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Eomesodermin is expressed in mouse oocytes and pre-implantation embryos.

T-box genes are a highly conserved family of genes encoding transcription factors, which share a conserved DNA binding domain (the T-box). Appropriate temporal and spatial expression of this gene family is critical for gastrulation and organogenesis in a number of species. The T-box containing gene Eomesodermin was first identified in Xenopus, where it plays a critical role in mesoderm formation. In situ analyses in mice have described the expression patterns of the mouse ortholog of this gene mEomesodermin (mEomes) at the time of implantation and during fetal development. Additional studies involving the disruption of the mEomes gene, have demonstrated an additional role for mEomes in trophoblast formation. However, these analyses did not address the possibility that maternally encoded or pre-blastocyst zygotic transcription of mEomes may also contribute to embryonic development. We show here that mEomes mRNA is present prior to blastocyst formation, and that the protein product of mEomes is associated with nuclear DNA during oocyte development and persistently localizes within all nuclei of the preimplantation embryo until the early blastocyst stage. mEomes protein is associated with the meiotic spindle in the unfertilized egg and with the mitotic spindle at each cell division. Our results are consistent with mEomesodermin having a role in early preimplantation development and inner cell mass formation in addition to its function in the trophoblast lineage.

Animals↗

Molecular mechanisms of endochondral bone development.

Endochondral bone development is a complex process in which undifferentiated mesenchymal cells differentiate into chondrocytes, which then undergo well-ordered and controlled phases of proliferation, hypertrophic differentiation, death, blood vessel invasion, and finally replacement of cartilage with bone. The process recapitulates basic and fundamental mechanisms of cell biology with a highly specific spatial and temporal pattern, and it thus constitutes an excellent model for the analysis of such mechanisms. In recent years, the tools provided by modern genetic both in mice and men have been instrumental in the process of identifying and dissecting basic molecular mechanisms of endochondral bone formation. This review is a brief summary of the current knowledge about some of the crucial factors involved in growth plate development.

Animals↗

Tissue-specific expression of the Ets gene Xsap-1 during Xenopus laevis development.

We report the cloning of Xenopus laevis Xsap-1 cDNA, encoding a member of the ternary complex factor subfamily of ETS transcription factors. The expression pattern of Xsap-1 was examined during Xenopus embryogenesis using whole-mount in situ hybridization. Spatial expression of Xsap-1 mRNA is first detected at the animal pole at the mid-blastula stage. During neurulation Xsap-1 is expressed in cells participating in neural tube formation, in the sensorial layer of the epidermal ectoderm, and in an anterior region of the ventral mesoderm. Later, Xsap-1 expression is observed in the eye, ear vesicle, branchial arches, heart, pronephros, in the somites, and the developing nervous system, such as fore-, mid-, and hindbrain as well as in the cranial ganglion X.

Amino Acid Sequence↗

Pattern formation induced by nonequilibrium global alternation of dynamics.

We recently proposed a mechanism for pattern formation based on the alternation of two dynamics, neither of which exhibits patterns. Here we analyze the mechanism in detail, showing by means of numerical simulations and theoretical calculations how the nonequilibrium process of switching between dynamics, either randomly or periodically, may induce both stationary and oscillatory spatial structures. Our theoretical analysis by means of mode amplitude equations shows that all features of the model can be understood in terms of the nonlinear interactions of a small number of Fourier modes.

Journal Article↗

Variability-induced transition in a net of neural elements: From oscillatory to excitable behavior.

Starting with an oscillatory net of neural elements, increasing variability induces a phase transition to excitability. This transition is explained by a systematic effect of the variability, which stabilizes the formerly unstable, spatially uniform, temporally constant solution of the net. Multiplicative noise may also influence the net in a systematic way and may thus induce a similar transition. Adding noise into the model, the interplay of noise and variability with respect to the reported transition is investigated. Finally, pattern formation in a diffusively coupled net is studied, because excitability implies the ability of pattern formation and information transmission.

Journal Article↗

Cyclooxygenase inhibition and atherothrombosis.

