Higher-order Forms Research Articles

Transverse Normal Strain Effect on Thermal Stress Analysis of Homogeneous and Layered Plates

A study of the transverse normal strain effect on the static thermoelastic response of homogeneous and multilayered plates is presented. Numerical evaluations have been given for classical, refined, and advanced zig-zag plate theories. Constant, linear, and higher-order forms of temperature profile in the plate thickness direction have been accounted for. Basic assumptions of the considered theories are quoted. The related governing equations are not given because these were derived from a unified formulation that was described elsewhere. Closed-form solutions are discussed by addressing three plate problems: a homogeneous plate made of an isotropic layer; a two-layered plate consisting of two layers made of different isotropic materials; a multilayered composite plate made of three cross-ply layers. It has been confirmed that any refinements of classical models are generally meaningless, unless the effects of transverse shear and normal strains are both taken into account in a plate theory. Furthermore, it has been found that transverse normal strains cannot be discarded even though thin plates are considered and the accurate description of the temperature profile in the plate thickness direction could result to be meaningless, unless transverse normal strains are taken into account, and vice versa.

Hippocampal Synaptic Metaplasticity Requires Inhibitory Autophosphorylation of Ca2+/Calmodulin-Dependent Kinase II

Virtually all CNS synapses display the potential for activity-dependent long-term potentiation (LTP) and/or long-term depression (LTD). Intriguingly, the potential to exhibit LTP or LTD at many central synapses itself is powerfully modulated by previous synaptic activity. This higher-order form of plasticity has been termed metaplasticity. Here, we show that inhibitory autophosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII) is required for hippocampal metaplasticity at the lateral perforant path-dentate granule cell synapse. Brief 10 Hz priming, which does not affect basal synaptic transmission, caused a dramatic, pathway-specific and long-lasting (up to 18 h) reduction in subsequently evoked LTP at lateral perforant path synapses. In contrast, LTD was unaffected by priming. The induction of lateral perforant path metaplasticity required the activation of NMDA receptors during priming. In addition, metaplasticity was absent in knock-in mice expressing alphaCaMKII that cannot undergo inhibitory phosphorylation, indicating that inhibitory autophosphorylation of alphaCaMKII at threonines 305/306 is required for metaplasticity. Metaplasticity was not observed in the medial perforant pathway, consistent with the observation that CaMKII activity was not required for the induction of LTP at this synapse. Thus, modulation of alphaCaMKII activity via autophosphorylation at Thr305/Thr306 is a key mechanism for metaplasticity that may be of importance in the integration of temporally separated episodes of activity.

A Mechanism for Assembly of Complexes of Vitronectin and Plasminogen Activator Inhibitor-1 from Sedimentation Velocity Analysis

Plasminogen activator inhibitor-1 (PAI-1) and vitronectin are cofactors involved in pathological conditions such as injury, inflammation, and cancer, during which local levels of PAI-1 are increased and the active serpin forms complexes with vitronectin. These complexes become deposited into surrounding tissue matrices, where they regulate cell adhesion and pericellular proteolysis. The mechanism for their co-localization has not been elucidated. We hypothesize that PAI-1-vitronectin complexes form in a stepwise and concentration-dependent fashion via 1:1 and 2:1 intermediates, with the 2:1 complex serving a key role in assembly of higher order complexes. To test this hypothesis, sedimentation velocity experiments in the analytical ultracentrifuge were performed to identify different PAI-1-vitronectin complexes. Analysis of sedimentation data invoked a novel multisignal method to discern the stoichiometry of the two proteins in the higher-order complexes formed (Balbo, A., Minor, K. H., Velikovsky, C. A., Mariuzza, R. A., Peterson, C. B., and Schuck, P. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 81-86). Our results demonstrate that PAI-1 and vitronectin assemble into higher order forms via a pathway that is triggered upon saturation of the two PAI-1-binding sites of vitronectin to form the 2:1 complex. This 2:1 PAI-1-vitronectin complex, with a sedimentation coefficient of 6.5 S, is the key intermediate for the assembly of higher order complexes.

