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Construction and characterization of a humanized, internalizing, B-cell (CD22)-specific, leukemia/lymphoma antibody, LL2.

The murine monoclonal antibody, LL2, is a B-cell (CD22)-specific IgG2a which has been demonstrated to be clinically significant in the radioimmunodetection of non-Hodgkin's B-cell lymphoma. The antibody carries a variable region-appended glycosylation site in the light chain and is rapidly internalized upon binding to Raji target cells. Humanization of LL2 was carried out in order to develop LL2 as a diagnostic and immunotherapeutic suitable for repeated administration. Based on the extent of sequence homology, and with the aid of computer modeling, we selected the EU framework regions (FR) 1, 2 and 3, and the NEWM FR4 as the scaffold for grafting the heavy chain complementarity determining regions (CDRs), and REI FRs for that of light chains. The light chain glycosylation site, however, was not included. Construction of the CDR-grafted variable regions was accomplished by a rapid and simplified method that involved long DNA oligonucleotide synthesis and the polymerase chain reaction (PCR). The humanized LL2 (hLL2), lacking light chain variable region glycosylation, exhibited immunoreactivities that were comparable to that of chimeric LL2 (cLL2), which was shown previously to have antigen-binding properties similar to its murine counterpart, suggesting that the VK-appended oligosaccharides found in mLL2 are not necessary for antigen binding. Moreover, the hLL2 retained its ability to be internalized into Raji cells at a rate similar to its murine and chimeric counterparts.

Amino Acid Sequence↗

Modelling of intersegmental coordination in the lamprey central pattern generator for locomotion.

Rhythmic motor activity requires coordination of different muscles or muscle groups so that they are all active with the same cycle duration and appropriate phase relationships. The neural mechanisms for such phase coupling in vertebrate locomotion are not known. Swimming in the lamprey is accomplished by the generation of a travelling wave of body curvature in which the phase coupling between segments is so controlled as to give approximately one full wavelength on the body at any swimming speed. This article reviews work that has combined mathematical analysis, biological experimentation and computer simulation to provide a conceptual framework within which intersegmental coordination can be investigated. Evidence is provided to suggest that in the lamprey, ascending coupling is dominant over descending coupling and controls the intersegmental phase lag during locomotion. The significance of long-range intersegmental coupling is also discussed.

Animals↗

Measurement of a 103Pd solution using the TDCR method by LSC.

Palladium 103 is a radionuclide used in brachytherapy sources for the treatment of prostate cancers and also for other medical applications. It decays through electron capture to excited levels of 103Rh. This paper describes the calculation method used to compute the detection efficiency in the framework of the triple to double coincidence ratio model. The calculation of the energy transferred to the scintillator is made by considering the various atomic events following the electron capture and the electron conversion. The energy deposited in the scintillator after the absorption of X-rays is calculated using the PENELOPE stochastic calculation code. The main contributors to the final uncertainty and their covariance matrix are discussed. As the calculation method cannot be reduced to an explicit function, this paper describes the Monte Carlo method used for the evaluation of uncertainties.

Algorithms↗

The efficacy of posterior three-unit zirconium-oxide-based ceramic fixed partial dental prostheses: a prospective clinical pilot study.

STATEMENT OF PROBLEM: Although zirconium-oxide-based restorations for fixed partial denture prostheses (FPDPs) are available for use, clinical studies evaluating their longevity and related complications have not been published. PURPOSE: The aim of this pilot clinical study was to assess the efficacy of zirconia-based posterior 3-unit FPDPs. MATERIAL AND METHODS: Twenty 3-unit posterior FPDPs (Lava) were placed in 16 subjects who were missing a second premolar or a first molar, met specific inclusion and exclusion criteria, and provided informed consent. All teeth were prepared in a standardized manner: occlusal reduction of 1.5 to 2 mm; axial reduction of 1 to 1.5 mm; a 1.0-mm, 360-degree rounded shoulder placed 0.5 mm subgingivally on the facial aspect and supragingivally on the lingual aspect on sound tooth structure; and rounded internal line angles. Impressions were made with vinyl polysiloxane (Express) impression material. Frameworks were fabricated using a computer-aided design/computer-assisted manufacturing technique with a retainer thickness of 0.6 mm, and a minimal connector surface area of 9 mm(2). Restorations were luted with resin-modified glass-ionomer cement (Rely X luting). Recall appointments were made after 2 weeks and 6, 12, 18, 24, and 36 months. Clinical fracture resistance, marginal discoloration, marginal adaptation, radiographic proximal recurrent decay, and periapical pathoses were assessed over time using modified Ryge criteria. The probability distributions of these variables were calculated for the baseline data as well as for recall data. RESULTS: Mean follow-up was 31.2 months. Fifteen restorations were rated Alpha in all measured parameters. Minor chipping of veneering porcelain was detected in 5 restorations rated Bravo for clinical fracture resistance and Alpha for all other assessed parameters. One restoration was rated Bravo in terms of marginal integrity at 36 months. CONCLUSIONS: Zirconia-based posterior 3-unit FPDPs performed well after short-term service.

