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PubMed2001

Microtubule patterning during meiotic maturation in mouse oocytes is determined by cell cycle-specific sorting and redistribution of gamma-tubulin.

The topography of microtubule assembly events during meiotic maturation of animal oocytes demands tight spatial control and temporal precision. To better understand what regulates the timing and location of microtubule assembly, synchronously maturing mouse oocytes were evaluated with respect to gamma-tubulin, pericentrin, and total tubulin polymer fractions at specific stages of meiotic progression. gamma-Tubulin remained associated with cytoplasmic centrosomes through diakinesis of meiosis-1. Following chromatin condensation and perinuclear centrosome aggregation, gamma-tubulin relocated to a nuclear lamina-bounded compartment in which meiosis-1 spindle assembly occurred. gamma-Tubulin was stably associated with the meiotic spindle from prometaphase-1 through to anaphase-2, but also exhibited cell cycle-specific relocalization to cytoplasmic centrosomes. Specifically, anaphase onset of both meiosis-1 and -2 was characterized by the concomitant appearance of gamma-tubulin and microtubule nucleation in subcortical centrosomes. Brief pulses of taxol applied at specific cell cycle stages enhanced detection of gamma-tubulin compartmentalization, consistent with a gamma-tubulin localization-dependent spatial restriction of microtubule assembly during meiotic progression. In addition, a taxol pulse during meiotic resumption impaired subsequent gamma-tubulin sorting, resulting in monopolar spindle formation and cell cycle arrest in meiosis-1; despite cell cycle arrest, polar body extrusion occurred roughly on schedule. Therefore, sorting of gamma-tubulin is involved in both the timing of location of meiotic spindle assembly as well as the coordination of karyokinesis and cytokinesis in mouse oocytes.

Angiogenesis Inhibitors↗
PubMed1998

Cooperation between the activin and Wnt pathways in the spatial control of organizer gene expression.

The normal expression pattern of the Wnt responsive homeobox gene Siamois is restricted to the dorso-vegetal region of the Xenopus embryo. Because the Wnt signaling pathway (via beta-catenin) is active on the entire dorsal side of the early embryo, we have asked why Siamois expression is not seen in the dorsal ectoderm. Only Wnt signaling, via activation of beta-catenin, can induce directly Siamois, and signaling via the SMAD1 (BMP2/4) or SMAD2 (activin/Vg-1) pathways cannot. We now directly show that the SMAD2 pathway can cooperate with the Wnt pathway to induce expression of Siamois much more strongly than the Wnt pathway alone, in normal embryos. We demonstrate the significance of this cooperation in normal embryos by blocking the SMAD2 signaling pathway with a dominant negative activin receptor. The activin dominant negative receptor blocks this cooperative effect and reduces the expression of Siamois by threefold in early embryos. Furthermore, we find that this cooperative relationship between the SMAD2 and Wnt pathways is reciprocal. Thus, in normal embryos, the Wnt pathway can enhance induction, by the SMAD 2 pathway, of the organizer genes Gsc and Chd but not the pan-mesodermal marker genes Xbra and Eomes. We conclude that the Wnt and SMAD2 signaling pathways cooperate to induce the expression of Spemann-organizer specific genes and so help to localize their spatial expression.

Activin Receptors↗
PubMed1992

Expression and localization of villin, fimbrin, and myosin I in differentiating mouse F9 teratocarcinoma cells.

F9 embryonic carcinoma cells are a multipotent cell line which can be induced to differentiate into cells resembling the visceral endoderm, an extraembryonic absorptive epithelium characterized by apical microvilli. We have examined the role of villin, fimbrin, and myosin I, the major actin-binding proteins in the intestinal and visceral yolk sac microvilli, in the development of epithelial polarity and the assembly of the microvillus cytoskeleton in differentiating F9 cells. By immunoblot analysis villin was first detected at 4 days of differentiation. Confocal microscopy localized villin at Day 4 to the apical surface and by Day 6 to the basolateral surfaces as well. In comparison, fimbrin and myosin I were both present in undifferentiated F9 cells and became associated with the apical surface after villin during differentiation to visceral endoderm. The accumulation of villin, fimbrin, and myosin I at the apical surface in differentiating F9 cells correlated with the appearance of microvilli containing organized actin filament bundles. Two mouse villin cDNAs were isolated and characterized to examine villin expression during F9 differentiation. Mouse villin was encoded by two transcripts (3.8 and 3.4 kb) which differ in their 3'-noncoding region. Both villin mRNAs were first detected by Day 4 of differentiation and their appearance coincided with expression of the visceral endoderm marker alpha-fetoprotein. The pattern of expression and order of accumulation of villin, fimbrin, and myosin I in differentiating F9 cells are common to developing gut and yolk sac epithelium. This suggests that microvillus assembly is directed by a sequence of temporally and spatially regulated localizations of these actin-binding proteins.