Derivatives, forms and vector fields on the -deformed Euclidean space

The model of kappa-deformed space is an interesting example of a noncommutative space, since it allows a deformed symmetry. In this paper we present new results concerning different sets of derivatives on the coordinate algebra of kappa-deformed Euclidean space. We introduce a differential calculus with two interesting sets of one-forms and higher-order forms. The transformation law of vector fields is constructed in accordance with the transformation behaviour of derivatives. The crucial property of the different derivatives, forms and vector fields is that in an n-dimensional spacetime there are always n of them. This is the key difference with respect to conventional approaches, in which the differential calculus is (n+1)-dimensional. This work shows that derivative-valued quantities such as derivative-valued vector fields appear in a generic way on noncommutative spaces.

Oligomerization of the Human ARF Tumor Suppressor and Its Response to Oxidative Stress

The tumor suppressor ARF plays an important role as an inhibitor of the Mdm2-mediated degradation of p53. Here we demonstrate that human ARF (p14ARF) can form homo-oligomers. The stability of the oligomers is favored by oxidizing agents in a reversible fashion and involves all three cysteine residues in p14ARF. Furthermore, the effect of p14ARF in clonogenic assays is moderately but reproducibly increased by the mutation of its cysteine residues. We also observed that altering the amino terminus of p14ARF resulted in the appearance of remarkably stable oligomers. This indicates that the amino terminus of p14ARF interferes with the ability of the protein to form multimeric complexes. These observations suggest that p14ARF activity may be linked to its oligomerization status and sensitive to the redox status of the cell.

Surfactant protein D-mediated aggregation of Pneumocystis carinii impairs phagocytosis by alveolar macrophages.

Pneumocystis carinii remains an important and potentially fatal cause of opportunistic pneumonia. Animal studies reveal that substantial quantities of surfactant protein D (SP-D) accumulate in the airspaces during P. carinii pneumonia and are particularly abundant in aggregates of organisms. Due to the multimeric structure of SP-D, we hypothesized that SP-D mediates aggregation of the organism. From previous clinical studies it is known that aggregated organisms are conspicuous in sections of lung tissue and bronchoalveolar lavage (BAL) fluids of humans with active P. carinii pneumonia. Herein, we observe that SP-D levels increased at least fourfold in BAL fluids of patients with P. carinii pneumonia. Next, a spectrophotometric sedimentation assay was developed to assess the aggregation of P. carinii in vitro by SP-D. P. carinii organisms were first stripped with glutathione to remove bound SP-D and subsequently incubated in the presence of SP-D and 2 mM calcium. P. carinii incubated with natural SP-D (10 micro g/ml) containing dodecamers and higher-order forms exhibited aggregation and enhanced sedimentation compared to that of glutathione-stripped P. carinii. Aggregation was also enhanced by the concentrated supernatant of rat BAL fluid, and this effect was abolished by the selective removal of SP-D from the lavage fluid. P. carinii aggregation was reduced by maltose, mannose, and EDTA, consistent with the role of the SP-D C-type lectin domain (CRD) in the aggregation event. Comparisons of different molecular forms of SP-D showed that dodecamers-but not trimeric subunits-mediate optimal aggregation of P. carinii. Aggregation of P. carinii by SP-D was shown to be responsible for the impaired phagocytosis of the organisms by alveolar macrophages. Thus, SP-D-mediated aggregation of P. carinii may represent one means by which the organism avoids elimination by the host.

Neighboring Optimal Feedback Law for Higher-Order Dynamic Systems

In recent years, using tools from linear and nonlinear systems theory, it has been shown that classes of dynamic systems in first-order forms can be alternatively written in higher-order forms, i.e., as sets of higher-order differential equations. Input-state linearization is one of the most popular tools to achieve such a representation. The equations of motion of mechanical systems naturally have a second-order form, arising from the application of Newton’s laws. In the last five years, effective computational tools have been developed by the authors to compute optimal trajectories of such systems, while exploiting the inherent structure of the dynamic equations. In this paper, we address the question of computing the neighboring optimal for systems in higher-order forms. It must be pointed out that the classical solution of the neighboring optimal problem is well known only for systems in the first-order form. The main contributions of this paper are: (i) derivation of the optimal feedback law for higher-order linear quadratic terminal controller using extended Hamilton-Jacobi equations; (ii) application of the feedback law to compute the neighboring optimal solution.