Cyclooxygenases represent a major target of pharmaceutical therapy. Cyclooxygenase inhibitors are applied in order to reduce inflammation, to relieve from pain, or to prevent atherothrombotic complications in cardiovascular disease. Inhibition of platelet aggregation by aspirin, which is due to inhibition of platelet cyclooxygenase-dependent formation of thromboxane A2, is a cheap, safe and effective strategy to prevent myocardial infarction or stroke and is thus the most established strategy of secondary prevention of atherothrombotic disease. However, the existence of several isoforms of the cyclooxygenase enzyme, their tissue-specific expression patterns, their spatial and functional association with enzymes that further degrade the major cyclooxygenase products and the specific pharmacological properties of substances that have the potential of inhibiting cyclooxygenase make the ultimate physiological effects of a specific cyclooxygenase inhibitor a highly sophisticated pharmacological question. Specific inhibitors of the cyclooxygenase-2 isoform (COX-2) have at first promised to represent a major improvement of pharmaceutical therapy, but later have been suggested to enhance the risk of atherothrombotic events in vivo. This has led to the withdrawal of some of these substances from global markets and also initiated a discussion as to whether some non-selective cyclooxygenase inhibitors (non-steroidal anti-inflammatory drugs, NSAID), such as naproxen would also have an antithrombotic effect in vivo. This review summarizes current pathophysiological and clinical knowledge about the effects on atherothrombosis of drugs that target cyclooxygenases either as specific inhibitors of a cyclooxygenase isoform, or as non-specific cyclooxygenase inhibitors. It specifically discusses the question, whether all selective COX-2 inhibitors may have an intrinsic risk of enhancing the risk of atherothrombosis.

Animals↗

Neuronal activity in the primate hippocampal formation during a conditional association task based on the subject's location.

The hippocampal formation (HF) functions in two domains of memory: spatial and nonspatial associative memory. The HF includes the hippocampus proper, the dentate gyrus, and the subicular complex. Studies of spatial correlates of HF neuronal activity have revealed that a subject's location in space can impose critical constraints on patterns of neuronal activity in the HF. This report compares monkey HF neuronal responses in two kinds of stimulus-response association tasks (go/no-go tasks with symmetrical reinforcement). In a place-dependent, conditional, stimulus-response association (PCA) task, the subject's location was the condition upon which stimulus (object)-behavioral response association depended. In a place-in-dependent, simple, stimulus-response association (ISA) task, the object-behavioral response contingency was independent of the subject's location. Of 329 neurons recorded, the activity of 88 increased or decreased significantly in response to the presentation of an object during the PCA task. Responses of 17 neurons depended differentially on specific combinations of object, place, and behavior in the PCA task (specific-combination neurons). These specific-combination responses do not simply reflect object-behavioral response association in the PCA task, since neuronal responses in the same object-behavioral response association were not restored in the ISA task in which there was no dependence on the subject's location. This suggests the influence of location on HF neuronal responses in object-behavioral response association when the subject's location is imposed as a condition. Responses of 12 neurons differentiated the kind of object in the PCA task (object-differential neurons). In the ISA task, most object-differential responses diminished or disappeared. Since the HF object-differential responses elicited by the conditions imposed by the PCA task. Characteristics of the two neuron types suggest that HF neurons encode both stimulus percept and attributes such as the place where the stimulus is presented and the conditional relation imposed in the task.

Animals↗

Temporal and spatial modulation of Rho GTPases during in vitro formation of capillary vascular network. Adherens junctions and myosin light chain as targets of Rac1 and RhoA.

Endothelial cells (ECs) self-organize into capillary networks when plated on extracellular matrix. In this process, Rho GTPases-mediated cytoskeletal dynamics control cell movement and organization of cell-to-matrix and cell-to-cell contacts. Time course analysis of RhoA and Rac1 activation matches specific morphological aspects of nascent pattern. RhoA-GTP increases early during EC adhesion and accumulates at sites of membrane ruffling. Rac1 is activated later and localizes in lamellipodia and at cell-to-cell contacts of organized cell chains. When ECs stretch and remodel to form capillary structures, RhoA-GTP increases again and associates with stress fibers running along the major cell axis. N17Rac1 and N19RhoA mutants impair pattern formation. Cell-to-cell contacts and myosin light chains (MLC) are targets of Rac1 and RhoA, respectively. N17Rac1 reduces the shift of beta-catenin and vascular endothelial cadherin to Triton X-100-insoluble fraction and impairs beta-catenin distribution at adherens junctions, suggesting that Rac1 controls the dynamics of cadherin-catenin complex with F-actin. During the remodeling phase of network formation, ECs show an intense staining for phosphorylated MLC along the plasma membrane; in contrast, MLC is less phosphorylated and widely diffused in N19RhoA ECs. Both N17Rac1 and N19RhoA have been used to investigate the role of wild type molecules in the main steps characterizing in vitro angiogenesis: (i) cell adhesion to the substrate, (ii) cell movement, and (iii) mechanical remodeling of matrix. N17Rac1 has a striking inhibitory effect on haptotaxis, whereas N19RhoA slightly inhibits EC adhesion and motility but more markedly Matrigel contraction. We conclude that different Rho GTPases control distinct morphogenetic aspects of vascular morphogenesis.