Adult↗

Object recognition and segmentation by a fragment-based hierarchy.

How do we learn to recognize visual categories, such as dogs and cats? Somehow, the brain uses limited variable examples to extract the essential characteristics of new visual categories. Here, I describe an approach to category learning and recognition that is based on recent computational advances. In this approach, objects are represented by a hierarchy of fragments that are extracted during learning from observed examples. The fragments are class-specific features and are selected to deliver a high amount of information for categorization. The same fragments hierarchy is then used for general categorization, individual object recognition and object-parts identification. Recognition is also combined with object segmentation, using stored fragments, to provide a top-down process that delineates object boundaries in complex cluttered scenes. The approach is computationally effective and provides a possible framework for categorization, recognition and segmentation in human vision.

Form Perception↗

Measuring fit at the implant prosthodontic interface.

Four centers in the United States and Sweden have been working for 2 years to develop systems and methods for measuring fit at the prosthodontic interface. Two systems are based on stylus contact techniques, one system uses a laser as its reader source, and one system is photogrammetric. All the systems are capable of providing data as three-dimensional x, y, and z axes coordinate values that can be transformed into linear and angular data that characterize the bearing surfaces of abutments or abutment replicas and their mating components in the prosthesis framework. The centroid, a single point computed from the collected data, was the measurement unit, derived for these bearing surfaces, that was used to compare the systems. All four methods can most likely detect misfits that are relevant in the clinical setting; however, only one system can be used intraorally. When any measurement system is assessed, the data should always be examined for repeatability to establish the reliability of the system. This investigation made comparisons among the measurement methods used at the four centers. It was apparent from this study that comparisons of data from measurement systems should be rounded to the nearest 10 microns. The SDs determined in the comparisons were larger than 5 microns and therefore misfits should be calculated in terms smaller than 10 microns. This final point is important to the clinician who relies on research reports about precision of fit when selecting treatment approaches in caring for the implant prosthodontic needs of their patients.

Calibration↗

Speechreading: illusion or window into pattern recognition.

In the Fuzzy Logical Model of Perception (FLMP) perceivers are conceptualized as forming perceptual judgments by evaluating and integrating multiple ambiguous sources of information, in an optimal manner based on relative goodness of match. This model has been tested favorably against a variety of competing theories and models. Recent extensions of the FLMP are described in this article along with empirical applications and verification, and progress in the study of speech perception by ear and eye is reviewed within this general theoretical framework. The model illuminates the differences that are observed across different languages in terms of information as opposed to information-processing. Pattern recognition of bimodal speech is representative of pattern recognition in a variety of other domains, such as emotion perception, and there are several domain-dependent reasons why multimodal presentation of audible and visible speech is particularly conducive to accurate pattern recognition. We believe that the positive outcome of this research provides a framework for the development of computer-animated agents, which can serve as language tutors and as conversational characters in other domains, easing the interaction of humans and machines.

Journal Article↗

DFT study on the five isomers of PW(12)O(40)(3)(-): relative stabilization upon reduction.

The electronic characteristics and the redox properties of each isomer of PW(12)O(40)(3)(-) depend on the arrangement adopted by the metal-oxide framework. At the DFT/BP86 level, we computed the structures of the five isomers of PW(12)O(40)(3)(-) in oxidized form. The energy scale fits the experimental findings as well as the number of rotated triads of the metal-oxide core since the energy grows as follows: alpha < beta < gamma < delta < epsilon. The reduced clusters behave differently as long as the beta form becomes the most stable isomer after the second reduction. The gamma isomer also gains stability upon reduction, but not enough to be competitive with beta. For the 4-fold reduced PW(12) cluster, the energy difference computed between beta and gamma in solution is 11 kcal mol(-)(1). This large difference proves that the beta --> gamma isomerization is not favored upon simple reduction. The other isomers, delta and epsilon, are much more unstable than alpha or beta in any reduction state.