A co-generic perspective on problems involving a shift between systems' different levels of analysis

A co-generic system is characterized by having processes, rather than entities, as its components. The aim of this paper is to present the concept of a co-generic system, elaborate upon its unique properties and demonstrate its power as an alternative epistemology for the study of non-mechanistic systems. By describing the unique properties of process-laden systems--co-generic systems--I aim to illustrate the simple and elegant basic process which is responsible for the shift between different logical levels of analysis, a shift which is evident in the emergence of higher order forms out of basic units. In this context, special emphasis is given to Gregory Bateson's theory.

Preformulation studies as an essential guide to formulation development and manufacture of protein pharmaceuticals.

Preformulation generally refers to a process in which a bulk drug material is characterized to a sufficient extent that it can be converted to a pharmaceutically acceptable drug substance. In the case of conventional, small-molecule (nonmacromolecular) pharmaceuticals, this procedure can usually be accomplished to a high degree of scientific rigor. For example, the atomic level structures of these compounds are usually known from a combination of X-ray crystallography, nuclear magnetic resonance (NMR), and mass spectrometry. Furthermore, the sensitivity of modern high-performance chromatography systems coupled to mass spectrometric detectors often permits altered forms of these molecules to be simply detected and identified. Unfortunately, the increased complexity of proteins, arising from a combination of their large size and higher order forms (secondary, tertiary, quaternary) of structure does not yet permit the more straightforward type of analysis utilized for small molecules to be simply applied. Nevertheless, it is still possible to treat proteins primarily as chemical (rather than biological) entities through an understanding of their structure and stability and use of a more complex array of lower resolution methodologies.

INTRODUCTION BY GUEST EDITORS

The information technology revolution threatens to swamp us in vast amounts of electronic data. Novel computing techniques based on notions gleaned from the information processing capabilities of biological neural systems provide some hope. The common themes are the compression of information into compact higher order forms. This can also be called automated knowledge or information extraction. The development of systems or components of systems to perform such tasks is becoming increasingly important.

Cholesterol-dependent interaction of syncollin with the membrane of the pancreatic zymogen granule

Syncollin is a protein of the pancreatic zymogen granule that was isolated through its ability to bind to syntaxin. Despite this in vitro interaction, it is now clear that syncollin is present on the luminal side of the zymogen granule membrane. Here we show that there are two pools of syncollin within the zymogen granule: one free in the lumen and the other tightly associated with the granule membrane. When unheated or cross-linked samples of membrane-derived syncollin are analysed by SDS/PAGE, higher-order forms are seen in addition to the monomer, which has an apparent molecular mass of 16kDa. Extraction of cholesterol from the granule membrane by treatment with methyl-β-cyclodextrin causes the detachment of syncollin, and this effect is enhanced at a high salt concentration. Purified syncollin is able to bind to brain liposomes at pH5.0, but not at pH11.0, a condition that also causes its extraction from granule membranes. Syncollin binds only poorly to dioleoyl phosphatidylcholine liposomes, but binding is dramatically enhanced by the inclusion of cholesterol. Finally, cholesterol can be co-immunoprecipitated with syncollin. We conclude that syncollin is able to interact directly with membrane lipids, and to insert into the granule membrane in a cholesterol-dependent manner. Membrane-associated syncollin apparently exists as a homo-oligomer, possibly consisting of six subunits, and its association with the membrane may be stabilized by electrostatic interactions with either other proteins or phospholipids.

Cholesterol-dependent interaction of syncollin with the membrane of the pancreatic zymogen granule.