Adherens Junctions↗

Dynamics of formation of symmetrical patterns by chemotactic bacteria.

Motile cells of Escherichia coli aggregate to form stable patterns of remarkable regularity when grown from a single point on certain substrates. Central to this self-organization is chemotaxis, the motion of bacteria along gradients of a chemical attractant that the cells themselves excrete. Here we show how these complex patterns develop. The long-range spatial order arises from interactions between two multicellular aggregate structures: a 'swarm ring' that expands radially, and focal aggregates that have lower mobility. Patterning occurs through alternating domination by these two sources of excreted attractant (which we identify here as aspartate). The pattern geometries vary in a systematic way, depending on how long an aggregate remains active; this depends, in turn, on the initial concentration of substrate (here, succinate).

Aspartic Acid↗

Angiogenic network formation in the developing vertebrate trunk.

We have used time-lapse multiphoton microscopy of living Tg(fli1:EGFP)y1 zebrafish embryos to examine how a patterned, functional network of angiogenic blood vessels is generated in the early vertebrate trunk. Angiogenic vascular sprouts emerge from the longitudinal trunk axial vessels (the dorsal aorta and posterior cardinal vein) in two spatially and temporally distinct steps. Dorsal aorta-derived sprouts form an initial primary network of vascular segments, followed by emergence of vein-derived secondary vascular sprouts that interact and interconnect dynamically with the primary network to initiate vascular flow. Using transgenic silent heart mutant embryos, we show that the gross anatomical patterning of this network of vessels does not require blood circulation. However, our results suggest that circulatory flow dynamics play an important role in helping to determine the pattern of interconnections between the primary network and secondary sprouts, and thus the final arterial or venous identity of the vessels in the functional network. We discuss a model to explain our results combining genetic programming of overall vascular architecture with hemodynamic determination of circulatory flow patterns.

Animals↗

Kinetics of domain formation by sickle hemoglobin polymers.

We have monitored the growth of domains of sickle hemoglobin polymers by using temporally and spatially resolved light scattering and birefringence measured pseudosimultaneously on a 50-microns square area. Polymerization was induced and indefinitely maintained by photolysis of the carbonmonoxy derivative using an argon ion laser. Intensity of scattering and birefringence (measured as intensity transmitted through crossed polarizers) were measured using a silicon-intensified target vidicon interfaced to a computer. Polymer concentration, as inferred by light scattering, grew with primarily circular symmetry, with approximately 20% of the signal initially in a twofold symmetric pattern. In time the circular symmetry increased. A distinct decrease in the scattering signal developed which spread outward from the center of the domain. Birefringence lagged the scattering and initially grew in a twofold pattern, with the formation of a characteristic Maltese cross only appearing much later, and well after the scattering signal had peaked. Radial profiles of the domain scattering and birefringence were both approximately gaussian. We successfully modeled the decrease in scattering by fitting the profiles to a large gaussian from which a second smaller gaussian was subtracted. This second gaussian had the width of the birefringence gaussian. The width of the birefringence gaussian grew linearly in time, while the width of the scattering gaussian showed a notable acceleration. We conclude that domains form primarily as disordered arrays which align at later times. We explain the above observations, including the shape of the birefringence progress curves, as the result of an alignment transition which is solely due to a redistribution of monomers from short to long, and from entangled to radial, polymers. We present a theoretical justification for this process in an appendix. In a separate paper (Zhou, H. X., and F. A. Ferrone, manuscript submitted for publication) we show that the gaussian shapes and acceleration of the width naturally arise from a generalization of the double nucleation mechanism for sickle hemoglobin gelation (Ferrone, F. A., J. Hofrichter, H. Sunshine, and W. A. Eaton 1980. Biophys. J. 32:361-377; Ferrone, F. A., J. Hofrichter, and W. A. Eaton. 1985. J. Mol. Biol. 183:611-631).

