Synthetic Domain Research Articles

Effect of human acetylcholinesterase subunit assembly on its circulatory residence

Sialylated recombinant human acetylcholinesterase (rHuAChE), produced by stably transfected cells, is composed of a mixed population of monomers, dimers and tetramers and manifests a time-dependent circulatory enrichment of the higher-order oligomeric forms. To investigate this phenomenon further, homogeneous preparations of rHuAChE differing in their oligomerization statuses were generated: (1) monomers, represented by the oligomerization-impaired C580A-rHuAChE mutant, (2) wild-type (WT) dimers and (3) tetramers of WT-rHuAChE generated in vitro by complexation with a synthetic ColQ-derived proline-rich attachment domain (‘PRAD’) peptide. Three different series of each of these three oligoform preparations were produced: (1) partly sialylated, derived from HEK-293 cells; (2) fully sialylated, derived from engineered HEK-293 cells expressing high levels of sialyltransferase; and (3) desialylated, after treatment with sialidase to remove sialic acid termini quantitatively. The oligosaccharides associated with each of the various preparations were extensively analysed by matrix-assisted laser desorption ionization–time-of-flight MS. With the enzyme preparations comprising the fully sialylated series, a clear linear relationship between oligomerization and circulatory mean residence time (MRT) was observed. Thus monomers, dimers and tetramers exhibited MRTs of 110, 195 and 740min respectively. As the level of sialylation decreased, this differential behaviour became less pronounced; eventually, after desialylation all oligoforms had the same MRT (5min). These observations suggest that multiple removal systems contribute to the elimination of AChE from the circulation. Here we also demonstrate that by the combined modulation of sialylation and tetramerization it is possible to generate a rHuAChE displaying a circulatory residence exceeding that of all other known forms of native or recombinant human AChE.

Toward a culturally inclusive understanding of wisdom: historical roots in the East and West.

To establish a clearer definition of wisdom as a psychological concept, Western and Eastern historical literatures were reviewed and assessed within a general analytical/synthetic framework. In the West, either in an ancient Egyptian, biblical, or philosophical sense, wisdom had been often identified as a form of analytical ability such as an increase in the knowledge database or an increase in information processing efficiency. By contrast, the Eastern understanding of wisdom, primarily derived from the ancient Vedic text, had been more inclusive, with both analytical and synthetic domains regarded as necessary moments to the whole of wisdom. The inclusive account was also discussed with respect to two important Eastern themes of wisdom: "void" and "codependence."

Some axiomatic results in synthetic domain theory

Some axiomatic results in synthetic domain theory

Axioms and (counter)examples in synthetic domain theory

An axiomatic treatment of synthetic domain theory is presented, in the framework of the internal logic of an arbitrary topos. We present new proofs of known facts, new equivalences between our axioms and known principles, and proofs of new facts, such as the theorem that the regular complete objects are closed under lifting (and hence well-complete). In Sections 2–4 we investigate models, and obtain independence results. In Section 2 we look at a model in de Modified realizability Topos, where the Scott Principle fails, and the complete objects are not closed under lifting. Section 3 treats the standard model in the Effective Topos. Theorem 3.2 gives a new characterization of the initial lift-algebra relative to the dominance. We prove that in the standard case it is not the internal colimit of the chain 0 → L(0) → L 2(0) → ⋯ . The models in Sections 2 and 3 compare via an adjunction. Section 4 discusses a model in a Grothendieck topos. A feature here is that N is not well-complete (where N is the natural numbers object), whereas 2 is.

Activation of the Chemotactic Peptide Receptor FPRL1 in Monocytes Phosphorylates the Chemokine Receptor CCR5 and Attenuates Cell Responses to Selected Chemokines

FPRL1 is a seven-transmembrane (STM), G-protein coupled receptor which was originally identified as a low affinity receptor for the bacterial chemotactic formyl peptide and a high affinity receptor for the lipid metabolite lipoxin A4. We recently discovered that a number of peptides, including several synthetic domains of the HIV-1 envelope proteins and the serum amyloid A, use FPRL1 to induce migration and calcium mobilization in human monocytes and neutrophils. In this study, we report that a synthetic peptide domain of the V3 region of the HIV-1 envelope gp120, activates the FPRL1 receptor in monocytes and neutrophils. Furthermore, monocytes prestimulated with V3 peptide showed reduced response to several chemokines that use multiple cell receptors. This is associated with a rapid phosphorylation of the chemokine receptor CCR5 on the serine residues. Our study suggests that FPRL1, as a classical chemoattractant receptor, may play an important role in modulating monocyte activation in the presence of multiple stimuli.

