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In the lymphoid system, T cells respond to space or under-crowding by dividing to maintain their numbers. In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes.
We analyze here the minimal conditions for directional motion (net flow in phase space) of a molecular motor placed on a mirror-symmetric environment and driven by a center-symmetric and time-periodic force field. The complete characterization of the deterministic limit of the dissipative dynamics of several realizations of this minimal model reveals a complex structure in the phase diagram in parameter space, with intertwined regions of pinning (closed orbits) and directional motion. This demonstrates that the mirror symmetry breaking, which is needed for directional motion to occur, can operate through an internal degree of freedom coupled to the translational one.
The lethal effects of freezing on cells are currently attributed to the crystallization of extracellular water which leaves concentrated solutions of salts, macromolecules and so forth in the extracellular space. This concentrated fluid establishes a strong osmotic gradient which draws water from the cells. Thus, a cell surrounded by ice can survive only if means can be found for reducing the osmotically driven outflow of cellular water. This is usually attempted through vitrification of the extracellular space, but may also be attained through suitable modifications of cellular plasms. Starting from microscopic observations on early rabbit embryos and related cryotolerance, we investigated purified actin solutions under similar conditions, and found that sol-gel processing could result in the formation of homogeneous glass, and through drying, give rise to monolithic solids, glasses and composites. The first process may be at least partially responsible for the induced cryotolerance of cells, while the second may be representative of new and useful biomaterials.
We have investigated the conformational properties of a truncated analogue of mastoparan and of mastoparan X, both peptides from wasp venom. The electrostatically driven Monte Carlo method was used to explore the conformational space of these short peptides. The initial conformations used in this study, mainly random ones, led to alpha-helical conformations. The alpha-helical conformations thus found exhibit an amphipathic character. These results are in accord with experimental data from NMR and CD spectroscopy.
This work presents a framework driven by parcellation of brain gray matter in standard normalized space to classify the neuronal fibers obtained from diffusion tensor imaging (DTI) in entire human brain. Classification of fiber bundles into groups is an important step for the interpretation of DTI data in terms of functional correlates of white matter structures. Connections between anatomically delineated brain regions that are considered to form functional units, such as a short-term memory network, are identified by first clustering fibers based on their terminations in anatomically defined zones of gray matter according to Talairach Atlas, and then refining these groups based on geometric similarity criteria. Fiber groups identified this way can then be interpreted in terms of their functional properties using knowledge of functional neuroanatomy of individual brain regions specified in standard anatomical space, as provided by functional neuroimaging and brain lesion studies.
The contribution of this paper is the adaptation of data driven methods for non-Euclidean metric decomposition of tangent space shape coordinates. The basic idea is to extend principal component analysis (PCA) to take into account the noise variance at different landmarks and at different shapes. We show examples where these non-Euclidean metric methods allow for easier interpretation by decomposition into meaningful modes of variation. The extensions to PCA are based on adaptation of maximum autocorrelation factors and the minimum noise fraction transform to shape decomposition. A common basis of the methods applied is the assessment of the annotation noise variance at individual landmarks. These assessments are based on local models or repeated annotations by independent operators. We show that the Molgedey-Schuster independent component analysis is equivalent to the maximum autocorrelation factors. Finally, the different subspace methods are compared using a probabilistic formulation based on their ability to represent the data.
High-frequency ventilation (HFV) provides respiratory gas exchange using positive airway pressure-driven tidal breaths that are often smaller than anatomic dead space and breathing frequencies several times faster than normal. Gas transport with HFV involves nonconvective mechanisms such as Taylor dispersion, coaxial flow, and augmented diffusion. Devices to deliver HFV include the jet (an airway injector delivers jet pulses) and the oscillator (a piston oscillates a bias flow of fresh gas). The conceptual advantage to HFV is that maximal airway pressures are limited by the small tidal breath and lung recruitment is optimized by the intrinsic positive end expiratory pressure effect. Outcome has been shown to be improved in pediatric patients at risk for volutrauma. Adult outcome data are still lacking.