Birefringence↗

Object-based selection operates on a grouped array of locations.

In two experiments, space- and object-based selection effects were investigated, using variants of the ring-cuing paradigm of Egly and Homa (1984). The results revealed significant cuing modulation for nonring configurations of target locations spanning a range of retinal eccentricities, with the cuing effects independent of eccentricity and confined to the configuration of locations (rather than extending to locations within the space enclosed by the cued configuration). These results are consistent with object-based selection operating on a grouped spatial array (Vecera & Farah, 1994). Object selection may be based on a supradimensional saliency map representation of the field, modulated by feature-specific segmentation mechanisms (e.g., an object may be made salient on the basis of its color). Complex objects may be represented by grouped saliency signals. In this way, a two-dimensional spatial (saliency) representation may provide the common format for object-based selection, prior to full object definition.

Adult↗

Chicken tibial dyschondroplasia: a limb mutant with two growth plates and possible defects of collagen crosslinking.

In the cartilaginous epiphyseal growth plate, extracellular matrix molecules such as collagens are believed to play important roles during both normal and abnormal development. One defect of the epiphyseal plate occurs in chickens with a condition termed tibial dyschondroplasia (TD). This abnormality occurs in certain strains of juvenile chickens and other rapidly developing animals. It is characterized by the presence of a mass of avascular, uncalcified cartilage which is retained in the proximal metaphysis of the tibiotarsus. To elucidate the developmental events which may be involved in this lesion, we have performed both immunohistochemistry and in situ hybridizations for collagen types II and X, known components of the extracellular matrix of the growth plate. By immunohistochemical analyses, the TD lesion contains both of these collagen types; therefore, the presence of these molecules per se is not sufficient for calcification of vascularization to occur. Since type X collagen is expressed exclusively in hypertrophic cartilage, the chondrocytes in the lesion must have undergone hypertrophy before their developmental arrest. The matrix of the lesion also reacted with a monoclonal antibody which is directed against an epitope in the NH2-terminal telopeptide of the alpha 1(II) chain. Our previous data suggest that this epitope is rendered unavailable in type II collagen which has undergone crosslink formation; its availability in the lesion suggests that crosslinking may be abnormal. Lastly, analyses by in situ hybridization failed to detect mRNA for either type II or type X collagen within the lesion, but chondrocytes distal to the lesion do contain mRNAs for these collagens in a spatial pattern suggesting the presence of a second growth plate.

Animals↗

Early rearing environment and dorsal hippocampal ibotenic acid lesions: long-term influences on spatial learning and alternation in the rat.

Behavioural responses in a set of spatial and cue tasks were assessed in adult rats that had been given ibotenic acid lesions of the dorsal hippocampus at weaning. The lesions or sham operations were immediately followed by one month of differential rearing, either in enriched, social or isolated housing environments. The differential rearing was followed by standard (social) housing conditions until behavioural testing began at 4 months of age. Compared to sham-operated rats, the rats with early cytotoxic lesions showed substantial impairments on learning and efficient strategy formation in radial arm maze, retention of a spatial location, but not of a cue-marked location, in a + maze and spontaneous alternation. Differential rearing had some long-term effects depending on the task. Sham-operated rats which had been housed in isolation used a pattern of strategies in the radial arm maze that resembled the pattern used by rats with lesions. Early enrichment, on the other hand, alleviated lesion deficits only in a spontaneous alternation task in a T-maze where the variety and salience of proximal cues were maximised. Enrichment increased lesion deficits in the radial maze task, where distal cues only could guide performance. The results suggest that the hippocampus may play an important role in the use of contextual information and that behavioural recovery after early hippocampal damage--limited to situations in which featural information is highly salient--may be permanently induced by rearing in environments, as in enriched ones, where rats can attend to and manipulate environmental cues.