Postulated Role of Interdomain Interaction within the Ryanodine Receptor in Ca2+ Channel Regulation

Localized distribution of malignant hyperthermia (MH) and central core disease (CCD) mutations in N-terminal and central domains of the ryanodine receptor suggests that the interaction between these domains may be involved in Ca(2+) channel regulation. To test this hypothesis, we investigated the effects of a new synthetic domain peptide DP4 corresponding to the Leu(2442)-Pro(2477) region of the central domain. DP4 enhanced ryanodine binding and induced a rapid Ca(2+) release. The concentration for half-maximal activation by agonists was considerably reduced in the presence of DP4. These effects of DP4 are analogous to the functional modifications of the ryanodine receptor caused by MH/CCD mutations (viz. hyperactivation of the channel and hypersensitization of the channel to agonists). Replacement of Arg of DP4 with Cys, mimicking the in vivo Arg(2458)-to-Cys(2458) mutation, abolished the activating effects of DP4. An N-terminal domain peptide DP1 (El-Hayek, R., Saiki, Y., Yamamoto, T., and Ikemoto, N. (1999) J. Biol. Chem. 274, 33341-33347) shows similar activation/sensitization effects. The addition of both DP4 and DP1 produced mutual interference of their activating functions. We tentatively propose that contact between the two (N-terminal and central) domains closes the channel, whereas removal of the contact by these domain peptides or by MH/CCD mutations de-blocks the channel, resulting in hyperactivation/hyper-sensitization effects.

Some axiomatic results in synthetic domain theory

Working in a model of intuitionistic higher order logic, a topos, we start by taking a dominance, a subobject S of the subobject classifier W satisfying some axioms. These axioms imply that we have a monad L on the topos, also called the lifting monad, which classifies S-partial maps. L has both an initial algebra I and a final coalgebra F; an object X of the topos is complete iff it is orthogonal to the canonical map I → F. The talk presented a new proof for Jibladze's formula for L, and under the additional assumptions that S is complete and ¬¬-separated, it was proved that for a complete algebra for the monad L, every function has a fixed point. Moreover, the complete regular S-posets are closed under the functor L.The material of the talk is in the paper ‘Axioms and (counter)examples in synthetic domain theory, Ann. Pure Appl. Logic 104 (2000) 233-278’ by J. van Oosten and A.K. Simpson.

Preface: Volume 35

This volume contains elaborations of most of the talks presented at the Workshop on Domains IV held at Haus Humboldtstein, Remagen-Rolandseck, from October 2nd to October 4th, 1998.The workshop was aimed at computer scientists and mathematicians alike who share an active interest in the mathematical foundations of computer science. It focussed on domains, their applications, closely related topics such as axiomatic and synthetic domain theory, and connections to type theory, recursion theory and topology.The workshop was organized by Dieter Spreen, Ralf Greb, Holger Schulz (University of Siegen) and Michel Schellekens (National University of Ireland, Cork).Domains IV was the fourth in a series of workshops started 1994 in Darmstadt and continued 1996 in Braunschweig and 1997 in Munich. It was attended by forty young as well as established researchers from a growing number of countries in Europe and overseas, underlining the lively interest in this meeting series. Due to the excellent conditions provided by Haus Humboldtstein, a last century villa overlooking the beautiful Rhine valley, the workshop took place in an informal and relaxed atmosphere.But it is only through the common efforts of the participants and the speakers that this workshop became such a success. Thomas Ehrhard, Dag Normann and Giovanni Sambin agreed to give invited lectures.Some people who registered were not able to attend. Nevertheless, their contributions are included in the volume.The workshop would not have been possible in this form without the financial support by the Deutsche Forschungsgemeinschaft, the Sparkasse Siegen, and the University of Siegen. Thanks are also due to the staff of Haus Humboldtstein. By their help we could concentrate on science only.The publication of the proceedings volume would not have been possible without the great help of my Ph.D. students Ralf Greb and Holger Schulz. I am very grateful. I also would like to thank Mike Mislove, Managing Editor of the Electronic Notes in Theoretical Computer science, for his suggestion to publish the workshop proceedings in this series and for his support and advice during the preparation of this electronic volume.Dieter Spreen, Guest Editor

Secretion of functional salivary peptide by Streptococcus gordonii which inhibits fimbria-mediated adhesion of Porphyromonas gingivalis.