Animals↗
PubMed2002

Impact of computed tomography-positron emission tomography fusion in staging patients with thoracic malignancies.

BACKGROUND: Positron emission tomography (PET) has been demonstrated to improve staging in patients with thoracic malignancies. This study evaluates the ability of a new imaging technique to improve the spatial resolution and accuracy of PET. METHODS: Patients with known or suspected malignancy (n = 21) who were referred for a dedicated PET scan were also evaluated with a new camera-based PET system, which uniquely allows simultaneous computed tomography (CT) and fusion of the camera-based PET images with the CT images. The dedicated PET scan was obtained 1 hour after intravenous injection of fluorodeoxyglucose. The camera-based PET imaging was fused with the CT images at approximately 2 hours after injection. The camera-based PET and CT-PET fusion images were read independently and blindly by 2 experienced observers and the presence and location of abnormalities was compared with dedicated PET scans. RESULTS: Dedicated PET identified 18 sites in the chest as abnormal. The CT-PET fusion was superior to the camera-based PET alone, concordant with the dedicated PET in 16 of 21 patients compared with 13 of 21 by camera-based PET. The lesions missed by the camera-based PET were less than 1 cm in diameter. Fused CT-PET images provided superior anatomic localization and spatial resolution compared with dedicated PET and camera-based PET. CONCLUSIONS: CT-PET fusion images were more accurate than camera-based PET alone. CT-PET fusion improves the spatial resolution compared with dedicated PET and may improve the availability and efficacy of staging of patients with thoracic malignancies.

Humans↗
PubMed2006

Effects of bilateral versus unilateral hearing aid fitting on abilities measured by the Speech, Spatial, and Qualities of Hearing Scale (SSQ).

The Speech, Spatial and Qualities of Hearing Scale (Gatehouse & Noble, 2004) was applied to three independent clinical groups: 144 people prior to being fitted with amplification; 118 people with six months experience with unilateral amplification; and 42 people with six months experience with bilateral amplification. For traditional speech hearing contexts (one-on-one, in groups, in quiet, in noise) there was benefit with one aid, and no further benefit with two. By contrast, hearing speech in demanding contexts (divided or rapidly switching attention) showed benefit with one aid and further benefit with two. In the spatial domain, directional hearing showed some benefit with one hearing aid, and particular further benefit in distance and movement discrimination from fitting with two. There was some benefit from unilateral fitting for elements of the qualities domains (clarity, naturalness, recognisability, segregation of sounds), with no consistent sign of further benefit from two. Bilateral fitting added benefit with respect to listening effort. Two hearing aids offer advantage in demanding and dynamic contexts; these contexts are argued as significant in the maintenance of social competence and emotional wellbeing. The present results go toward establishing the real-world advantages of bilateral hearing aid fitting and suggest that previous, inconclusive clinical findings reflect inquiry limited to more traditional areas of hearing function.

Aged↗
PubMed2006

Navigation performance with a virtual auditory display: effects of beacon sound, capture radius, and practice.

