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PubMed1986

A study of calcification in the leg tendons from the domestic turkey.

Details are presented of the structure and the spatial and temporal sequence of calcification within leg tendons obtained from the domestic turkey, Meleagris gallopavo. Histological and ultrastructural examination of the tissues reveals the development of large tendonoblasts, disposed in columns parallel to tendon long axes. Maturing cells are characterized by organelles active in protein synthesis, few mitochondrial granules, and an extensive system of processes. Deposition of mineral in the extracellular tissue spaces appears initially associated with small vesicular structures located between collagen fibrils. As calcification progresses, mineral is associated predominantly with collagen. Electron diffraction and electron probe microanalysis indicate that the mineral is a poorly crystalline hydroxyapatite having a Ca/P molar ratio ranging between 0.9 and 1.5. Following decalcification and staining of tissue sections, vesicular structures retain integrity by uptake of lead and uranium salts while collagen stains only poorly. Implications of these results are discussed with respect to the physicochemical and biological events of vertebrate calcification.

Animals↗
PubMed1989

First bone formation and the dissection of an osteogenic lineage in the embryonic chick tibia is revealed by monoclonal antibodies against osteoblasts.

Detailed studies of the origin and differentiation of osteogenic cells can be facilitated by cell-specific markers. To this end, we immunized mice with a heterogeneous population of chick embryonic bone cells and subsequently generated and selected for monoclonal antibodies against cell surface determinants. Supernatants from growing hybridoma colonies were screened immunohistochemically against frozen sections of embryonic stage 35 (day 9.5) chick tibiae. Three cell lines, SB-1, SB-2, and SB-3, which each secrete a different antibody against osteogenic cells, have been successfully cloned, stabilized, and immortalized. Antibody SB-1 reacts with a family of cells in embryonic bone, liver, kidney, and intestine, which are identically stained by the histochemical stain for alkaline phosphatase. The SB-2 antigen is present only on osteoblasts, while the SB-3 antigen is expressed on the surface of osteoblasts, ependymal cells and ventricular myoblasts. Studies on the developmental progression of osteoblasts in the embryonic tibia indicate that the determinants recognized by SB-1, SB-2, and SB-3 are temporally coupled to the appearance of the pre-osteoblast marker alkaline phosphatase. Detailed morphologic analyses reveal that SB-1 reacts with a large family of osteogenic cells residing between the surface of newly formed bone and the overlying periosteal osteoprogenitor cells. By contrast, SB-2 and SB-3 appear to react with those mature osteoblasts involved in the secretion and mineralization of osteoid. Cells which are imprisoned within bone matrix (osteocytes) of the developing tibia are not recognized by these antibodies, but are immunostained by an osteocyte-specific monoclonal antibody which does not react with SB-1, SB-2 or SB-3 positive cells. The results reported here suggest the existence of an osteogenic cell lineage which is characterized by a series of discrete cell states prior to the overt expression of the Secretory Osteoblastic phenotype. We propose that the emergence and abatement of phenotypically distinct osteogenic cell surface antigens follows a precise spatial and temporal sequence which reflects the position of cells within the osteogenic lineage.

Alkaline Phosphatase↗
PubMed2006

Memory formation by neuronal synchronization.

Cognitive functions not only depend on the localization of neural activity, but also on the precise temporal pattern of activity in neural assemblies. Synchronization of action potential discharges provides a link between large-scale EEG recordings and cellular plasticity mechanisms. Here, we focus on the role of neuronal synchronization in different frequency domains for the subsequent stages of memory formation. Recent EEG studies suggest that synchronized neural activity in the gamma frequency range (around 30-100 Hz) plays a functional role for the formation of declarative long-term memories in humans. On the cellular level, gamma synchronization between hippocampal and parahippocampal regions may induce LTP in the CA3 region of the hippocampus. In order to encode spatial locations or sequences of multiple items and to guarantee a defined temporal order of memory processing, synchronization in the gamma frequency range has to be accompanied by a stimulus-locked phase reset of ongoing theta oscillations. Simultaneous gamma- and theta-dependent plasticity leads to complex learning rules required for realistic declarative memory formation. Subsequently, consolidation of declarative memories may occur via replay of newly acquired patterns in so-called sharp wave-ripple complexes, predominantly during slow-wave sleep. These irregular bursts induce longer lasting forms of synaptic plasticity in output regions of the hippocampus and in the neocortex. In summary, synchronization of neural assemblies in different frequency ranges induces specific forms of cellular plasticity during subsequent stages of memory formation.