Porphyromonas gingivalis, a putative periodontopathogen, can bind to human salivary components with its fimbriae. We have previously shown that fimbriae specifically bind to a peptide domain shared by a major salivary component, i.e., proline-rich (glyco)proteins (PRPs). The synthetic domain peptide PRP-C (pPRP-C) significantly inhibits the fimbrial binding to PRPs. In this study, a recombinant strain of Streptococcus gordonii secreting pPRP-C was generated as a model of a possible approach to prevent the oral colonization by the pathogen. A duplicate DNA fragment (prpC) encoding pPRP-C was obtained by self-complementary annealing of synthetic oligonucleotides. prpC was connected downstream to a promoter and a gene encoding a signal peptide of Streptococcus downei glucosyltransferase I in frame. The linked fragments were inserted into the plasmid pMNK-4 derived from pVA838. The constructed plasmid was inserted to produce the transformant S. gordonii G9B, which then successfully secreted recombinant pPRP-C (r-pPRP-C) of the expected size. The concentrated bacterial culture supernatant containing r-pPRP-C inhibited the binding of P. gingivalis cells and fimbriae to PRP1 in a dose-dependent manner up to 72 and 77%, respectively. The r-pPRP-C concentrate also inhibited the coaggregation of P. gingivalis with various streptococcal strains as effectively as synthetic pPRP-C in a dose-dependent manner. Collectively, pPRP-C was found to be able to prevent P. gingivalis adherence to salivary receptor protein and plaque-forming bacteria. These results suggest that this recombination approach with a nonperiodontopathic bacterium may be suitable for the therapeutic prevention of P. gingivalis adherence to the oral cavity.

General synthetic domain theory – a logical approach

Synthetic domain theory (SDT) is a version of Domain Theory where ‘all functions are continuous’. Following the original suggestion of Dana Scott, several approaches to SDT have been developed that are logical or categorical, axiomatic or model-oriented in character and that are either specialised towards Scott domains or aim at providing a general theory axiomatising the structure common to the various notions of domains studied so far.In Reus and Streicher (1993), Reus (1995) and Reus (1998), we have developed a logical and axiomatic version of SDT, which is special in the sense that it captures the essence of Domain Theory à la Scott but rules out, for example, Stable Domain Theory, as it requires order on function spaces to be pointwise. In this article we will give a logical and axiomatic account of a general SDT with the aim of grasping the structure common to all notions of domains.As in loc.cit., the underlying logic is a sufficiently expressive version of constructive type theory. We start with a few basic axioms giving rise to a core theory on top of which we study various notions of predomains (such as, for example, complete and well-complete S-spaces (Longley and Simpson 1997)), define the appropriate notion of domain and verify the usual induction principles of domain theory.Although each domain carries a logically definable ‘specialization order’, we avoid order-theoretic notions as much as possible in the formulation of axioms and theorems. The reason is that the order on function spaces cannot be required to be pointwise, as this would rule out the model of stable domains à la Berry.The consequent use of logical language – understood as the internal language of some categorical model of type theory – avoids the irritating coexistence of the internal and the external view pervading purely categorical approaches. Therefore, the paper is aimed at providing an elementary introduction to synthetic domain theory, albeit requiring some knowledge of basic type theory.

Extensional Σ-Spaces in Type Theory

Synthetic Domain Theory provides a setting far denotational semantics following Dana Scott's slogan 'domains as sets' in which all functions are continuous. Several approaches can be found in the literature, but they are either model-dependent or if they use an axiomatic setting then not uniformly and not explicitly. We present a completely logical approach to Synthetic Domain Theory (SDT), axiomatizing (complete) Extensional PERs. On these grounds some basic domain theory is developed. Special attention is devoted to admissibility. The axiomatic approach is advantageous since it allows for easy formalization and comparison to other axiomatic settings.

Completeness Classes of Equilogical Spaces

Equilogical spaces form a cartesian closed complete category that contains all τ0 spaces. Assemblies (on algebraic lattices) are a slight generalisation of an equivalent description of this category. They too form a cartesian closed complete category that even contains all topological spaces. We introduce various notions of completeness for assemblies, some inspired by Synthetic Domain Theory, and others inspired by topology, e.g., sobriety. Finally, we introduce the class of ordered assemblies that still contains all topological spaces, but excludes certain pathologies.

