Cooperativity,absolute interaction,and algebraic optimization

We consider a measure of cooperativity based on the minimal interaction required to generate an observed titration behavior. We describe the corresponding algebraic optimization problem and show how it can be solved using the nonlinear algebra tool SCIP. Moreover, we compute the minimal interactions and minimal molecules for several binding polynomials that describe the oxygen binding of various hemoglobins under different conditions. We compare their minimal interaction with the maximal slope of the Hill plot, and discuss similarities and discrepancies with a view towards the shapes of the binding curves.

     

An in silico central pattern generator: silicon oscillator,coupling, entrainment,and physical computation

 In biological systems, the task of computing a gait trajectory is shared between the biomechanical and nervous systems. We take the perspective that both of these seemingly different computations are examples of physical computation. Here we describe the progress that has been made toward building a minimal biped system that illustrates this idea. We embed a significant portion of the computation in physical devices, such as capacitors and transistors, to underline the potential power of emphasizing the understanding of physical computation. We describe results in the exploitation of physical computation by (1) using a passive knee to assist in dynamics computation, (2) using an oscillator to drive a monoped mechanism based on the passive knee, (3) using sensory entrainment to coordinate the mechanics with the neural oscillator, (4) coupling two such systems together mechanically at the hip and computationally via the resulting two oscillators to create a biped mechanism, and (5) demonstrating the resulting gait generation in the biped mechanism. Received: 31 October 2001 / Accepted in revised form: 17 September 2002 Correspondence to: M.A. Lewis     

Methods for analysis of unbalanced,longitudinal, growth data

We describe an approach to analysis of growth that does not depend on assumptions about the underlying functional growth pattern and that allows for multiple observations arising from individual-specific, irregularly spaced data. We produce estimated growth curves for predefined subject groups by using LOWESS, a nonparametric smoothing algorithm. We describe how statistical significance of curve features may be evaluated by using the “jackknife,” a sample re-use method; this technique can be used to assess differences between subject groups. We then obtain residuals at each data point by reference to the estimated curve. Consistency of residuals is evaluated as a characteristic of individual subjects, and in the presence of individual consistency, relative size-for-age is then scored by the average residual for each individual. This allows study of relationships between relative size and other individual characteristics such as birth order, dominance rank, or age of maturation. Finally, we indicate flexibility of these methods and alternatives, propose uses related to other questions about growth, and suggest potential applications to variables other than body size. Appendices demonstrate application of the LOWESS and jackknife algorithms to the problem of testing sex differences in growth. © 1992 Wiley-Liss, Inc.     

New cytotoxic benzosuberene analogs. Synthesis,molecular modeling and biological evaluation

In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results.     

Case-control and case-only designs with genotype and family history data: estimating relative risk, residual familial aggregation, and cumulative risk

In case-control studies of inherited diseases, participating subjects (probands) are often interviewed to collect detailed data about disease history and age-at-onset information in their family members. Genotype data are typically collected from the probands, but not from their relatives. In this article, we introduce an approach that combines case-control analysis of data on the probands with kin-cohort analysis of disease history data on relatives. Assuming a marginally specified multivariate survival model for joint risk of disease among family members, we describe methods for estimating relative risk, cumulative risk, and residual familial aggregation. We also describe a variation of the methodology that can be used for kin-cohort analysis of the family history data from a sample of genotyped cases only. We perform simulation studies to assess performance of the proposed methodologies with correct and mis-specified models for familial aggregation. We illustrate the proposed methodologies by estimating the risk of breast cancer from BRCA1/2 mutations using data from the Washington Ashkenazi Study.     

The prominent mandibular angle: preoperative management, operative technique, and results in 42 patients

A prominent mandibular angle is considered to be unattractive in the Orient because it gives the face a square and muscular appearance. While described infrequently in the United States, this entity is commonly encountered in the Orient owing to different facial characteristics and different aesthetic sensibilities. We present a retrospective study of 42 female patients who presented requesting the reduction of a prominent mandibular angle for cosmetic reasons. We describe our approach, which utilizes formal planimetry, cephalometric tracings, and Panorex mandibular radiographs. We utilize the intraoral approach and use an oscillating saw to resect the predetermined segment of bone. In 18 of the 42 patients, we resected muscle as well. We also describe using the preauricular incision in a patient undergoing a concomitant rhytidectomy. Our cosmetic results have been generally satisfactory, with only one inaccurate osteotomy. We had three infections which resolved without sequelae.     

