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PubMed2002

q-Space high b value diffusion MRI of hemi-crush in rat spinal cord: evidence for spontaneous regeneration.

The development of the damage following hemi-crush trauma in rat spinal cord was studied ex vivo using high b value (bmax = 1 x 10(7) s cm(-2)) q-space diffusion weighted MRI (DWI) at five days, ten days and six weeks post-trauma. Rat spinal cord trauma, produced by hemi-crush of 15s and 60s duration, was studied. The water signal decay in these diffusion experiments was found to be non mono-exponential and was analyzed using the q-space approach. The q-space MRI parameters were compared with T1 and T2 MR images, behavioral tests and histopathological osmium staining. A very good anatomical correlation was found between the q-space MRI parameters and the osmium staining. Interestingly, we found that in the 15s hemi-crush model significant recovery was observed in both the q-space MR images and the osmium staining six weeks post-trauma. However, in the 60s hemi-crush trauma model very little recovery was observed. These results paralleled those obtained from behavioral tests demonstrating that partial spontaneous recovery seems to occur in the 15s hemi-crush spinal cord model, which should be taken in consideration when using it to evaluate new therapies.

Animals↗
PubMed1997

The Local Structure of Space-variant Images.

Local image structure is widely used in theories of both machine and biological vision. The form of the differential operators describing this structure for space-invariant images has been well documented. Although space-variant coordinates are universally used in mammalian visual systems, the form of the operators in the space-variant coordinate system has received little attention. In this report we derive the form of the most common differential operators and surface characteristics in the space-variant domain and show examples of their use. The operators include the Laplacian, the gradient and the divergence, as well as the fundamental forms of the image treated as a surface. We illustrate the use of these results by deriving the space-variant form of corner detection and image enhancement algorithms. The latter is shown to have interesting properties in the complex log domain, implicitly encoding a variable grid-size integration of the underlying PDE, allowing rapid enhancement of large scale peripheral features while preserving high spatial frequencies in the fovea. Copyright 1997 Elsevier Science Ltd.

Journal Article↗
PubMedDate not supplied

How can squint change the spacing of ocular dominance columns?

The pattern of ocular dominance columns in primary visual cortex of mammals such as cats and macaque monkeys arises during development by the activity-dependent refinement of thalamocortical connections. Manipulating visual experience in kittens by the induction of squint leads to the emergence of ocular dominance columns with a larger size and larger column-to-column spacing than in normally raised animals. The mechanism underlying this phenomenon is presently unknown. Theory suggests that experience cannot influence the spacing of columns if the development proceeds through purely Hebbian mechanisms. Here we study a developmental model in which Hebbian mechanisms are complemented by activity-dependent regulation of the total strength of afferent synapses converging onto a cortical neurone. We show that this model implies an influence of visual experience on the spacing of ocular dominance columns and provides a conceptually simple explanation for the emergence of larger sized columns in squinting animals. Assuming that during development cortical neurones become active in local groups, which we call co-activated cortical domains (CCDs), ocular dominance segregation is controlled by the size of these groups: (1) Size and spacing of ocular dominance columns are proportional to the size sigma of CCDs. (2) There is a critical size sigma* of CCDs such that ocular dominance columns form if sigma sigma*. This critical size of CCDs is determined by the correlation functions of activity patterns in the two eyes and specifies the influence of experience on ocular dominance segregation. We show that sigma* is larger with squint than with normal visual experience. Since experimental evidence indicates that the size of CCDs decreases during development, ocular dominance columns are predicted to form earlier and with a larger spacing in squinters compared to normal animals.

Animals↗
PubMed2001

A primary role for the epidermal growth factor receptor in ommatidial spacing in the Drosophila eye.