Kinetic and affinity constants of epitope specific anti-carcinoembryonic antigen (CEA) monoclonal antibodies for CEA and engineered CEA domain constructs

Background: Carcinoembryonic antigen (CEA) is a human tumor antigen with the domain structure N-A1-B1-A2-B2-A3-B3, in which each domain is predicted to have an Ig-like fold and is known to bind epitope specific anti-CEA antibodies. Objective: To determine the affinity constants of several domain specific anti-CEA antibodies using purified recombinant or synthetic domains. Results and Conclusion: We have determined the kinetic and affinity constants of several anti-CEA antibodies for CEA, CEA domains (A3-B3) expressed in HeLa cells, and a synthetic peptide corresponding to the A3 domain using a BIAcore biosensor. There was no difference in affinity for CEA among a murine (mT84.66), a mouse/human chimeric form (cT84.66) or a disulfide deleted version (ΔSScT84.66) of this antibody. There was less than a five-fold drop in affinity of murine T84.66 for the A3-B3 domain expressed in HeLa cells compared to CEA. The synthetic A3 domain had an affinity constant for mT84.66 which was ten-fold less than for CEA. The affinity constants for CEA with several other anti-CEA monoclonal antibodies, including three antibodies which have almost identical CDR sequences (CEA.281, CEA.11 and CEM231) were also determined. CEM231 which had a two-fold higher affinity constant for CEA than either CEA.281 or CEA.11 had a two-fold faster on-rate which accounts for its higher affinity constant. This difference may be due to one or more of the amino acid differences present in H1 (N vs. S or D) and H3 (A vs. V).

Optimal 3-D traveltime tomography

We propose a practical new method for 3-D traveltime tomography. The method combines an efficient approximation to the extended Kalman filter for rapid, accurate, nonlinear tomography, with the concept of data‐driven zonation, in which the dimensionality and geometry of the parameterization are dynamically determined using cluster analysis and region merging by random field union. The Bayesian filter uses geostatistics as it recursively incorporates measurements in an optimal (minimum‐variance) manner. Geologic knowledge is introduced through a priori estimates of the parameter field and its spatial covariance. Conditional estimates of the parameter number, geometry, value, and covariance are evolved. An initial decomposition of the 3-D domain into 2-D slices, the simplified filter design, and the data‐driven reduction in parameter dimensionality, all contribute to make the method computationally feasible for large 3-D domains. The method is verified by the inversion of crosswell seismic traveltimes to 3-D estimates of seismic slowness in four synthetic heterogeneous domains. Starting with homogeneous, fully distributed slowness fields, and no knowledge of the true covariance structure, the method is able to accurately and efficiently resolve the structure and values of markedly different domains.

Learning Coordination Strategies for Cooperative Multiagent Systems

A central issue in the design of cooperative multiagent systems is how to coordinate the behavior of the agents to meet the goals of the designer. Traditionally, this had been accomplished by hand-coding the coordination strategies. However, this task is complex due to the interactions that can take place among agents. Recent work in the area has focused on how strategies can be learned. Yet, many of these systems suffer from convergence, complexity and performance problems. This paper presents a new approach for learning multiagent coordination strategies that addresses these issues. The effectiveness of the technique is demonstrated using a synthetic domain and the predator and prey pursuit problem.

Some Lambda Calculus and Type Theory Formalized

"This paper is about our hobby." That is the first sentence of [MP93], the first report on our formal development of lambda calculus and type theory, written in autumn 1992. We have continued to pursue this hobby on and off ever since, and have developed a substantial body of formal knowledge, including Church-Rosser and standardization<br />theorems for beta reduction, and the basic theory of<br />Pure Type Systems (PTS) leading to the strengthening theorem and type checking algorithms for PTS. Some of this work is reported in [MP93, vBJMP94, Pol94b, Pol95]. In the present paper we survey this work, including some new proofs, and point out what we feel has been learned about the general issues of formalizing mathematics. On the technical side, we describe an abstract, and simplified, proof of standardization for beta reduction, not previously published, that does<br />not mention redex positions or residuals. On the general issues, we emphasize the search for formal definitions that are convenient for formal proof and convincingly represent the intended informal concepts. The LEGO Proof Development System [LP92] was used to check the work in an implementation of the Extended Calculus of Constructions<br />(ECC) with inductive types [Luo94]. LEGO is a refinement style<br />proof checker, publicly available by ftp and WWW, with a User's Manual [LP92] and a large collection of examples. Section 1.3 contains information on accessing the formal development described in this paper. Other interesting examples formalized in LEGO include program specification and data refinement [Luo91], strong normalization of System F [Alt93], synthetic domain theory [Reu95, Reu96], and operational semantics for imperative programs [Sch97].

Two models of synthetic domain theory

Two models of synthetic domain theory encompassing traditional categories of domains are introduced. First, we present a Grothendieck topos embedding the category ω- Cpo of ω-complete posets and ω-continuous functions as a reflective exponential ideal. Second, we obtain analogous results with respect to a category of domains and stable functions.