A line cancellation task was performed by 36 right brain-damaged patients with unilateral neglect under four different conditions: normal and mirror-reversed view, with and without cueing. Two types of unilateral neglect were distinguished by directing ophthalmo- and melokinetic components of visuomanual scanning to opposite sides of the stimulus array. In ophthalmokinetic neglect, contralesional visual scanning of the stimulus array was defective, while manual scanning was unimpaired. The converse was true of melokinetic neglect. Ophthalmokinetic neglect was predominantly associated with posterior brain damage, while melokinetic neglect was predominantly associated with frontal or subcortical brain damage. In a few instances, cueing visuomanual scanning toward the neglected side of the stimulus array converted ophthalmokinetic into melokinetic neglect, and vice versa. The results are held to be indicative of two components of space representation and to provide further evidence of response-driven modulation of perceptual awareness.
An orthodontic measurement and simulation system (OMSS) is introduced. The major component of the system consists of two force-moment sensors capable of measuring forces and moments in all three planes of space simultaneously. The two sensors are mounted on motor-driven positioning tables with full three-dimensional mobility. All mechanical components are built in a temperature-controlled chamber. A control programme executed by a personal computer performs various types of measurement which can be classified as absolute measurements (e.g. force-deflection diagrams) and simulations of orthodontic tooth movement. By using the OMSS any orthodontic problem at the level of a two-tooth model can be analysed statically and dynamically. Besides other applications, the study evaluates three mechanical systems available for uprighting molars, namely a straight wire, a conventional uprighting spring, and a modified Burstone uprighting spring. It was found that the force systems produced by the straight wire and by the conventional uprighting spring showed a severe extrusive force component which may lead to occlusal trauma. The uprighting performance of the straight wire was inadequate. The conventional uprighting spring produced a large uprighting moment (17.8 Nmm), but also a strong lingual tipping moment (1.5 Nmm). The modified Burstone loop showed the best static and dynamic performance. It produced a force system with substantial uprighting moments in both the sagittal (11.6 Nmm) and frontal plane (4.2 Nmm). A slight intrusive force (0.09 N) might prevent the development of occlusal trauma during treatment. However, concern should be addressed to the fact that intra-oral adjustment of this uprighting spring is difficult because of its high susceptibility to minor modifications of its geometry.
We address the surface-tension-driven dynamics of porous media in nearly saturated pore-space solutions. We linearize this dynamics in the reaction-limited regime near its fixed points--surfaces of constant mean curvature (CMC surfaces). We prove that the only stable interface for this dynamics is the plane and estimate the time scale for a CMC surface to become unstable. We also discuss the differences between dynamics in open and closed environments, pointing out the unlikelihood that CMC surfaces are ever realized in such environments on any time scale.
The space-uniform amplitude envelope of the ion-temperature-gradient driven turbulence is unstable to small perturbations and evolves to nonuniform, solitonlike modulated profiles. The induced poloidal asymmetry of the transport fluxes can generate spontaneous poloidal spin-up of the tokamak plasma.
The researchers and practitioners of today create models, algorithms, functions, and other constructs defined in abstract spaces. The research of the future will likely be data driven. Symbolic and numeric data that are becoming available in large volumes will define the need for new data analysis techniques and tools. Data mining is an emerging area of computational intelligence that offers new theories, techniques, and tools for analysis of large data sets. In this paper, a novel approach for autonomous decision-making is developed based on the rough set theory of data mining. The approach has been tested on a medical data set for patients with lung abnormalities referred to as solitary pulmonary nodules (SPNs). The two independent algorithms developed in this paper either generate an accurate diagnosis or make no decision. The methodolgy discussed in the paper depart from the developments in data mining as well as current medical literature, thus creating a variable approach for autonomous decision-making.