Rapid color change in fish and amphibians – function,regulation, and emerging applications

Physiological color change is important for background matching, thermoregulation as well as signaling and is in vertebrates mediated by synchronous intracellular transport of pigmented organelles in chromatophores. We describe functions of and animal situations where color change occurs. A summary of endogenous and external factors that regulate this color change in fish and amphibians is provided, with special emphasis on extracellular stimuli. We describe not only color change in skin, but also highlight studies on color change that occurs using chromatophores in other areas such as iris and on the inside of the body. In addition, we discuss the growing field that applies melanophores and skin color in toxicology and as biosensors, and point out research areas with future potential.     

Genome-wide comparative analysis of putative bidirectional promoters from rice, Arabidopsis and Populus

A bidirectional promoter can regulate the expression of two flanking genes arranged in a divergent manner. Although reports pertaining to bidirectional promoters on a genomic scale exist in mammals, little progress has been made in plants. In the present study, we performed a computational analysis of this unique class of promoters to identify overrepresented cis-regulatory motifs from three sequenced plant genomes: rice (Oryza sativa), Arabidopsis thaliana, and Populus trichocarpa using the Plant Cis-acting Regulatory DNA Elements (PLACE) and PLANT CARE databases. We describe these overrepresented elements and their possible regulatory mechanisms. We also discuss similarities and differences with human bidirectional promoters. Furthermore, we describe in detail a few coexpressed and evolutionarily conserved divergent gene pairs and their bidirectional promoters. This study provides insights into bidirectional promoters in three plant species, thereby laying a foundation for their experimental analysis.     

Suspension (S)-FISH, a new technique for interphase nuclei.

We describe a versatile method for performing fluorescence in situ hybridization (FISH) in suspension instead of on a slide as usually done. This so-called suspension-FISH (S-FISH) opens new possibilities for the analysis of shape and functions of the human interphase nucleus. The procedure is described and the first results using this approach are presented.     

Video on the Internet: An introduction to the digital encoding, compression, and transmission of moving image data

In this paper, we seek to provide an introduction to the fast-moving field of digital video on the Internet, from the viewpoint of the biological microscopist who might wish to store or access videos, for instance in image databases such as the BioImage Database (http://www.bioimage.org). We describe and evaluate the principal methods used for encoding and compressing moving image data for digital storage and transmission over the Internet, which involve compromises between compression efficiency and retention of image fidelity, and describe the existing alternate software technologies for downloading or streaming compressed digitized videos using a Web browser. We report the results of experiments on video microscopy recordings and three-dimensional confocal animations of biological specimens to evaluate the compression efficiencies of the principal video compression-decompression algorithms (codecs) and to document the artefacts associated with each of them. Because MPEG-1 gives very high compression while yet retaining reasonable image quality, these studies lead us to recommend that video databases should store both a high-resolution original version of each video, ideally either uncompressed or losslessly compressed, and a separate edited and highly compressed MPEG-1 preview version that can be rapidly downloaded for interactive viewing by the database user.     

MEG (Model Extender for Gepasi): a program for the modelling of complex, heterogeneous, cellular systems

SUMMARY: We describe a program for the construction of spatially distributed metabolic models, which may then be simulated using the metabolic simulator GEPASI: This is useful for the modelling of heterogeneous systems whether as liquid cultures or as spatially organised systems with specified interconnections.     

Lead Diversification 2: application to P38, gMTP and lead compounds

Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.     

Spreading speed, traveling waves, and minimal domain size in impulsive reaction-diffusion models