OBJECTIVE: We examined whether spatialized nonspeech beacons could guide navigation and how sound timbre, waypoint capture radius, and practice affect performance. BACKGROUND: Auditory displays may assist mobility and wayfinding for those with temporary or permanent visual impairment, but they remain understudied. Previous systems have used speech-based interfaces. METHOD: Participants (108 undergraduates) navigated three maps, guided by one of three beacons (pink noise, sonar ping, or 1000-Hz pure tone) spatialized by a virtual reality engine. Dependent measures were efficiency of time and path length. RESULTS: Overall navigation was very successful, with significant effects of practice and capture radius, and interactions with beacon sound. Overshooting and subsequent hunting for waypoints was exacerbated for small radius conditions. A human-scale capture radius (1.5 m) and sonar-like beacon yielded the optimal combination for safety and efficiency. CONCLUSION: The selection of beacon sound and capture radius depend on the specific application, including whether speed of travel or adherence to path are of primary concern. Extended use affects sound preferences and quickly leads to improvements in both speed and accuracy. APPLICATION: These findings should lead to improved wayfinding systems for the visually impaired as well as for first responders (e.g., firefighters) and soldiers.

Adolescent↗
PubMed2026

A regulatory network underlying idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which genetic susceptibility interacts with epithelial, immune, and mesenchymal remodeling. Although the chromosome 11p15.5 locus contains established IPF susceptibility signals near MUC5B and TOLLIP, the broader regulatory architecture of this region remains incompletely resolved. METHODS: We integrated IPF genome-wide association study summary statistics with methylation, expression, and protein quantitative trait loci using summary-data-based Mendelian randomization (SMR). SMR-prioritized candidates were evaluated in independent transcriptomic and methylation cohorts and further contextualized using microRNA, transcription-factor, protein-interaction, machine-learning, single-cell, and spatial transcriptomic analyses. Fibrosis-associated expression patterns were assessed in a bleomycin-induced pulmonary fibrosis rat model. RESULTS: The analyses recovered the established MUC5B and TOLLIP signals and prioritized BRSK2 as a comparatively underexplored candidate supported by eQTL-based SMR and independent molecular evidence. The BRSK2 pQTL association did not pass the HEIDI test and was therefore not interpreted as convergent protein-level genetic evidence. Network analyses linked BRSK2 to cell-cycle, metabolic-stress, and senescence-related programs, while cross-cohort machine learning prioritized FOXA2, CDC25B, and NFE2 as informative network features. Single-cell and spatial analyses localized BRSK2 preferentially to fibroblast and myofibroblast compartments and to regions with greater histological fibrosis severity. In fibrotic rat lungs, BRSK2 expression increased, whereas FOXA2 and CDC25B decreased at the transcript and protein levels. CONCLUSIONS: These findings refine the molecular landscape of the chromosome 11p15.5 IPF susceptibility locus and prioritize BRSK2 as a candidate component of an IPF-associated profibrotic fibroblast state. Its causal contribution, direct regulatory relationships, and therapeutic tractability require targeted mechanistic validation.

Idiopathic Pulmonary Fibrosis↗
PubMed1999

Hepatocyte growth factor expression in the developing myocardium: evidence for a role in the regulation of the mesenchymal cell phenotype and urokinase expression.

During development of the heart, the endocardium of the developing cushion tissue transforms into mesenchymal cells that rapidly invade the underlying extracellular matrix. This invasive process, along with subsequent proliferation and differentiation of the mesenchyme, are essential for the normal formation of valvular and septal structures. Several factors have been identified that appear to initiate and/or control this transformation process, including the growth factor TGF-beta. In these studies we have investigated whether hepatocyte growth factor/scatter factor (HGF/SF) may also be involved in some aspects of this transformation process. Using an immunohistochemical approach we have detected a spatially restricted localization of HGF/SF to the myocardial cells of the cushion tissue. HGF was detected in extracts of the developing heart, and the presence of the active form correlated with the onset of the transformation process and the elevation of urokinase activity. The endocardial-derived mesenchymal cells of the cushion tissue were found to express the c-met HGF receptor. Isolated endocardial cells responded to the addition of HGF with increases in motility, proliferation, and urokinase production. The results from these studies suggest that HGF may function as a myocardial-derived mediator of the epithelial-mesenchymal transformation by inducing and/or maintaining the mesenchymal cell phenotype. The increase in urokinase expression by the cushion tissue cells, in response to HGF, may facilitate the invasive abilities of these cells and also provide a means of maintaining high levels of active HGF required for the stimulation of cell proliferation and migration.

Animals↗
PubMed2000

Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2.