BACKGROUND: The differentiation of regularly spaced structures within an epithelium is a common feature of developmental pattern formation. The regular spacing of ommatidia in the Drosophila eye imaginal disc provides a good model for this phenomenon. The correct spacing of ommatidia is a central event in establishing the precise hexagonal pattern of ommatidia in the Drosophila compound eye. The R8 photoreceptors are the founder cells of each of the ommatidia that comprise the adult eye and are specified by a bHLH transcription factor, Atonal. RESULTS: We find that the epidermal growth factor receptor (Egfr) has a primary function in regulating R8 spacing. The receptor's activation within nascent ommatidia induces the expression of a secreted inhibitor that blocks atonal expression, and therefore ommatidial initiation, in nearby cells. The identity of the secreted inhibitor remains elusive but, contrary to previous suggestions, we show that it is not Argos. This Egfr-dependent inhibition acts in parallel to the inhibition of atonal by the secreted protein Scabrous. The activation of the Egfr pathway is dependent on Atonal function via the expression of Rhomboid-1. Our results also allow us to conclude that Egfr's role in promoting cell survival is largely independent of its role in photoreceptor recruitment; even when cell death is blocked, most photoreceptors fail to form. CONCLUSIONS: Based on our data and those of others, we propose a model for R8 spacing that comprises a self-organizing network of signaling molecules. This model describes how successive rows of ommatidia form out of phase with each other, leading to the hexagonal array of facets in the compound eye.

Animals↗
PubMed1999

Time-resolved measurements with single droplet introduction to investigate space-charge effects in plasma mass spectrometry.

An investigation of the space-charge induced effects of high concentrations of Pb+ matrix ions on Li+ analyte ions in inductively coupled plasma mass spectrometry (ICP-MS) is presented using a vertically oriented mass spectrometer with single droplet introduction. Greater reproducibility and stability in droplet-to-droplet sample introduction using the monodisperse microparticulate injector (MDMI) was achieved with the vertical orientation. Typical variation (%RSD) in the droplet-to-droplet arrival times, and mass spectrometry peak analytical areas are better than 5%. With this precision, a more quantitative description of the space-charge effect on a single cloud of ions is obtained. Both radial and axial space-charge effects were found to occur in the ion beam. Radial effects result in a loss in intensity because of poor transmission or collisions at surfaces within the mass spectrometer. Axial effects modify the kinetic energy distribution of background ion beam components (e.g., 16O+ and 40Ar+) and sampled ion cloud constituents (e.g., 7Li+). However, axial effects do not appear to generate significant broadening of sampled ion clouds within the mass spectrometer. At the point of charge separation and high ion-beam charge density, the ion cloud maxima for Li and Pb are not coincident. This is because of mass dependent diffusion in the ICP as the ion clouds approach the sampling orifice. Space-charge induced ion loss occurs predominantly at a localized region after the Li+ sampled cloud peak maximum. When the Pb concentration in the sample is sufficiently high the 7Li+ sampled signal has a bimodal peak shape. The existence of the dip and its relative location in the bimodal 7Li+ sampled signal suggests that space-charge effects are localized to the region of high charge density occurring just after charge separation.

Algorithms↗
PubMed1996

Effects of sustained unilateral molar clenching on the temporomandibular joint space.

OBJECTIVE: To measure the effect of unilateral sustained clenching on the temporomandibular joints, changes in the minimum joint space dimension were assessed. STUDY DESIGN: Ten healthy subjects performed a sustained clench on a bite force transducer in the first molar region for 5 minutes with a constant force of 170 N. Three separate sagittal tomograms were bilaterally obtained with the transducer in place before clenching and during the beginning and at the end of the contraction. Changes were quantified with a computerized image analysis system. RESULTS: The minimum joint space of the contralateral temporomandibular joint was significantly reduced both at the beginning and at the end of the contraction task. Further the minimum joint space was also significantly less at the end than at the beginning of the contraction even though bite force level was identical. The ipsilateral condyle images showed no significant shift in the minimum joint space. CONCLUSIONS: These data suggest that unilateral molar clenching induces a significant reduction of the minimum joint space in the contralateral temporomandibular joint and a sustained condition remarkably increases this change.

Adult↗
PubMed1999

Radiographic evaluation of mandibular third molar eruption space.