How growth, mortality, and dispersal in a species affect the species' spread and persistence constitutes a central problem in spatial ecology. We propose impulsive reaction-diffusion equation models for species with distinct reproductive and dispersal stages. These models can describe a seasonal birth pulse plus nonlinear mortality and dispersal throughout the year. Alternatively, they can describe seasonal harvesting, plus nonlinear birth and mortality as well as dispersal throughout the year. The population dynamics in the seasonal pulse is described by a discrete map that gives the density of the population at the end of a pulse as a possibly nonmonotone function of the density of the population at the beginning of the pulse. The dynamics in the dispersal stage is governed by a nonlinear reaction-diffusion equation in a bounded or unbounded domain. We develop a spatially explicit theoretical framework that links species vital rates (mortality or fecundity) and dispersal characteristics with species' spreading speeds, traveling wave speeds, as well as minimal domain size for species persistence. We provide an explicit formula for the spreading speed in terms of model parameters, and show that the spreading speed can be characterized as the slowest speed of a class of traveling wave solutions. We also give an explicit formula for the minimal domain size using model parameters. Our results show how the diffusion coefficient, and the combination of discrete- and continuous-time growth and mortality determine the spread and persistence dynamics of the population in a wide variety of ecological scenarios. Numerical simulations are presented to demonstrate the theoretical results.     

Bounds and inequalities relating h-index, g-index, e-index and generalized impact factor: an improvement over existing models

In this paper, we describe some bounds and inequalities relating h-index, g-index, e-index, and generalized impact factor. We derive the bounds and inequalities relating these indexing parameters from their basic definitions and without assuming any continuous model to be followed by any of them. We verify the theorems using citation data for five Price Medalists. We observe that the lower bound for h-index given by Theorem 2, [formula: see text], g ≥ 1, comes out to be more accurate as compared to Schubert-Glanzel relation h is proportional to C(2/3)P(-1/3) for a proportionality constant of 1, where C is the number of citations and P is the number of papers referenced. Also, the values of h-index obtained using Theorem 2 outperform those obtained using Egghe-Liang-Rousseau power law model for the given citation data of Price Medalists. Further, we computed the values of upper bound on g-index given by Theorem 3, g ≤ (h + e), where e denotes the value of e-index. We observe that the upper bound on g-index given by Theorem 3 is reasonably tight for the given citation record of Price Medalists.     

Parsimony, likelihood, and the role of models in molecular phylogenetics

Methods such as maximum parsimony (MP) are frequently criticized as being statistically unsound and not being based on any "model." On the other hand, advocates of MP claim that maximum likelihood (ML) has some fundamental problems. Here, we explore the connection between the different versions of MP and ML methods, particularly in light of recent theoretical results. We describe links between the two methods--for example, we describe how MP can be regarded as an ML method when there is no common mechanism between sites (such as might occur with morphological data and certain forms of molecular data). In the process, we clarify certain historical points of disagreement between proponents of the two methodologies, including a discussion of several forms of the ML optimality criterion. We also describe some additional results that shed light on how much needs to be assumed about underlying models of sequence evolution in order to successfully reconstruct evolutionary trees.     

Solubilization, stabilization, and purification of chemokine receptors using biosensor technology

Establishing solubilization conditions for membrane-associated receptors is often a tedious empirical process. Here we describe a novel application of SPR biosensor technology to screen solubilization conditions automatically and to assess receptor activity directly. We focus on two chemokine receptors, CXCR4 and CCR5, which are important in HIV cell invasion. The autosampler in Biacore 3000 permitted whole cells expressing C-terminally tagged receptors to be automatically lysed under a given solubilization condition and the lysates to be injected over an antibody surface. The total amount of solubilized receptor could be quantitated from the antibody capture level, whereas the amount of active receptor could be quantitated using a subsequent injection of conformationally sensitive antibody or protein. Using this approach, we identified detergent/lipid/buffer combinations that enhanced and maintained receptor activity. We also used the biosensor to demonstrate CD4-dependent binding of gp120 to solubilized CCR5 and to develop affinity chromatography-based purification methods that increased receptor activity more than 300%. Together, these results illustrate the benefits of using the biosensor as a tool for isolating functional membrane receptors and for analyzing ligand/receptor interactions.     

Monovalent, reduced-size quantum dots for imaging receptors on living cells

We describe a method to generate monovalent quantum dots (QDs) using agarose gel electrophoresis. We passivated QDs with a carboxy-terminated polyethylene-glycol ligand, yielding particles with half the diameter of commercial QDs, which we conjugated to a single copy of a high-affinity targeting moiety (monovalent streptavidin or antibody to carcinoembryonic antigen) to label cell-surface proteins. The small size improved access of QD-labeled glutamate receptors to neuronal synapses, and monovalency prevented EphA3 tyrosine kinase activation.