Journal Article↗

Effect of the metal fragment in the thermal cycloaddition between alkynyl metal(0) Fischer carbene complexes and nitrones.

The thermal cycloaddition between alkynyl metal(0) Fischer carbenes and nitrones has been studied computationally within the Density Functional Theory framework. It is found that the [3 + 2] cycloaddition takes place via transition structures that are more asynchronous and less aromatic than their nonorganometallic analogues. These reactions are also found to be completely regioselective in favor of the cycloadduct possessing the Fischer carbene moiety and the oxygen atom of the nitrone in a 1,3-relative disposition. These results are consistent with the role of the Fischer carbene moiety as an electron withdrawing group that enhances the electrophilic character of the alkyne group acting as a Michael acceptor as a dipolarophile. In terms of the isolobal analogy model, it can be concluded that alkynylalkoxy metal(0) carbene complexes act in this reaction as organometallic analogues of organic alkyl-propiolates with enhanced electrophilic character.

Journal Article↗

Ab initio simulation of carbon clustering on an Ni(111) surface: a model of the poisoning of nickel-based catalysts.

In this work, we studied the poisoning of a nickel surface due to carbon. Performing ab initio simulations, within the framework of density functional theory, we computed the surface energy of the nickel (111) surface as a function of carbon coverage. On the basis of these results, we can assert that the stable state of the nickel/carbon surface is either a clean nickel surface or a fully carbon-covered nickel surface, which has a graphitic configuration. The relative stability of the two states depends on the temperature and partial pressure of the carbon gas. At fixed nominal carbon coverage, the most stable configurations are those forming carbon clusters. However, the nickel sites hosting these clusters change from hexagonal close packed/face centered cubic (hcp/fcc) sites to on-top sites when going toward larger clusters. This indicates that poisoning due to graphitic patches occurs on on-top sites.

Journal Article↗

Epigenesis and dynamic similarity in two regulatory networks in Pseudomonas aeruginosa.

Mucoidy and cytotoxicity arise from two independent modifications of the phenotype of the bacterium Pseudomonas aeruginosa that contribute to the mortality and morbidity of cystic fibrosis. We show that, even though the transcriptional regulatory networks controlling both processes are quite different from a molecular or mechanistic point of view, they may be identical from a dynamic point of view: epigenesis may in both cases be the cause of the acquisition of these new phenotypes. This was highlighted by the identity of formal graphs modelling these networks. A mathematical framework based on formal methods from computer science was defined and implemented with a software environment. It allows an easy and rigorous validation and certification of these models and of the experimental methods that can be proposed to falsify or validate the underlying hypothesis.

Epigenesis, Genetic↗

The balance of storage and computation in morphological processing: the role of word formation type, affixal homonymy, and productivity.

This article is concerned with the way in which the balance of storage-storing and processing words through full-form representations-and computation-storing and processing words through morpheme-based representations-in lexical processing in the visual modality is affected by the following 3 factors: word formation type (roughly, inflection vs. derivation), productivity, and affixal homonymy. Experimental results for 5 different Dutch suffixes, combined with previous results obtained for 4 comparable Finnish suffixes (R. Bertram, M. Laine, & K. Karvinen, 1999) and 2 Dutch suffixes (R. H. Baayen, T. Dijkstra, & R. Schreuder, 1997), show that none of these factors in isolation is a reliable cross-linguistic predictor of the balance of storage and computation. The authors offer a general framework that outlines how morphological processing is influenced by the interaction of word formation type, productivity, and affixal homonymy.

Adult↗

Phenotypic and dynamical transitions in model genetic networks. I. Emergence of patterns and genotype-phenotype relationships.

Genotype-phenotype interactions during the evolution of form in multicellular organisms is a complex problem but one that can be aided by computational approaches. We present here a framework within which developmental patterns and their underlying genetic networks can be simulated. Gene networks were chosen to reflect realistic regulatory circuits, including positive and negative feedback control, and the exchange of a subset of gene products between cells, or within a syncytium. Some of these networks generate stable spatial patterns of a subset of their molecular constituents, and can be assigned to categories (e.g., "emergent" or "hierarchic") based on the topology of molecular circuitry. These categories roughly correspond to what has been discussed in the literature as "self-organizing" and "programmed" processes of development. The capability of such networks to form patterns of repeating stripes was studied in network ensembles in which parameters of gene-gene interaction were caused to vary in a manner analogous to genetic mutation. The evolution under mutational change of individual representative networks of each category was also simulated. We have found that patterns with few stripes (< or =3) are most likely to originate in the form of a hierarchic network, whereas those with greater numbers of stripes (> or =4) originate most readily as emergent networks. However, regardless of how many stripes it contains, once a pattern is established, there appears to be an evolutionary tendency for emergent mechanisms to be replaced by hierarchic mechanisms. These results have potential significance for the understanding of genotype-phenotype relationships in the evolution of metazoan form.