OBJECTIVE: The purpose of this study was to investigate variables in third molar and arch dimensions among subjects with impacted and erupted mandibular third molars. STUDY DESIGN: Standardized panoramic radiographs were taken for 134 subjects (60 males and 74 females with 213 third molars) with an average age of 19.8 years. For the impacted group, only those who had mesioangular inclination of the third molars were recorded. The radiographic features studied were angulation of tooth, level of eruption, development of root, mesiodistal crown width, retromolar space, and gonial angle. RESULTS: Third molar angulation in the impacted group (69 subjects with 101 third molars) averaged 16.28 degrees (SD +/- 11.88 degrees), with no significant gender differences. The retromolar space was significantly smaller in the impacted group than in the erupted group (P < .001). This space was also the only significant variable (P < .05) associated with lateral asymmetry in the eruption/impaction status of third molars. In the impacted group, 83% of subjects had third molar space/crown width ratios less than 1, whereas in the erupted group 69% had ratios of at least 1. The average space/crown width ratios in the impacted and erupted groups were 0.78 and 1.06, respectively (P < .001). The impacted and erupted groups did not differ significantly with respect to mesiodistal crown width and gonial angle. Approximately 76% of impacted third molars had complete root formation, 20% had two thirds root formation, and only 4% displayed one third root formation. Of the impacted third molars, 66% were partially erupted and the rest were unerupted. There was a strong positive relationship between frequency of third molar impaction and degree of angulation (P < .001), but the former was inversely associated with retromolar space (P < .001). CONCLUSIONS: The most significant variable associated with third molar impaction is inadequate space. The vast majority of impacted third molars had space/crown width ratios of less than 1.

Adolescent↗
PubMed2003

Life-cycle experiments of medaka fish aboard the international space station.

Fish are the most likely candidates to be the first vertebrate to live their life cycle aboard the International Space Station (ISS). In the space-shuttle experiment using medaka, the fry born in space had the same number of germ cells as the ground control fish, and these germ cells later developed to produce the offspring on the ground. Fry hatched in space did not exhibit any looping behavior regardless of their strain, visual acuity, etc. The aquatic habitat (AQH) is a space habitat designed for long-term breeding of medaka, zebrafish and Xenopus, and recent advancements in this hardware also support fish life-cycle experiments. From the crosses between two strains, fish having good eyesight and less sensitivity to gravity were obtained, and their tolerance to microgravity was tested by parabolic flight using an airplane. The fish exhibited less looping and no differences in degree of looping between light and dark conditions. These are possible candidates for the first adult medaka (parent fish) to start a life cycle aboard ISS. Embryos were treated with a three-dimensional clinostat. Such simulated microgravity caused no differences in tissue architecture or in gene expression within the retina, nor in formation of cartilage (head skeleton). Otolith formation in embryos and fry was investigated for wild-type and mutant (ha) medaka. The ha embryos could not form utricular otoliths. They formed saccular otoliths but with a delay. Fry of the mutant fish lacking the utricular otoliths are highly light-dependent at the time of hatching, showing a perfect dorsal-light response (DLR). As they grow, they eventually shift from being light dependent to gravity dependent. Continuous treatment of the fry with altered light direction suppressed this shift to gravity dependence. Being less dependent on gravity, these fish can serve as model fish in studying the differences expected for the fish that have experienced a life cycle in microgravity.

Animals↗
PubMed2000

Invasions of personal space in demented and nondemented elderly persons.

Personal space has been a research issue in both social psychology and nursing in the past 20 years. In the context of behavioral and psychological signs and symptoms in dementia (BPSSD), however, personal space and other basic paradigms of social psychology sparsely play a role. In order to assess personal space in demented (n = 10) and nondemented (n = 10) elderly participants, we replicated the original study addressing personal space by Felipe and Sommer (1966). The two groups differed in the overall number of participants showing a specific reaction, in the mean duration until specific reactions occurred, and in the percentage of participants within a group showing a specific reaction at a given point in time. The argument is being made that such findings might reflect situational as well as disease-specific changes in the perception of and reactions to invasions of personal space in demented patients. We suggest that further research in that field could bring about more information on the nature of dementia, and especially BPSSD. Implications for therapy and care of dementia patients are being discussed.

Aged↗
PubMedDate not supplied

Exploring chemical rings in a simple topological-descriptor space.