1. What is the neural mechanism of vestibuloocular reflex (VOR) cancellation when a subject fixates a target moving with the head? One theory is that the moving target evokes pursuit eye movements that add to and cancel the VOR. A recent finding with implications for this theory is that eye velocity vectors of both pursuit and the VOR vary with eye position, but in different ways, because pursuit follows Listing's law whereas the VOR obeys a "half-Listing" strategy. As a result, pursuit cannot exactly cancel the VOR in most eye positions, and so the pursuit superposition theory predicts an eye-position-dependent pattern of residual eye velocities during cancellation. To test these predictions, we measured eye velocity vectors in humans during VOR, pursuit, and cancellation in response to torsional, vertical, and horizontal stimuli with the eyes in different positions. 2. For example, if a subject is rolling clockwise (CW, frequency 0.3 Hz, maximum speed 37.5 deg/s) while looking 20 deg up, the VOR generates an eye velocity that is mainly counterclockwise (CCW), but also leftward. If we then turn on a small target light, located 20 deg up and moving with the subject, then pursuit superposition predicts that the CCW component of eye velocity will shrink and the horizontal component will reverse, from leftward to rightward. This pattern was seen in all subjects. 3. Velocities depended on eye position in the predicted way; e.g., when subjects looked 20 deg down, instead of 20 deg up, during CW roll, the reversal of horizontal eye velocity went the other way, from rightward to leftward. And when gaze was 20 deg right or left, analogous reversals occurred in the vertical eye velocity, again as predicted. 4. Analogous predictions for horizontal and vertical stimulation were also borne out by the data. For example, when subjects rotated rightward while looking 20 deg up, the VOR response was leftward and CCW. When the target light switched on, the torsional component of the response reversed, becoming CW. And analogous predictions for other eye positions and for vertical stimulation also held. 5. For all axes of stimulation and all eye positions, eye velocity during cancellation was roughly parallel with the gaze line. This alignment is predicted by pursuit superposition and has the effect of reducing retinal image slip over the fovea. 6. The fact that the complex dependence of eye velocity on the stimulation axis and eye position predicted by pursuit superposition was seen in all subjects and conditions suggests strongly that the VOR indeed is canceled additively by pursuit. However, eye velocities during cancellation were consistently smaller than predicted. This shrinkage indicates that a second mechanism, besides pursuit superposition, attenuates eye velocities during cancellation. The results can be explained if VOR gain is reduced by approximately 30%, and if, in addition, pursuit is driven by retinal slip rather than reconstructed target velocity in space.
Tissue dynamics during dorsal closure, a stage of Drosophila development, provide a model system for cell sheet morphogenesis and wound healing. Dorsal closure is characterized by complex cell sheet movements, driven by multiple tissue specific forces, which are coordinated in space, synchronized in time, and resilient to UV-laser perturbations. The mechanisms responsible for these attributes are not fully understood. We measured spatial, kinematic, and dynamic antero-posterior asymmetries to biophysically characterize both resiliency to laser perturbations and failure of closure in mutant embryos and compared them to natural asymmetries in unperturbed, wild-type closure. We quantified and mathematically modeled two processes that are upregulated to provide resiliency--contractility of the amnioserosa and formation of a seam between advancing epidermal sheets, i.e., zipping. Both processes are spatially removed from the laser-targeted site, indicating they are not a local response to laser-induced wounding and suggesting mechanosensitive and/or chemosensitive mechanisms for upregulation. In mutant embryos, tissue junctions initially fail at the anterior end indicating inhomogeneous mechanical stresses attributable to head involution, another developmental process that occurs concomitant with the end stages of closure. Asymmetries in these mutants are reversed compared to wild-type, and inhomogeneous stresses may cause asymmetries in wild-type closure.
Pattern specification in early amphibians (Xenopus) was monitored in embryos subjected to gravity compensation (microgravity simulation) by constant low-speed rotation on a horizontal axis (clinostat). The useful range of clinostat speeds was determined empirically. The results were interpreted in terms of a set of models which account for the reorganization of the egg cytoplasm that follows fertilization and that correlates with the establishment of dorsal/ventral polarity. Large percentages of clinostated eggs displayed a positive result (normal axial structure morphogenesis). Consequently, normal development of amphibian eggs in the microgravity environment of space should be possible. Models which depend upon gravity-driven rearrangements for cytoplasmic organization (e.g. dorsal/ventral polarization) of the early embryo should, therefore, not be favoured. At several clinostat speeds symmetrization of the egg in accordance with the site of sperm penetration, a natural phenomenon, was altered. The results at those clinostat speeds indicate that models which employ sperm entrance as an obligatory feature of the cytoplasmic rearrangements that generate egg polarity are not applicable.