Cranial neural crest cells emigrate from the posterior midbrain and anterior hindbrain to populate the first branchial arch and eventually differentiate into multiple cell lineages in the maxilla and mandible during craniofacial morphogenesis. In the developing mouse mandibular process, the expression profiles of BMP4, Msx2, Sox9, and type II collagen demonstrate temporally and spatially restrictive localization patterns suggestive of their functions in the patterning and differentiation of cartilage. Under serumless culture conditions, beads soaked in BMP4 and implanted into embryonic day 10 (E10) mouse mandibular explants induced ectopic cartilage formation in the proximal position of the explant. However, BMP4-soaked beads implanted at the rostral position did not have an inductive effect. Ectopic chondrogenesis was associated with the up-regulation of Sox9 and Msx2 expression in the immediate vicinity of the BMP4 beads 24 hours after implantation. Control beads had no effect on cartilage induction or Msx2 and Sox9 expression. Sox9 was induced at all sites of BMP4 bead implantation. In contrast, Msx2 expression was induced more intensely at the rostral position when compared with the proximal position, and suggested that Msx2 expression was inhibitory to chondrogenesis. To test the hypothesis that over-expression of Msx2 inhibits chondrogenesis, we ectopically expressed Msx2 in the mandibular process organ culture system using adenovirus gene delivery strategy. Microinjection of the Msx2-adenovirus to the proximal position inhibited BMP4-induced chondrogenesis. Over-expression of Msx2 also resulted in the abrogation of endogenous cartilage and the down-regulation of type II collagen expression. Taken together, these results suggest that BMP4 induces chondrogenesis, the pattern of which is positively regulated by Sox9 and negatively by Msx2. Chondrogenesis only occurs at sites where Sox9 expression is high relative to that of Msx2. The combinatorial action of these transcription factors appear to establish a threshold for Sox9 function and thereby restricts the position of chondrogenesis.

Animals↗
PubMed1979

Neurological development of kittens.

The neurological development of the kitten was studied from birth to 120 days of age. Three motor features present at birth disappeared within the 1st 45 days of life. The labyrinthine head and body righting reactions were present at birth; the latter matured only by 25 days of age when the air righting reaction (mature by 35 days) started to appear. Limb placing reactions developed progressively with proprioceptive components being present at birth whereas tactile components evolved slowly from early contact lifting to forepaws contact placing (60 days) and narrow plank walking (75 days). Standing and walking were well developed by 45 days. Eye opening occurred at 9.5 days and several eyeblink reactions (including blink to light) were present at birth. Adequate binocular coordination was seen by 47 days. Vision progressed parallel to the clearing of the ocular media which were fairly transparent by 32 days. Visually guided paw placing and the visuopalpebral blink reflex matured later (by 37 and 59 days, respectively). The external auditory canal and pinna were fully developed by 12 and 31 days, respectively; spontaneous and tactile pinna movements were present at birth; orienting to animal and nonanimal sounds was well developed by 6.5 and 18 days, respectively; spatial sound localization was developed by 16 days and differential responding to animal sounds matured by 24.5 days. Somatic responses and olfaction were present at birth but matured further thereafter. Playful interactions between kittens started by 10--15 days and well developed play behavior was seen by 36--40 days. In brief, all neurological functions mature progressively during the 1st 3 postnatal months.

Animals↗
PubMed2004

Ultrasound-guided MRI: preliminary results using a motion phantom.

In principal, both ultrasound (US) imaging and MRI can be performed simultaneously within the magnetic field of the scanner due to their different physical natures (i.e., sound waves vs. electromagnetic radiation). One potential application is to use US information for dynamic spatial organ localization to improve MR imaging, similar to MR navigator echoes. In this work, preliminary results are presented for US-guided MRI using position and orientation information extracted from US data to update the image slice position of an SSFP sequence in real time. Effective prospective motion compensation is shown for a phantom whose sinusoidal displacement can be fully corrected. Possible applications of simultaneous US-MRI acquisitions include real-time US-guided cardiac MRI or interventional procedures.

Algorithms↗
PubMed1992

Oscillations in a model of repression with external control.