Action Potentials↗
PubMed2004

Does looping and clustering in the nucleus regulate gene expression?

There has been considerable interest in the way that chromatin is spatially organised within the cell nucleus and how that may relate to gene expression and its control. New molecular techniques have identified looped chromatin domains at the mammalian beta-globin and the Drosophila hsp70 loci. Looped domains may insulate chromatin from the influence of neighbouring domains, and the bases of loops may also act to concentrate proteins locally within the nucleus. The spatial clustering of sequences from the Drosophila bithorax complex, located in trans, has also been demonstrated. An emerging theme is that bringing DNA and proteins together within a defined sub-region of the nuclear volume facilitates both the activation and the repression of gene expression. Nuclear compartments may also be involved in the post-translational modification of proteins by sumoylation and ubiquitylation.

Animals↗
PubMed2005

Multiple-quantum vector field imaging by magnetic resonance.

We introduce a method for non-invasively mapping fiber orientation in materials and biological tissues using intermolecular multiple-quantum coherences. The nuclear magnetic dipole field of water molecules is configured by a CRAZED sequence to encode spatial distributions of material heterogeneities. At any given point r in space, we obtain the spherical coordinates of fiber orientation (theta,phi) with respect to the external field by comparing three signals ||G(X)||, ||(Y)||, and ||G(Z)|| (modulus), acquired with linear gradients applied along the X, Y, and Z axes, respectively. For homogeneous isotropic materials, a subtraction ||G(Z)|| - ||G(X)|| - ||G(Y)|| gives zero. With anisotropic materials, we find an empirical relationship relating ||G(Z)|| - ||G(X)|| - ||G(Y)||/(||G(X)|| + ||G(Y)|| + ||G(Z)||) to the polar angle theta, while ||G(X|| - ||G(Y)||/(||G(X)|| + ||G(Y)|| + ||G(Z)||) is related to the azimuthal angle phi. Experiments in structured media confirm the structural sensitivity. This technique can probe length scales not accessible by conventional MRI and diffusion tensor imaging.

Animals↗
PubMed2005

The phylogeography of the gecko Cyrtopodion kotschyi (Reptilia: Gekkonidae) in the Aegean archipelago.

Cyrtopodion kotschyi is a small gecko, widely distributed on the islands of the Aegean archipelago and the adjacent mainland. We unveiled the phylogeography of the species by using a portion of the cytochrome oxidase I mitochondrial DNA gene from 35 insular and mainland populations. The distinct geographic distribution of the major clades of the phylogenetic tree and its topology suggest a spatial and temporal sequence of phylogenetic separations that coincide with some major paleogeographical separations during the geological history of the Aegean and support a mainly vicariant pattern of differentiation. The separation times and 95% confidence limits among the different clades were estimated according to two different paleogeographical scenarios. The very high interpopulation genetic divergence (up to 20% uncorrected pairwise distances) and the better concordance between paleogeographical and phylogenetic separations for one of the scenarios suggest that species differentiation started during Miocene (about 10 Mya) due to the fragmentation of the united landmass of "Agais" that was Aegean at that time.

Animals↗
PubMed2001

Visualizing excitation waves inside cardiac muscle using transillumination.

Voltage-sensitive fluorescent dyes have become powerful tools for the visualization of excitation propagation in the heart. However, until recently they were used exclusively for surface recordings. Here we demonstrate the possibility of visualizing the electrical activity from inside cardiac muscle via fluorescence measurements in the transillumination mode (in which the light source and photodetector are on opposite sides of the preparation). This mode enables the detection of light escaping from layers deep within the tissue. Experiments were conducted in perfused (8 mm thick) slabs of sheep right ventricular wall stained with the voltage-sensitive dye di-4-ANEPPS. Although the amplitude and signal-to-noise ratio recorded in the transillumination mode were significantly smaller than those recorded in the epi-illumination mode, they were sufficient to reliably determine the activation sequence. Penetration depths (spatial decay constants) derived from measurements of light attenuation in cardiac muscle were 0.8 mm for excitation (520 +/- 30 nm) and 1.3 mm for emission wavelengths (640 +/- 50 nm). Estimates of emitted fluorescence based on these attenuation values in 8-mm-thick tissue suggest that 90% of the transillumination signal originates from a 4-mm-thick layer near the illuminated surface. A 69% fraction of the recorded signal originates from > or =1 mm below the surface. Transillumination recordings may be combined with endocardial and epicardial surface recordings to obtain information about three-dimensional propagation in the thickness of the myocardial wall. We show an example in which transillumination reveals an intramural reentry, undetectable in surface recordings.