Syncollin is a protein of the pancreatic zymogen granule that was isolated through its ability to bind to syntaxin. Despite this in vitro interaction, it is now clear that syncollin is present on the luminal side of the zymogen granule membrane. Here we show that there are two pools of syncollin within the zymogen granule: one free in the lumen and the other tightly associated with the granule membrane. When unheated or cross-linked samples of membrane-derived syncollin are analysed by SDS/PAGE, higher-order forms are seen in addition to the monomer, which has an apparent molecular mass of 16 kDa. Extraction of cholesterol from the granule membrane by treatment with methyl-beta-cyclodextrin causes the detachment of syncollin, and this effect is enhanced at a high salt concentration. Purified syncollin is able to bind to brain liposomes at pH 5.0, but not at pH 11.0, a condition that also causes its extraction from granule membranes. Syncollin binds only poorly to dioleoyl phosphatidylcholine liposomes, but binding is dramatically enhanced by the inclusion of cholesterol. Finally, cholesterol can be co-immunoprecipitated with syncollin. We conclude that syncollin is able to interact directly with membrane lipids, and to insert into the granule membrane in a cholesterol-dependent manner. Membrane-associated syncollin apparently exists as a homo-oligomer, possibly consisting of six subunits, and its association with the membrane may be stabilized by electrostatic interactions with either other proteins or phospholipids.

Integrating electrophysiology and neuroimaging of spatial selective attention to simple isolated visual stimuli

Visual-spatial attention involves modulations of activity in human visual cortex as indexed by electrophysiological and functional neuroimaging measures. Prior studies investigating the time course and functional anatomy of spatial attention mechanisms in visual cortex have used higher-order discrimination tasks with complex stimuli (e.g. symbol matching in bilateral stimulus arrays, or letter discrimination), or simple detection tasks but in the presence of complex distracting information (e.g. luminance detection with superimposed symbols as distractors). Here we tested the hypothesis that short-latency modulations of incoming sensory signals in extrastriate visual cortex reflect an early spatially specific attentional mechanism. We sought evidence of attentional modulations of sensory input processing for simple, isolated stimuli requiring only an elementary discrimination (i.e. size discrimination). As in prior studies using complex symbols, we observed attention-related changes in regional cerebral blood flow in extrastriate visual cortex that were associated with changes in event-related potentials at a specific latency range. These findings support the idea that early in cortical processing, spatially-specific attentional selection mechanisms can modulate incoming sensory signals based on their spatial location and perhaps independently of higher-order stimulus form.

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.

New Computational Framework for Trajectory Optimization of Higher-Order Dynamic Systems

Using tools from systems theory, it is now well known that classes of linear and nonlinear dynamic systems in firstorder form can be alternatively written in higher-order form, i.e., as sets of higher-order differential equations. Input-state linearization is one of the popular tools to achieve such a transformation. For mechanical systems, the equations of motion naturally have a second-order form. For real-time planning and control, a higher-order form offers a number of advantages compared to the first-order form. In this paper, we address the question of trajectory optimization of higher-order systems with general nonlinear constraints. First, we develop the optimality conditions directly using their higher-order form. These conditions are then used to develop computational approaches. A general purpose program has been developed to benchmark computations between problems posed in alternate higher-order and firstorder forms. The program implements both direct and indirect methods and uses collocation in conjunction with a nonlinear programming solver. infancy. However, a few studies in the literature address this issue applied to limited classes of problems. For example, a direct method was used for PVTOL systems to compute the optimal solution, where the inequality constraints were not considered [3]. In recent work, Agrawal and coworkers have used the indirect method to compute the optimal solution in the absence of inequality constraints. In these studies, the system equations were explicitly embedded into the cost functional. The results from higher-order variational theory were used to find the optimality conditions [4]. This approach was applied successfully to linear systems ([5], [6]) and feedback linearizable nonlinear systems [7]. The purpose of this paper is to extend the optimality theory applicable to higher-order systems, without converting the system equations to the first-order form. Using the resulting optimality conditions, direct and indirect computational algorithms are developed and implemented. The same direct or indirect algorithm is used to solve the firstorder and the higher-order optimization problems, thereby, allowing to benchmark the computation requirements in a systematic manner.

Contribution of GABA-A receptors to metaplasticity in the spinal dorsal horn

Metaplasticity is a higher-order form of synaptic plasticity that is induced by synaptic or cellular activity, which by itself may not produce changes in synaptic strength, but which modifies subsequent changes in synaptic efficacy. In this description of metaplasticity in the spinal dorsal horn, we report that a 50 Hz high-frequency tetanus, previously shown to elicit a potentiation of sciatic-evoked A-fiber spinal dorsal horn potentials, caused a depression when coupled with a more rapid rate of repetitive stimulation. This depression appeared to be dependent upon GABA A receptor activation because the 50 Hz tetanus elicited a persistent potentiation when the GABA A antagonist bicuculline was injected at 1 mg/kg (but not at 0.5 mg/kg) prior to tetanic stimulation. These data suggest the presence of strong inhibitory inputs in the spinal dorsal horn that are activated by an increased rate of primary afferent firing. The activation of these inputs may be necessary to prevent prolonged bursts of afferent activity from modifying synaptic strength because the latter may contribute to the development of persistent pain following peripheral nerve injury.