A new method for organizing chemical rings based on their topology is presented. It uses three simple descriptors that characterize separate aspects of ring topology. These descriptors are integers and can thus be interpreted as the coordinates of discrete cells in a three-dimensional space. The descriptor values of any ring topology correspond to the coordinates of some cell. A database of rings can be distributed in this descriptor space by assigning each of them to the corresponding cell. This approach is applied to a database of 40 182 different ring topologies, derived from a comprehensive collection of chemical rings extracted from the CAS Registry File. This database is distributed among 7387 cells, and the population statistics and spatial distribution of these cells are discussed. An examination of selected cells shows that ring topologies which are similar tend to be close together in descriptor space. Some results of using this space to study ring diversity are presented. It is found that the distribution of the ring-topology database is not highly compact but has many significant voids. It is also found that the distribution of medicinally relevant rings in this space shows the influence of certain structural constraints on drug molecules.

Journal Article↗
PubMedDate not supplied

Molecular similarity analysis and virtual screening by mapping of consensus positions in binary-transformed chemical descriptor spaces with variable dimensionality.

A novel compound classification algorithm is described that operates in binary molecular descriptor spaces and groups active compounds together in a computationally highly efficient manner. The method involves the transformation of continuous descriptor value ranges into a binary format, subsequent definition of simplified descriptor spaces, identification of consensus positions of specific compound sets in these spaces, and iterative adjustments of the dimensionality of the descriptor spaces in order to discriminate compounds sharing similar activity from others. We term this approach Dynamic Mapping of Consensus positions (DMC) because the definition of reference spaces is tuned toward specific compound classes and their dimensionality is increased as the analysis proceeds. When applied to virtual screening, sets of bait compounds are added to a large screening database to identify hidden active molecules. In these calculations, molecules that map to consensus positions after elimination of most of the database compounds are considered hit candidates. In a benchmark study on five biological activity classes, hits for randomly assembled sets of bait molecules were correctly identified in 95% of virtual screening calculations in a source database containing more than 1.3 million molecules, thus providing a measure of the sensitivity of the DMC technique.

Journal Article↗
PubMedDate not supplied

Scalable partitioning and exploration of chemical spaces using geometric hashing.

Virtual screening (VS) has become a preferred tool to augment high-throughput screening(1) and determine new leads in the drug discovery process. The core of a VS informatics pipeline includes several data mining algorithms that work on huge databases of chemical compounds containing millions of molecular structures and their associated data. Thus, scaling traditional applications such as classification, partitioning, and outlier detection for huge chemical data sets without a significant loss in accuracy is very important. In this paper, we introduce a data mining framework built on top of a recently developed fast approximate nearest-neighbor-finding algorithm(2) called locality-sensitive hashing (LSH) that can be used to mine huge chemical spaces in a scalable fashion using very modest computational resources. The core LSH algorithm hashes chemical descriptors so that points close to each other in the descriptor space are also close to each other in the hashed space. Using this data structure, one can perform approximate nearest-neighbor searches very quickly, in sublinear time. We validate the accuracy and performance of our framework on three real data sets of sizes ranging from 4337 to 249 071 molecules. Results indicate that the identification of nearest neighbors using the LSH algorithm is at least 2 orders of magnitude faster than the traditional k-nearest-neighbor method and is over 94% accurate for most query parameters. Furthermore, when viewed as a data-partitioning procedure, the LSH algorithm lends itself to easy parallelization of nearest-neighbor classification or regression. We also apply our framework to detect outlying (diverse) compounds in a given chemical space; this algorithm is extremely rapid in determining whether a compound is located in a sparse region of chemical space or not, and it is quite accurate when compared to results obtained using principal-component-analysis-based heuristics.

Journal Article↗
PubMedDate not supplied

"Bayes affinity fingerprints" improve retrieval rates in virtual screening and define orthogonal bioactivity space: when are multitarget drugs a feasible concept?

