience undergo a process of technologization. Technologization is understood as a transition from research techniques to systematic use of technologies. Biotechnologies are claimed to have a double socio-biological helix network structure. Each network is formed as a kind of ad hoc "factory" and is aimed at solving specific research problems. (shrink)

The author discusses B.G. Yudin's image technoscience as having two contours, the external one dealing with science, business and society, and the internal one represented by laboratories. Together these two contours present a multidimensional net of relations between science and technology in conducting experiments, development of instruments (e.g. visualization tools), etc. The author argues that, in such a system, coordinated activity of the internal and the external contours is provided by a synergy of regulatory principles of truth, good and usefulness. (...) He discusses a case of synthetic biology which, as he argues, demonstrates that the internal and external contours of technoscience undergo a process of technologization. Technologization is understood as a transition from research techniques to systematic use of technologies. Biotechnologies are claimed to have a double socio-biological helix network structure. Each network is formed as a kind of ad hoc "factory" and is aimed at solving specific research problems. (shrink)

The Protein Ontology (PRO) provides a formal, logically-based classification of specific protein classes including structured representations of protein isoforms, variants and modified forms. Initially focused on proteins found in human, mouse and Escherichia coli, PRO now includes representations of protein complexes. The PRO Consortium works in concert with the developers of other biomedical ontologies and protein knowledge bases to provide the ability to formally organize and integrate representations of precise protein forms so as to (...) enhance accessibility to results of protein research. PRO (http://pir.georgetown.edu/pro) is part of the Open Biomedical Ontologies (OBO) Foundry. (shrink)

Quadruple Helix Collaborations (QHCs) is a cooperation model in which industry, government, academia, and the public interact to innovate. This paper analyses the impact of a training intervention to provide specific knowledge, skills, and attitudes to deal with barriers commonly found in the progress of QHCs. We designed, implemented, and evaluated three training programs in Austrian, Colombian, Danish, and Spanish institutions. We analysed trainees’ (n = 66) and trainers’ (n = 9) perceptions to identify the competencies acquired with the (...) intervention and the approach’s limitations. We used online questionnaires (35 trainees; 9 trainers), semi-structured interviews (10 trainees), and a focus group (6 trainers). Trainees answered positively regarding their self-perception about the impact of the course and highlighted the acquisition of inspiration for their practice (score 4.1 out of 5.0) and knowledge (3.7). In contrast, they perceived that a deeper interaction with other participants (2.7) was challenging. After the courses, 74% of respondents indicated that they know more about how QHCs work in practice, and 86% about collaboration or engagement methods. Moreover, participants plan to be more sensitive towards setting common goals (71%) and power imbalances (63%). Trainers’ perceptions align with those expressed by participants, except that they considered that the interaction amongst participants during the course was higher. Qualitative analysis of interviews with participants and the focus group with trainers provides more detail about the strengths and weaknesses of the intervention. Our study shows that the collaborative design and implementation of training impact the participant’s learning competencies, with potential implications in their medium- to long-term practice. (shrink)

The first attempt to represent the Periodic system graphically was the Telluric Helix presented in 1862 by Alexandre-Emile Béguyer de Chancourtois, in which the sequence of elements was wound round a cylinder. This has hardly been attempted since, because the intervals between periodic returns vary in length from 2 to 32 elements, but Charles Janet presented a model wound round four nested cylinders. The rows in Janet’s table are defined by a constant sum of the first two quantum numbers, (...) n and l, so that they end with the s-block, headed by hydrogen and helium. By combining Janet’s table, Edward Mazurs’ version, in which each row represents an electron shell and Valery Tsimmerman’s use of a half square for each element, I have produced a representation that can be printed out and wound round to make a cylinder with manageable dimensions. In the unwound version, I have placed the s-block in the middle, to emphasise its pivotal nature, since it both ends each row and contributes electrons to the valence of elements in the next row; it thus does not necessarily belong either on the left or the right side of a table. The downward arrows that link subshells within each series graphically illustrate the Janet Effect. To acknowledge my debt to Chancourtois, Janet, Mazurs and Tsimmerman, I call my design the ‘Telluric Remix’. (shrink)

The Triple Helix is a global model originating in developed economies but less developed countries have also made attempts to implement it into their national contexts. Meanwhile, the national context can be characterised by means-ends decoupling at the state level which implies that policies and practices of the state are disconnected from its core goal of creating public welfare. It refers to the oligarchic economies in which the state is captured by exploitative, rent-seeking oligarchies in business and politics. Ukraine (...) is an example of such a country. Thus, the research question is: how did means-ends decoupling at the state level affect the implementation of the Triple Helix model in Ukraine? To answer this question, we employed both rational choice institutionalism and sociological institutionalism. The data emanate from interviews with the senior managers of four universities and science parks established within them. The findings reveal that means-ends decoupling at the state level, caused by the rent-seeking behaviour of business and political oligarchies, led to the implementation of the Triple Helix model in Ukraine also reflecting a case of means-ends decoupling. The greater the institutional complexity experienced by the science park and the more the senior managers of the university and the science park maintain a logic of confidence in practices that deviate from the Triple Helix model, the greater rent-seeking and means-ends decoupling at the organisational level. Both rent-seeking and means-ends decoupling were found to not only hinder economic growth but also result in a diversion of human intellectual capital. (shrink)

We consider iterations of general elementary embeddings and, using this notion, point out helices of consistency-wise implications between large large cardinals.Up to now, large cardinal properties have been considered as properties which cannot be accessed by any weaker properties and it has been known that, with respect to this relation, they form a proper hierarchy. The helices we point out significantly change this situation: the same sequence of large cardinal properties occurs repeatedly, changing only the parameters.As results of our investigation (...) of this helical structure, we have new characterizations of extendible cardinals and of Vopěnkan cardinals in terms of elementary embeddings from the universe V, a new large large cardinal property which looks like Shelahness properly between Vopěnkaness and almost hugeness, and a more direct relation between Vopěnkaness and Woodinness than already known.We also consider limits of the helices and relations with the axioms I1–I3. (shrink)

사용-참신성 예측주의에 따르면, 가설 구성에 사용된 자료는 증거가 되기 어렵다. DNA 이중 나선 구조의 발견에 대한 사례 연구는 이에 대한 반례를 제공한다. 로잘린드 프랭클린의 DNA X선 회절 사진은 이중 나선 가설의 구성에 사용된 동시에 증거로도 사용되었다. 이 사례에서 증거는 제약에 의한 대안가설의 명시적 제거에 의존하는 증거와 제약들 사이의 정합성 확인에 의존하는 증거로 구분되며, 두 증거 모두 ‘사용-참신한 예측’이라는 조건에는 의존하지 않는다.

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (...) (GO). PRO relates to UniProtKB in that PRO’s organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO’s representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments. (shrink)

R&D collaborations between industry, government, civil society, and research (also known as ‘quadruple helix collaborations’ (QHCs)) have recently gained attention from R&D theorists and practitioners. In aiming to come to grips with their complexity, past models have generally taken a stakeholder-analytical approach based on stakeholder types. Yet stakeholder types are difficult to operationalise. We therefore argue that a processual model is more suited for studying the interaction in QHCs because it eschews matters of titles and identities. We develop such (...) a model in which the QHC is represented as a process of generating four types of value: research value, market value, political value, and societal value. We then apply this processual model in analysing reallife cases of friction in QHCs. Friction is seen, not as an interpersonal clash, but as a discrepancy between two or more value-creation processes that compete for limited resources (some overperforming while others under-performing). (shrink)