Biological Evolution↗

[What to do if statistical power is low? A practical strategy for pre-post-designs].

This article deals with the issue of statistical validity when evaluating interventions. The most common study design with two groups and two points of measurement is discussed. In clinical research settings, unsatisfactory statistical validity is often seen due to small sample sizes. In order to resolve this problem, a strategy based on an approach by Hager is proposed which takes both significance testing and effects sizes systematically into account. Using an example from clinical research practice the problematic issue of statistical power is introduced and methods to increase the power of tests are discussed. Within this framework, Erdfelder's compromise power analysis (computing alpha levels according to a predetermined beta/alpha error ratio) is crucial as well as a lowering of the number of applied tests by data reduction and the improved detection of potential effects by methods to reduce error variance. The results show that significance tests should not be used in case of small sample and effect sizes. In these cases different approaches should be used.

Data Interpretation, Statistical↗

Clusters of interacting receptors can stabilize synaptic efficacies.

Synaptic weights store memories that can last a lifetime. Yet, memory depends on synaptic protein receptors that are recycled in and out of the membrane at a fast rate, possibly several times an hour. Several proposals to bridge this vast gap in time scales between memory and its molecular substrate have relied on bistable molecular switches. Here, we propose an alternative to this approach based on clusters of interacting receptors in the synaptic membrane. We show that such clusters can be metastable and that the lifetime of such clusters can be many orders of magnitude larger than the lifetime of the receptors of which they are composed. We also demonstrate how bidirectional synaptic plasticity can be implemented in this framework.

Computer Simulation↗

Dispersal, eviction, and conflict in meerkats (Suricata suricatta): an evolutionarily stable strategy model.

Decisions regarding immigration and emigration are crucial to understanding group dynamics in social animals, but dispersal is rarely treated in models of optimal behavior. We developed a model of evolutionarily stable dispersal and eviction strategies for a cooperative mammal, the meerkat Suricata suricatta. Using rank and group size as state variables, we determined state-specific probabilities that subordinate females would disperse and contrasted these with probabilities of eviction by the dominant female, based on the long-term fitness consequences of these behaviors but incorporating the potential for error. We examined whether long-term fitness considerations explain group size regulation in meerkats; whether long-term fitness considerations can lead to conflict between dominant and subordinate female group members; and under what circumstances those conflicts were likely to lead to stability, dispersal, or eviction. Our results indicated that long-term fitness considerations can explain group size regulation in meerkats. Group size distributions expected from predicted dispersal and eviction strategies matched empirical distributions most closely when emigrant survival was approximately that determined from the field study. Long-term fitness considerations may lead to conflicts between dominant and subordinate female meerkats, and eviction is the most likely result of these conflicts. Our model is computationally intensive but provides a general framework for incorporating future changes in the size of multimember cooperative breeding groups.

Animal Migration↗

Hartree-fock approximation for inverse many-body problems

A new method is presented to reconstruct the potential of a quantum mechanical many-body system from observational data, combining a nonparametric Bayesian approach with a Hartree-Fock approximation. A priori information is implemented as a stochastic process, defined on the space of potentials. The method is computationally feasible and provides a general framework to treat inverse problems for quantum mechanical many-body systems.

Journal Article↗

A spectral color correction framework for medical applications.

This paper presents a new spectral approach to color correction for medical image analysis applications. Linear estimation with regularization by a constrained principal eigenvector method is used for calibration of the camera system and estimation of the illumination spectrum while spectral surface reflectivities are determined by Wiener inverse estimation. Nonlinear devices are handled by piecewise linear interpolation and any linear color preprocessing inside the camera is explicitly modeled. All measurement and estimation processes are combined into a spectral calibration framework for practical application in computer-assisted image analysis. The novelty of our approach lies in the generalization of the image formation model allowing for linear preprocessing inside the camera system. Such transforms would lead to erroneous results with positivity constraint based algorithms or a monochromator based measurement. We provide experimental results from a comprehensive set of reference measurements acquired with a video endoscopy system for gastroscopic application.

Algorithms↗