Conventional similarity searching of molecules compares single (or multiple) active query structures to each other in a relative framework, by means of a structural descriptor and a similarity measure. While this often works well, depending on the target, we show here that retrieval rates can be improved considerably by incorporating an external framework describing ligand bioactivity space for comparisons ("Bayes affinity fingerprints"). Structures are described by Bayes scores for a ligand panel comprising about 1000 activity classes extracted from the WOMBAT database. The comparison of structures is performed via the Pearson correlation coefficient of activity classes, that is, the order in which two structures are similar to the panel activity classes. Compound retrieval on a recently published data set could be improved by as much as 24% relative (9% absolute). Knowledge about the shape of the "bioactive chemical universe" is thus beneficial to identifying similar bioactivities. Principal component analysis was employed to further analyze activity space with the objective to define orthogonal ligand bioactive chemical space, leading to nine major (roughly orthogonal) activity axes. Employing only those nine activity classes, retrieval rates are still comparable to original Bayes affinity fingerprints; thus, the concept of orthogonal bioactive ligand chemical space was validated as being an information-rich but low-dimensional representation of bioactivity space. Correlations between activity classes are a major determinant to gauge whether the desired multitarget activity of drugs is (on the basis of current knowledge) a feasible concept because it measures the extent to which activities can be optimized independently, or only by strongly influencing one another.

Algorithms↗
PubMed2005

Range and sensitivity as descriptors of molecular property spaces in dynamic QSAR analyses.

In this paper, we report the first study aimed at correlating pharmacological properties with molecular parameters derived from the physicochemical property space of bioactive molecules. A dataset of 36 ligands of the alpha(1a)-, alpha(1b)-, and alpha(1d)-adrenoceptors as published by Bremner et al. (Bioorg. Med. Chem. 2000, 8, 201-214) was used. One thousand conformers were generated for each ligand by Monte Carlo conformational analysis, and four 3D-dependent physicochemical properties were computed for each conformer of each ligand, namely virtual lipophilicity (log P), dipole moment, polar surface area (PSA), and solvent-accessible surface area (SAS). Thus, a space of four physicochemical properties was obtained for each ligand. These spaces were assessed by two descriptors, namely their range and their sensitivity (i.e., the variation amplitude of a given physicochemical property for a given variation in molecular geometric properties). Little or no correlation was found to exist between the physicochemical properties and their range or sensitivity, indicating that the latter descriptors do not encode the same molecular information as the former properties. As expected, neither the range nor the sensitivity of any of the four physicochemical properties correlated with receptor affinities. In contrast, range and sensitivity showed promising correlations with deltapK(a-b) (i.e., the alpha(1a)/alpha(1b) selectivity) for the complete dataset. The correlations were lower for deltapK(a-d) (i.e., the alpha(1a)/alpha(1d) selectivity), whereas there was no correlation at all with deltapK(b-d). These results are consistent with the results of Bremner et al., which indicate that the alpha(1a)-AR ligands bind in an extended geometry, whereas the alpha(1b)-AR and alpha(1d)-AR ligands assume more folded conformations. Since the property space descriptors presented here take structural variability into account, their correlation with deltapK(a-b) and deltapK(a-d) indicates that these selectivities are indeed driven by differences in conformational behavior and hence in property spaces.

Chemical Phenomena↗
PubMed2005

Reappraisal of the role of size-extensive normalization for multireference coupled cluster (MRCC) theory using general model space: a valence universal MRCC approach.

We present a brief description of a valence-universal multireference coupled cluster (VU-MRCC) theory that can handle completely general incomplete model spaces, remaining close to the intermediate normalization (IN) condition for omega as much as possible without violating extensivity and without the use of a post facto correction. In this formalism, the connectedness of the cluster operators as well as effective Hamiltonian and hence the extensivity of the corresponding roots is achieved by invoking appropriate decoupling conditions on the special type of wave operator omega = {exp(S + X(cl))} satisfying the Bloch equations in the Fock-space S in an excitation operator and X is a closed operator (denoted by cl). This special type of wave-operator leads to a unique partition of the excitations from the model space into those generated by the cluster operators (open and quasi-open) and those generated by the effective Hamiltonian (closed). In this formulation, for every X(cl), there is a counterterm from {exp(S)}(cl) canceling each other. This leads to a connected expressions for cluster amplitudes, using the constraint omega(cl) = 1. The new form of the effective Hamiltonian preserves the extensivity of the target energies. Our analysis implies that IN for omega is a valid size-extensive normalization for certain special IMS such as the quasi-complete model space and the isolated incomplete model space.