Conceptual models of the atom preceded the mathematical model of the hydrogen atom in physics in the second decade of the 20th century. The computer modeling of the living cell in the 21st century may follow a similar course of development. A conceptual model of the cell called the Bhopalator was formulated in the mid-1980s, along with its twin theories known as the conformon theory of molecular machines and the cell language theory of biopolymer interactions [Ann. N.Y. Acad. Sci. 227 (1974) 211; BioSystems 44 (1997) 17; Ann. N.Y. Acad. Sci. 870 (1999a) 411; BioSystems 54 (2000) 107; Semiotica 138 (1-4) (2002a) 15; Fundamenta Informaticae 49 (2002b) 147]. The conformon theory accounts for the reversible actions of individual biopolymers coupled to irreversible chemical reactions, while the cell language theory provides a theoretical framework for understanding the complex networks of dynamic interactions among biopolymers in the cell. These two theories are reviewed and further elaborated for the benefit of both computational biologists and computer scientists who are interested in modeling the living cell and its functions. One of the critical components of the mechanisms of cell communication and cell computing has been postulated to be space- and time-organized teleonomic (i.e. goal-directed) shape changes of biopolymers that are driven by exergonic (free energy-releasing) chemical reactions. The generalized Franck-Condon principle is suggested to be essential in resolving the apparent paradox arising when one attempts to couple endergonic (free energy-requiring) biopolymer shape changes to the exergonic chemical reactions that are catalyzed by biopolymer shape changes themselves. Conformons, defined as sequence-specific mechanical strains of biopolymers first invoked three decades ago to account for energy coupling in mitochondria, have been identified as shape changers, the agents that cause shape changes in biopolymers. Given a set of space- and time-organized teleonomic shape changes of biopolymers driven by conformons, all of the functions of the cell can be accounted for in molecular terms-at least in principle. To convert a conceptual model of the cell into a computer model, it is necessary to represent the conceptual model in an algebraic language. To this end, we have begun to apply the process algebra of Milner [Communicating and Mobile Systems: The pi-calculus, Cambridge University Press, Cambridge, 1999] to develop what is here called the "shape algebra," capable of describing complex and mobile patterns of interactions among biomolecules leading to cell functions.
Normal bone remodeling and pathological bone destruction have been considered to be osteoclast-driven. Osteoclasts are able to attach to bare bone surface and produce an acidic subcellular space. This leads to acid dissolution of hydroxyapatite, allowing cathepsin K to degrade the organic type I collagen-rich osteoid matrix under the acidic condition prevailing in Howship lacunae. Using a sting pH electrode, the interface membrane around a loosened total hip replacement prosthesis was found to be acidic. Confocal laser scanning disclosed irregular demineralization of the bone surface in contact with the acidic interface. Cathepsin K, an acidic collagenolytic enzyme, was found in interface tissue macrophages/giant cells and pseudosynovial fluid. Tissue extracts contained high levels of cathepsin K messenger RNA (mRNA) and protein. These observations suggest the presence of an acid- and cathepsin K-driven pathological mechanism of bone resorption, mediated not by osteoclasts in subosteoclastic space, but rather by the uncontrolled activity of macrophages in extracellular space.
The large receptive fields of retinal horizontal cells result primarily from extensive intercellular coupling via gap (electrical) junctions; thus, the extent of the receptive field provides an index of the degree to which the cells are electrically coupled. For rod-driven horizontal cells in the dark-adapted skate retina, a space constant of 1.18 +/- 0.15 mm (SD) was obtained from measurements with a moving slit stimulus, and a comparable value (1.43 +/- 0.55 mm) was obtained with variation in spot diameter. These values, and the extensive spread of a fluorescent dye (Lucifer Yellow) from the site of injection to neighboring cells, indicate that the horizontal cells of the all-rod retina of skate are well coupled electrically. Neither the receptive field properties nor the gap-junctional features of skate horizontal cells were influenced by the adaptive state of the retina: (a) the receptive field organization was unaffected by light adaptation, (b) similar dye coupling was seen in both dark- and light-adapted retinae, and (c) no significant differences were found in the gap-junctional particle densities measured in dark- and light-adapted retinas, i.e., 3,184 +/- 286/microns 2 (n = 8) and 3,073 +/- 494/microns 2 (n = 11), respectively. Moreover, the receptive fields of skate horizontal cells were not altered by either dopamine, glycine, GABA, or the GABAA receptor antagonists bicuculline and picrotoxin. We conclude that the rod-driven horizontal cells of the skate retina are tightly coupled to one another, and that the coupling is not affected by photic and pharmacological conditions that are known to modulate intercellular coupling between cone-driven horizontal cells in other species.