Light-induced biogenesis of chlorophyll-protein complexes in developing wheat thylakoids.

It is shown that the apoproteins of core complexes (CC) I and II, the alpha- and beta-subunits of CF1 ATP-synthase complexes, are present in seedlings grown under intermittent light (IML). The levels of light-harvesting complex (LHC) apoproteins in the 30- to 18-kD region increase rapidly upon exposure to continuous light (CL). The newly synthesized LHC apoproteins appear to be present predominantly in monomeric forms that later assemble into higher-order oligomeric forms. During the early stages of greening of wheat seedlings, polypeptides in the 20.5-19 and 17.5-15.5 kD regions (so-called "early light-induced proteins" (ELIP)) are observed, but they disappear fully after 6 h. As greening proceeds, the 727-nm band in low-temperature fluorescence spectra (77 K) gradually shifts to longer wavelength (740-742 nm), which clearly demonstrates the light-driven biogenesis of LHC I and its assembly with CC I.

Mono-Implicit Runge-Kutta-Nyström Methods with Application to Boundary Value Ordinary Differential Equations

The successful use of mono-implicit Runge—Kutta methods has been demonstrated by several researchers who have employed these methods in software packages for the numerical solution of boundary value ordinary differential equations. However, these methods are only applicable to first order systems of equations while many boundary value systems involve higher order equations. While it is straightforward to convert such systems to first order, several advantages, including substantial gains in efficiency, higher continuity of the approximate solution, and lower storage requirements, are realized when the equations can be treated in their original higher order form. In this paper, we consider generalizations of mono-implicit Runge—Kutta methods, called mono-implicit Runge—Kutta—Nystrom methods, suitable for systems of second order ordinary differential equations having the general form, y″(t) = f(t,y(t),y′(t)), and derive optimal symmetric methods of orders two, four, and six. We also introduce continuous mono-implicit Runge—Kutta—Nystrom methods which allow us to provide continuous solution and derivative approximations. Numerical results are included to demonstrate the effectiveness of these methods; savings of 65% are attained in some instances.

Evaluating matrix-variate moments through higher-order differential forms and combinatorial algorithms

Higher-order chain rule for differential forms is used to obtain the (higher-order) moments of a random matrix from certain cumulants and vice versa. Computer algorithms are written for the above chain rule. In particular, computer algorithms for finding moments and cumulants of normal and Wishart random matrices are obtained.

Visualization of DNA-protein intermediates during activation of the Pu promoter of the TOL plasmid of Pseudomonas putida.

The ATP-dependent multimerization process undergone by the sigma(54)-dependent activator XylR of the TOL plasmid pWW0 of Pseudomonas putida when bound to the upstream activating sequences (UAS) of the cognate PU: promoter was examined by transmission electron microscopy (TEM). To this end, supercoiled DNA templates were combined with increasing concentrations of the constitutive XylR variant XylRDeltaA, with or without ATP or its non-hydrolysable analogue ATPgammaS, and the resulting complexes were visualized by TEM. The different types of DNA-protein association were analysed and a statistical study of the frequency of the various forms was made. ATP appeared to establish an equilibrium between different molecular associations, as well as major changes in the physical shape of the DNA-protein complexes. The formation of higher nucleoprotein structures frequently bearing DNA bends became manifest. Such complexes often engaged otherwise separated UAS-containing plasmids, indicating that the ATP-driven multimer included XylR molecules recruited in trans. Whilst ATP caused the different types of XylR-DNA complex to occur at quite balanced frequencies, ATPgammaS appeared to displace the distribution predominantly towards the higher order forms. These data are compatible with the notion that each time ATP is hydrolysed the transcriptional activation complex is disassembled.