Journal Article↗
PubMed1998

Z/I and A-band lattice spacings in frog skeletal muscle: effects of contraction and osmolarity.

A-band and Z-line/I-band lattice spacings were measured by small-angle X-ray diffraction from relaxed and isometrically-contracting whole frog sartorius muscles with lattice spacings reduced or swollen by changing the osmolarity of the bathing solution. A-band spacing increased by approximately 3% upon isometric contraction at reduced lattice spacings (245-356 mOsm) and decreased by approximately 1% at swollen spacings (172 mOsm), similarly to the behaviour of skinned muscles upon changing from the relaxed state to rigor. The Z/I lattice underwent a significant lattice expansion (3-8%) upon isometric contraction at all osmolarities, in qualitative agreement (but quantitative disagreement) with results from electron microscopy on mammalian skeletal muscle. Lattice areas calculated for the Z/I and A-band lattices indicate a barrel-shaped sarcomere in the resting state, which may provide a partial explanation for how longitudinal forces produced in the A-band can produce a radial expansive force in the Z-line during contraction. The radial component of cross-bridge stiffness was calculated from the A-band data for contracting muscle, using a lattice stability model incorporating structural, osmotic and electrostatic forces. The calculations gave a radial cross-bridge stiffness during contraction of about 9 x 10(5) N m-2, and outward radial force per thick filament in normal Ringer's solution of 6 x 10(-9) N, corresponding to a radial force per cross-bridge of 10(-11) N.

Animals↗
PubMed2001

Similarity searching in large combinatorial chemistry spaces.

We present a novel algorithm, called Ftrees-FS, for similarity searching in large chemistry spaces based on dynamic programming. Given a query compound, the algorithm generates sets of compounds from a given chemistry space that are similar to the query. The similarity search is based on the feature tree similarity measure representing molecules by tree structures. This descriptor allows handling combinatorial chemistry spaces as a whole instead of looking at subsets of enumerated compounds. Within few minutes of computing time, the algorithm is able to find the most similar compound in very large spaces as well as sets of compounds at an arbitrary similarity level. In addition, the diversity among the generated compounds can be controlled. A set of 17,000 fragments of known drugs, generated by the RECAP procedure from the World Drug Index, was used as the search chemistry space. These fragments can be combined to more than 10(18) compounds of reasonable size. For validation, known antagonists/inhibitors of several targets including dopamine D4, histamine H1, and COX2 are used as queries. Comparison of the compounds created by Ftrees-FS to other known actives demonstrates the ability of the method to jump between structurally unrelated molecule classes.

Algorithms↗
PubMed1999

Long-term outcome of RPE allografts to the subretinal space of rabbits.

PURPOSE: To determine the long-term RPE allograft survival in the subretinal space using suspensions of RPE cells and atraumatic transplantation surgery. METHODS: Nineteen albino rabbits were transplanted with suspensions of pigmented RPE cells from brown rabbits. Following pars plana vitrectomy, the RPE cell suspension was injected through a small retinotomy using a glass micropipette into the subretinal space under microscopic control. No immunosuppression was used. The eyes were monitored by biomicroscopy, color fundus photography, and fluorescein angiography. Rabbits were sacrificed at 1, 3 and 6 months, respectively, and the eyes processed for light and electron microscopy, using monoclonal antibodies for identifying macrophages. RESULTS: Transplanted RPE cells were present in the subretinal space in all eyes at 6 months. There was no fluorescein leakage. Generally, the RPE allograft formed a monolayer, but focal fragmentation and disruption with dispersion of melanin pigment occurred. Foci of multilayers of cells in the subretinal space, containing large macrophages, were associated with adjacent photoreceptor damage. There was no infiltration of lymphocytes but macrophages and glial cells were contiguous to the transplant. Cells harboring intracytoplasmatic melanin pigment were observed in the neural retina. CONCLUSION: Transplantation of RPE cell suspensions to the subretinal space generally forms a monolayer that persists at 6 months. However, in areas of multilayers of RPE cells and macrophages, graft failure occurs in combination with adjacent photoreceptor damage. Graft failure is not associated with the infiltration of lymphocytes, but other mechanisms seem to occur.

Animals↗