Animals↗

The roles of microfilament-associated proteins, drebrins, in brain morphogenesis: a review.

The cytoskeleton has been suggested to be one of the important endogenous factors that control neuronal morphogenesis. Analysis of the developmental changes in the protein composition of the brain led to the discovery of novel developmentally regulated actin-binding proteins, drebrins. Drebrins exhibit a number of characteristics that one might expect for an intracellular regulator of neuronal morphogenesis. Drebrin has three isoforms and the mRNA of each isoform is transcribed from a single gene through alternative RNA splicing mechanisms. The expression pattern of each isoform is regulated spatially and temporally in the developing brain. Drebrin and tropomyosin competitively bind to actin filaments, and the exclusion of tropomyosin from actin filaments by overexpression of drebrin in fibroblasts results in the appearance of thick, curving bundles of actin filaments, and the formation of cell processes. Taken together, these data indicate that drebrin is one of the intracellular regulators of the neuronal morphogenesis.

Actins↗

Patterns in small aspect ratio Bénard-Marangoni convection.

An experimental study of pattern formation in Bénard-Marangoni convection with small aspect ratio containers and high Prandtl number fluids is presented. The observed stationary patterns complete previous experimental works performed at different values of aspect ratio and supercriticality. Detailed experimental studies of the flow in some single structures are described, and spatial bifurcations between different stationary planforms for a fixed aspect ratio are shown. These experimental results agree qualitatively with linear theory analysis and with some previous numerical works about boundary conditions effects.

Journal Article↗

Overview of the radiology, histology, and bone morphogenetic protein expression during distraction osteogenesis of the mandible.

INTRODUCTION: Distraction osteogenesis (DO) is a form of in vivo tissue engineering during which an osteotomy and controlled distraction are used to lengthen bone. The molecular signals that govern distraction-induced bone formation have not been fully elucidated. Specifically, the role of bone morphogenetic proteins (BMPs) in DO of the mandible remains unclear. OBJECTIVE: To characterize the radiologic and histologic evolution of newly formed bone during DO of the mandible and to relate these changes to the expression of BMPs. METHODS: Fourteen skeletally mature male rabbits were used. A distractor device was surgically applied to one side of the mandible following osteotomy. After 1 week (latency period), distraction was started at a rate of 0.25 mm every 12 hours for 3 weeks (distraction period) and was followed by a 3-week consolidation period. Two animals were sacrificed each week after surgery (weeks 1 to 7). The mandible was resected and the new bone assessed by radiography and histology. The expression of BMPs was also analyzed using immunohistochemistry. RESULTS: There was radiographic and histologic evidence of bone formation during the distraction period. By week 6, there was mature woven bone within the distraction zone. Bone morphogenetic proteins 2 and 4 were strongly expressed in osteoblasts during distraction and in chondrocytes during consolidation. The expression of BMP-7 was relatively minor. CONCLUSION: The temporal and spatial pattern of BMP expression suggests that these proteins are important mediators of mandibular DO. Understanding the expression of BMPs may facilitate the use of recombinant proteins to enhance the rate and quality of bone generation during craniofacial DO.

Animals↗

Use of magnetic resonance imaging in spinal trauma: indications, techniques, and utility.

Magnetic resonance (MR) imaging of acute spinal injury provides excellent visualization of neurologic and soft-tissue structures in a noninvasive format. Advances in imaging-sequence techniques have made possible more rapid acquisition of images with greater spatial resolution. Appropriate selection of imaging sequences allows improved imaging and contrast of the pathologic processes involved in acute spinal trauma, including spinal cord, soft-tissue, and ligamentous injury. Three patterns of spinal cord injury have been identified. Type I is representative of acute cord hemorrhage. Type II represents spinal cord edema. Type III is a mixed hemorrhagic-edematous presentation. Correlation of MR findings with experimental and clinical spinal cord injury has given a relative predictive value to spinal cord injury patterns on MR images indicative of long-term neurologic outcome. Magnetic resonance imaging is useful in delineating soft-tissue injuries associated with spinal column trauma. Despite the improved spatial resolution of MR imaging, plain radiography and computed tomography remain the standard modalities for visualizing spinal fractures.

Acute Disease↗