Animals↗
PubMed1997

M and P components of the VEP and their visual field distribution.

To study components related to parallel processing of information across the visual field, multi-focal pattern reversal visual evoked potentials (VEPs) were recorded using binary m-sequences. Contrast, chromatic, spatial and temporal characteristics of the stimuli were varied in order to favor contributions from either M or P pathways. Responses were decomposed into two additive components whose behavior was consistent with that of M and P mechanisms. The results suggest that contributions to the VEP from the M pathway precede those from the P pathway, and that the ratio of P/M contributions decreases with eccentricity.

Adult↗
PubMedDate not supplied

Experimental study on HASTE sequences: impacts of parameters on liver imaging.

This study investigates the impacts of effective TE (TEeff), echo spacing and echo train lengths (ETLs) on the imaging quality of HASTE sequences for liver imaging through a slit and a liver phantom. The HASTE sequence with a short echo spacing demonstrated higher CNR for a phantom simulating hepatocellular carcinoma (HCC) than that with long echo spacing. With a long echo spacing, the HASTE sequence showed higher spatial resolution for hemangiomas and metastasis. The improvement of spatial resolution along with the increase in ETLs (imaging matrix) was more prominent for hemangioma than for HCC.

Carcinoma, Hepatocellular↗
PubMed2003

Evoked potentials to auditory movement sensation in duplex perception.

OBJECTIVE: The purpose of this study was to examine the processing of auditory movement sensation accompanying duplex perception in binaural hearing. METHODS: Stimuli were formant transitions (presented to the front, left or right of the subject) and base (presented to the front), that fused to result in vowel-consonant-vowel (V-C-V) sequences /aga/ and /ada/. An illusion of auditory movement (duplex sensation) accompanied the fusion of these V-C-V sequences when the spatial locations of the formant transitions and base were different. Ten right-handed, adult, native Hebrew speakers discriminated each fused stimulus, and the brain potentials associated with performance of the task were recorded from 21 electrodes. The processing of auditory movement was studied by a factorial design (ANOVA) and statistical non-parametric mapping (SnPM) of low resolution electromagnetic tomography (LORETA) images of the net-fusion response. Brain regions implicated in auditory movement processing were expected to be associated with the lateralized formant location, which gave rise to duplex perception. In addition, the time-course of significant activation in brain areas that differentiated between fusion conditions was determined. RESULTS: The posterior parietal, anterior cingulate and premotor cortices were found to be implicated in duplex processing. Auditory cortex involvement was also evident, and together with the latter two brain regions was affected by right-ear advantage. CONCLUSIONS: Duplex perception resulting from fusion of spatially separate sounds forming an auditory object results in activation of a network of brain regions reflecting enhanced allocation of attention and the effect of language processing.

Acoustic Stimulation↗
PubMed2003

Solid-phase synthesis for the identification of high-affinity bivalent lectin ligands.

The development of carbohydrate-based therapeutics has been frustrated by the low affinities that characterize protein-carbohydrate complexation. Because of the oligomeric nature of most lectins, the use of multivalency may offer a successful strategy for the creation of high-affinity ligands. The solid-phase evaluation of libraries of peptide-linked multivalent ligands facilitates rapid examination of a large fraction of linker structure space. If such solid-phase assays are to replicate solution binding behavior, the potential for intermolecular bivalent binding on bead surfaces must be eliminated. Here we report the solid-phase synthesis and analysis of peptide-linked, spatially segregated mono- and bivalent ligands for the legume lectin concanavalin A. Bead shaving protocols were used for the creation of beads displaying spatially segregated binding sequences on the surface of Tentagel resins. The same ligands were also synthesized on PEGA resin to determine the effect of ligand presentation on solid-phase binding. While we set out to determine the lower limit of assay sensitivity, the unexpected observation that intermolecular bivalent ligand binding is enhanced for bivalent ligands relative to monovalent ligands allowed direct observation of the level of surface blocking required to prevent intermolecular bivalent ligand binding. For a protein with binding sites separated by 65 A, approximately 99.9% of Tentagel(1) surface sites and 99.99% of the total sites on a PEGA bead must be blocked to prevent intermolecular bivalent binding. We also report agglutination and calorimetric solution-phase binding studies of mono- and bivalent peptide-linked ligands.