A mathematical model for control by repression by an extracellular substance is developed, including diffusion and time delays. The model examines how active transport of a nutrient can produce either oscillatory or stable responses depending on a variety of parameters, such as diffusivity, cell size, or nutrient concentration. The system of equations for the mathematical model is reduced to a system of delay differential equations and linear Volterra equations. After linearizing these equations and forming the limiting Volterra equations, the resulting linear system no longer has any spatial dependence. Local stability analysis of the radially symmetric model shows that the system of equations can undergo Hopf bifurcations for certain parameter values, while other ranges of the parameters guarantee asymptotic stability. One numerical study shows that the model can exhibit intracellular biochemical oscillations with increasing extracellular concentrations of the nutrient, which suggests a possible trigger mechanism for morphogenesis.

Bacterial Physiological Phenomena↗
PubMed1992

Biochemical organization of single motor units in two multi-tendoned muscles of the cat distal forelimb.

In anesthetized cats single motor units (MUs) of the extensor carpi ulnaris (ECU) and extensor digitorum communis (EDC) muscles were selectively activated by stimulation of cervical ventral root filaments. The distribution of force developed by single MUs at the four distal tendons of the EDC muscle and at three portions of the distal tendon of the ECU muscle was analysed. In general, single MUs of both muscles distributed force over all tendons in a unimodal pattern, with the maximal force levels generated at one specific tendon which was termed the best-tendon. Distributions of force were quantitatively described by a parameter representing the mean direction of force output (output-index) and a further one representing the dispersion of force over the distal tendons (divergence). Generally, these parameters and the best-tendon remained stable when a MU was stimulated at different frequencies, but varied from MU to MU. Despite the general stability of the force distribution, slight systematic changes were regularly found in EDC MUs, when they developed a higher amount of force due to a higher frequency of stimulation: the relative amount of force at the best-tendon increased; e.g. the MUs got more selective for the best-tendon. These changes were partly due to overcoming mechanical cross-coupling between neighbouring compartments of the EDC muscle. Such changes of force distribution were only found in a part of the ECU MUs; other ECU MUs did not change their force distribution at all or became less selective for the best-tendon. The phenomenon that MUs of multi-tendoned muscles distribute their force output to the distal tendons in specific patterns is probably due to mechanical partitioning of the parent muscles: the localization of spatial territories of MUs within different anatomical muscle compartments should correspond to the best-tendon. Complex mechanisms allowing passive transmission of force from limited territories along the transverse axis of both muscles must be assumed in order to explain why most MUs act on all tendons and why force distributions change with increasing stimulus frequency. In addition, specific relations between unit type and force distributions were found within both muscles. Fatigue-resistant EDC MUs have broader force distributions than fatigue-sensitive EDC MUs and slow ECU MUs were found to act predominantly on the most ulnar part of the distal tendon. These biomechanical properties of MUs are discussed as supporting the specific functions of the respective muscles.

Animals↗
PubMed1986

Detection of unrecognized liver metastases from colorectal cancers by routine use of operative ultrasonography.

The importance of diagnosis and detection of liver metastases cannot be overemphasized for the treatment and prognosis of colorectal cancers. As a new diagnostic technique, operative ultrasonography has been performed during 33 operations for colorectal cancers including three operations for metachronous liver metastases. Of these, in five patients (15.2 percent) ultrasonography using 5- or 7.5-MHz instruments identified metastatic tumors that had not been diagnosed during preoperative imaging studies or at exploration. Most of these tumors were approximately 1 cm in size and nonpalpable. Cases of these five patients are presented in this report. High-resolution operative ultrasonography is considered to be a valuable method for detection of unrecognized metastatic tumors and for precise localization and spatial assessment of these hepatic lesions. Because it is safe, simple, and highly sensitive, the routine use of operative ultrasound is encouraged during surgery upon colorectal cancers for systematic screening of metastatic liver tumors.

Adult↗
PubMed2002

Intraorbital aneurysm of the ophthalmic artery: a rare cause of apex orbitae compression syndrome.