Tracking Context Changes through Meta-Learning

The article deals with the problem of learning incrementally (‘on-line’) in domains where the target concepts are context-dependent, so that changes in context can produce more or less radical changes in the associated concepts. In particular, we concentrate on a class of learning tasks where the domain provides explicit clues as to the current context (e.g., attributes with characteristic values). A general two-level learning model is presented that effectively adjusts to changing contexts by trying to detect (via ‘meta-learning’) contextual clues and using this information to focus the learning process. Context learning and detection occur during regular on-line learning, without separate training phases for context recognition. Two operational systems based on this model are presented that differ in the underlying learning algorithm and in the way they use contextual information: METAL(B) combines meta-learning with a Bayesian classifier, while METAL(IB) is based on an instance-based learning algorithm. Experiments with synthetic domains as well as a number of ‘real-world’ problems show that the algorithms are robust in a variety of dimensions, and that meta-learning can produce substantial increases in accuracy over simple object-level learning in situations with changing contexts.

Effect of Depolymerized Holothurian Glycosaminoglycan (DHG) on Tissue Factor Pathway Inhibitor: In Vitro and In Vivo Studies

Depolymerized holothurian glycosaminoglycan (DHG) is a glycosaminoglycan extracted from the sea cucumber Stichopus japonicus Selenka. In previous studies, we demonstrated that DHG has antithrombotic and anticoagulant activities that are distinguishable from those of heparin and dermatan sulfate. In the present study, we examined the effect of DHG on the tissue factor pathway inhibitor (TFPI), which inhibits the initial reaction of the tissue factor (TF)-mediated coagulation pathway. We first examined the effect of DHG on factor Xa inhibition by TFPI and the inhibition of TF-factor VIIa by TFPI-factor Xa in in vitro experiments using human purified proteins. DHG increased the rate of factor Xa inhibition by TFPI, which was abolished either with a synthetic C-terminal peptide or with a synthetic K3 domain peptide of TFPI. In contrast, DHG reduced the rate of TF-factor VIIa inhibition by TFPI-factor Xa. Therefore, the effect of DHG on in vitro activity of TFPI appears to be contradictory. We then examined the effect of DHG on TFPI in cynomolgus monkeys and compared it with that of unfractionated heparin. DHG induced an increase in the circulating level of free-form TFPI in plasma about 20-fold when administered i.v. at 1 mg/kg. The prothrombin time (PT) in monkey plasma after DHG administration was longer than that estimated from the plasma concentrations of DHG. Therefore, free-form TFPI released by DHG seems to play an additive role in the anticoagulant mechanisms of DHG through the extrinsic pathway in vivo. From the results shown in the present work and in previous studies, we conclude that DHG shows anticoagulant activity at various stages of coagulation reactions, i.e., by inhibiting the initial reaction of the extrinsic pathway, by inhibiting the intrinsic Xase, and by inhibiting thrombin.

Two remarks on the Lifschitz realizability topos

The purpose of this note is to clarify two points about the topos Lif, introduced in [13] as a generalization of Lifschitz' realizability ([9, 12]). Lif is a subtopos of Hyland's Effective topos ([1]). The points I want to make are:Remark 1. Lif is the largest subtopos of satisfying the axiom (O):where denotes partial recursive application, and “∈ Tot” means that e and f range over codes for total recursive functions. One may read (O) as the statement “The union of two -sets is again a -set”. That is, let be a subtopos of . Then (O) is true in for the standard interpretation (the variables range over the natural numbers object of , etc.) if and only if the inclusion ↣ factors through the inclusion Lif ↣ .Remark 2. Like , Lif contains at least two weakly complete internal full subcategories, thus providing us with more models of polymorphism and other impredicative type theories.The principle (O) has some standing in the history of constructive mathematics:- H. Friedman has proved that (O) is equivalent to a formulation of intuitionistic completeness of the intuitionistic predicate calculus for Tarskian semantics; see [8]. This is not to imply that this result is of immediate relevance to Lif: Friedman works in a system of analysis, a theory of lawless sequences with an axiom of “open data” for arithmetical formulas, which at least for the domain of all functions from N to N fails in Lif. However, there might exist a “nonstandard model” of arithmetic and a corresponding system of analysis, in which we may be able to carry out his proof.- Moreover, Remark 2 entails that Lif should provide us with models of synthetic domain theory (for an exposition, see [3]), and one with the nice property that the dual of one of the axioms (axiom 7 in [3]) comes for free, by (O).