Amino Acid Sequence↗
PubMed2004

Equilibrium bifurcations and chaotic transitions in coupled microlaser lattices.

Analytic and simulation studies for the steady-state equilibria and bifurcations of coupled microlaser arrays are described. Lateral cavity interactions affect the gain in each cavity, leading to active photonic lattice behavior, equivalent to a nonlinear coupled oscillator lattice. The coupled-cavity rate equations are employed to follow the coherent photon and carrier population in each lattice site. Fixed-point-type steady states, of constant lattice phase shift, result for low coupling strengths; the radiation envelope for these states conforms with a periodic Bloch state over the array. Bifurcations to limit cycles of increasing complexity occur at higher coupling via period doubling sequences. The associated spatial patterns of photon and carrier lattice distribution resemble photonic convection cells. Limit cycles of different periods, emanating mathematically from different original fixed points, coexist at high strengths, each one accessible from different initial conditions. The multiplicity of possible limit cycles in systems with many degrees of freedom (number of lattice sites) combined with changes in their accessibility from initial conditions offers new insights to chaotic transitions, compared to low dimensionality paradigms.

Journal Article↗
PubMed2026

Dissecting spatial patterning and signaling with directional diffusion in spatial multi-omics.

Spatial multi-omics sequencing enables the simultaneous profiling of transcriptomics, proteomics, and epigenomics at a spatial resolution, offering insights into complex tissue organization and molecular regulation. However, the effective integration of multiple omics modalities in a spatial context remains a major challenge. Here, we present SpaDDM, a spatial multi-omics integration framework based on directional diffusion models (DDMs), which supports spatial pattern identification, cross-omics alignment, and inter-and intracellular signaling flow analysis. SpaDDM employs DDM-based graph networks to learn omics-specific representations by jointly incorporating spatial coordinates and molecular measurements within each modality, followed by an attention mechanism to align features across modalities. We benchmarked SpaDDM on diverse spatial multi-omics datasets, including transcriptomics-epigenomics and transcriptomics-proteomics combinations across multiple tissues and species. SpaDDM consistently outperformed existing methods by more accurately deciphering spatial tissue patterns and effectively reducing the boundary noise between spatial regions. Moreover, the learned low-dimensional coembedded representations of individual cells serve as integral mediators for inferring the signaling flows that underlie spatial patterning. Finally, we demonstrated that SpaDDM alignment of complementary information across multi-omics layers facilitates cross-omics translation and significantly improves the prediction of cell state alignments.

Multiomics↗
PubMed1975

Human globin gene expression and linkage in bone marrow and fetal liver.

During embryonic development there is a transition from embryonic and fetal to adult beta-type globin chains. The high-molecular-weight RNA found in nuclei from embryonic and adult human erythropoietic tissues, fetal liver, and bone marrow, have been investigated for the presence of gamma(fetal)- and beta(adult)-globin messenger RNA sequences by molecular hybridization. Unlike alpha- and beta-globin mRNA sequences, gamma-globin mRNA sequences are absent from both total and high-molecular-weight nuclear RNA isolated from adult bone marrow. The amount of cytoplasmic gamma-globin mRNA is proportional to the level of gamma-chain synthesis, demonstrating that translational control is not a major control mechanism in the expression of globin genes. Since the gamma-, delta-, and beta-globin genes are known to be closely linked genetically, transcriptional control can discriminate between similar gene sequences that are spatially adjacent to one another.

Bone Marrow↗
PubMed1994

Cellular epigenetics: topochronology of progressive "spontaneous" transformation of cells under growth constraint.