PURPOSE: The purpose of this study was to report the case of a patient with a saccular, intraorbital aneurysm of the ophthalmic artery and to analyze the correlation between clinical symptoms and aneurysm localization with regard to the literature. METHOD: We correlated the patient's clinical findings with anatomical substrates on magnetic resonance imaging and angiographic studies. RESULTS: A 64-year-old woman presented with a rapidly progressive loss of visual acuity in her right eye, temporo-basal visual field defects, a temporal pallor of the optic disc and third and sixth nerve palsies. This apex orbitae compression syndrome was due to an aneurysm of the proximal intraorbital segment of the ophthalmic artery at a position inferolateral to the optic nerve, inferior to the third and medial to the sixth cranial nerve. CONCLUSION: The symptoms caused by an aneurysm of the ophthalmic artery depend on its localization and spatial relationship to neural structures. While aneurysms of the intracranial and distal intraorbital segments may remain asymptomatic, those arising from the intracanalicular segment become clinically apparent with optic nerve conduction disorders. Aneurysms in the proximal intraorbital segment additionally provoke oculomotor disturbances due to compression of the third and sixth cranial nerves.

Abducens Nerve Diseases↗
PubMed2005

Differentiation of activated satellite cells in denervated muscle following single fusions in situ and in cell culture.

Satellite cells represent a cellular source of regeneration in adult skeletal muscle. It remains unclear why a large pool of stem myoblasts in denervated muscle does not compensate for the loss of muscle mass during post-denervation atrophy. In this study, we present evidence that satellite cells in long-term denervated rat muscle are able to activate synthesis of contractile proteins after single fusions in situ. This process of early differentiation leads to formation of abnormally diminutive myotubes. The localization of such dwarf myotubes beneath the intact basal lamina on the surface of differentiated muscle fibers shows that they form by fusion of neighboring satellites or by the progeny of a single satellite cell following one or two mitotic divisions. We demonstrated single fusions of myoblasts using electron microscopy, immunocytochemical labeling and high resolution confocal digital imaging. Sequestration of nascent myotubes by the rapidly forming basal laminae creates a barrier that limits further fusions. The recruitment of satellite cells in the formation of new muscle fibers results in a progressive decrease in their local densities, spatial separation and ultimate exhaustion of the myogenic cell pool. To determine whether the accumulation of aberrant dwarf myotubes is explained by the intrinsic decline of myogenic properties of satellite cells, or depends on their spatial separation and the environment in the tissue, we studied the fusion of myoblasts isolated from normal and denervated muscle in cell culture. The experiments with a culture system demonstrated that the capacity of myoblasts to synthesize contractile proteins without serial fusions depended on cell density and the availability of partners for fusion. Satellite cells isolated from denervated muscle and plated at fusion-permissive densities progressed through the myogenic program and actively formed myotubes, which shows that their myogenic potential is not considerably impaired. The results of this study suggest that under conditions of denervation, progressive spatial separation and confinement of many satellite cells within the endomysial tubes of atrophic muscle fibers and progressive interstitial fibrosis are the important factors that prevent their normal differentiation. Our findings also provide an explanation of why denervated muscle partially and temporarily is able to restore its functional capacity following injury and regeneration: the release of satellite cells from their sublaminal location provides the necessary space for a more active regenerative process.

Animals↗
PubMed2005

Biosynthesis of UDP-xylose: characterization of membrane-bound AtUxs2.

UDP-xylose (UDP-Xyl) is a sugar donor for the synthesis of glycoproteins, polysaccharides, various metabolites, and oligosaccharides in plants, vertebrates, and fungi. In plants, the biosynthesis of UDP-Xyl from UDP-glucuronic acid (UDP-GlcA) appears to be catalyzed by numerous UDP-glucuronic acid decarboxylase (Uxs) isoforms. For example, six Uxs isoforms in Arabidopsis thaliana (L.) and four in rice have been identified. However, the reason/s for the existence of several isoforms that are necessary for the synthesis of UDP-Xyl remains unknown. Here, we describe a Uxs isoform in Arabidopsis, AtUXS2, encoding an integral membrane protein that appears to be localized to the Golgi apparatus. The enzyme is a dimer and has distinct properties. Unlike the UXS3 isoform, which is shown here to be a soluble protein, the UXS2 isoform is membrane bound. The characteristics of the membrane-bound AtUxs2 and cytosolic AtUxs3 support the hypothesis that unique UDP-GlcA-DCs possessing distinct sub-cellular localizations can spatially regulate specific xylosylation events in plant cells.

Arabidopsis↗