Early passages of NIH 3T3 cells yield about 10 transformed foci for every 10(5) cells seeded after the cells multiply to confluence in a standardized 2-week assay. The question arose whether more cells would give rise to foci if given more time for their development. This question could not be answered simply by extending the incubation period, since the original foci spread to cover much of the area of the culture dish. Transformed cells can also detach into the medium from the original foci to initiate new foci by reattaching at a distance. These problems were averted by growing cells in multiwell plates which in effect simulated partitioned culture dishes. All the wells in a given plate were assayed for focus formation at successive intervals up to 14 weeks. The results indicated the spatial pattern and sequence of transformation on different parts of the "partitioned" dish. The number of multiwells containing focus-forming cells increased steadily with time, indicating that all parts of a dish eventually undergo transformation. Also, most of the transformations were recorded long after confluence in the multiwells was reached. Hence such a transformation is much more likely to occur in the nondividing state rather than in the dividing state of the cells and is thus inconsistent with a mutational basis. The results suggest that "spontaneous" transformation is a population-wide, epigenetic phenomenon. This agrees with the results from clonal analysis and other studies and is well described by the concept of progressive state selection, in which "spontaneous" transformation represents a heterogeneous, adaptive response of competent cells to moderate constraints on cell growth.

3T3 Cells↗
PubMed1997

Functional analysis of surfactant protein B (SP-B) promoter. Sp1, Sp3, TTF-1, and HNF-3alpha transcription factors are necessary for lung cell-specific activation of SP-B gene transcription.

Surfactant protein B (SP-B) is essential for maintenance of biophysical properties and physiological function of pulmonary surfactant. SP-B mRNA expression is restricted to alveolar type II epithelial cells and bronchiolar epithelial cells (Clara cells) of adult lung. We previously (Margana, R. K., and Boggaram, V. (1996) Am. J. Physiol. 270, L601-L612) found that a minimal promoter region (-236 to +39) of rabbit SP-B gene is sufficient for high level expression of chloramphenicol acetyltransferase reporter gene in NCI-H441 cells, a cell line with characteristics of Clara cells. In the present study we used mutational analysis, electrophoretic mobility shift assays, and DNase I footprinting to identify cis-DNA regulatory elements and trans-acting protein factors required for lung cell-specific expression of SP-B gene. We found that in addition to thyroid transcription factor 1 (TTF-1) and hepatocyte nuclear factor 3alpha (HNF-3alpha) binding sites, two spatially separate DNA sequences that bind Sp1 and Sp3 factors are necessary for the maintenance of SP-B promoter activity. Mutation of any one of the transcription factor binding sites caused a significant reduction in SP-B promoter activity suggesting that Sp1, Sp3, and TTF-1 and HNF-3alpha interact cooperatively with SP-B promoter to activate gene transcription.

Animals↗
PubMed2005

High-resolution magnetic resonance imaging of trabecular bone in the wrist at 3 tesla: initial results.

PURPOSE: To evaluate the feasibility of high-resolution magnetic resonance imaging (MRI) of trabecular bone of the wrist at 3 Tesla (3T) in vivo and to assess the potential benefit of the increased resolution for clinical assessment of structural changes in spongy bone. MATERIAL AND METHODS: High-resolution MRI of the wrist was performed with a whole-body 3T MR scanner using a dedicated circularly polarized transmit-receive wrist-coil. Two 3D-FISP sequences with a spatial resolution of 300 x 300 x 300 microm3 in a measuring time of TA = 7:51 min, and 200 x 200 x 200 microm3 in TA = 9:33 min were applied. Seven young healthy volunteers and three elderly subjects with suspected osteoporosis were examined. The signal-to-noise ratio (SNR) in the optimized setup at 3T was compared to measurements at 1.5T. RESULTS: The images at 3T allow microscopic analysis of the bone structure at an isotropic spatial resolution of 200 microm in examination times of <10 min. Differences in the structure of the spongy bone between normal and markedly osteoporotic subjects are well depicted. The SNR at 3T was found up to 16 times higher than at 1.5T applying unchanged imaging parameters. CONCLUSION: The proposed high-resolution MRI technique offers high potential in the diagnosis and follow-up of diseases with impaired bone structure of hand and/or wrist in clinical applications.

Adult↗