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At least 343 records · Page 19Linked to original sources
PubMed1992

Localized membrane depolarizations and localized calcium influx during electric field-guided neurite growth.

Our study explores the mechanisms behind neurite galvanotropism. Using phase, differential interference contrast and ratiometric fluorescence microscopy, we reveal four responses of N1E-115 mouse neuroblastoma cells to 0.1-1.0 mV/microns uniform DC electric fields: cathode-directed neurite initiation and elongation, cathode-biased growth cone filopodial protrusions, transient cathode-localized calcium increases, and persistent cathode-localized membrane depolarizations. These newly demonstrated events are temporally and spatially correlated, suggesting that they are causally related. The calcium increases are prevented by calcium channel blockers and by the removal of extracellular calcium. We therefore propose that the observed field-induced membrane depolarizations activate voltage-dependent calcium channels, resulting in cathode-localized calcium influx. This, in turn, may initiate the observed cathode-biased growth cone filopodial protrusions, followed by the cathode-directed neurite elongation.

Animals↗
PubMed2004

Binding proteins for mRNA localization and local translation, and their dysfunction in genetic neurological disease.

Neurons utilize mRNA transport and local translation as a means to influence development and plasticity. The molecular mechanisms for this mRNA sorting involve the recognition of cis-acting sequences by distinct mRNA binding proteins that have a dual role, acting in both mRNA transport and translational regulation. Other proteins play a part in the assembly of messenger ribonucleoprotein complexes into transport granules. mRNA binding proteins are crucial targets of phosphorylation signals that regulate local translation. Fragile X syndrome and spinal muscular atrophy have emerged as two genetic neurological diseases that could result, in part, from impaired assembly, localization, and translational regulation of these messenger ribonucleoproteins.

Active Transport, Cell Nucleus↗
PubMed2004

Regulation of subcellular localization of the antiproliferative protein Tob by its nuclear export signal and bipartite nuclear localization signal sequences.

Tob, a member of the Tob and BTG antiproliferative protein family, plays an important role in many cellular processes including cell proliferation. In this study, we have addressed molecular mechanisms regulating subcellular localization of Tob. Treatment with leptomycin B, an inhibitor of nuclear export signal (NES) receptor, resulted in a change in subcellular distribution of Tob from its pan-cellular distribution to nuclear accumulation, indicating the existence of NES in Tob. Our results have then identified an N-terminal region (residues 2-14) of Tob as a functional NES. They have also shown that Tob has a functional, bipartite nuclear localization signal (NLS) in residues 18-40. Thus, Tob is shuttling between the nucleus and the cytoplasm by its NES and NLS. To examine a possible relationship between subcellular distribution of Tob and its function, we exogenously added a strong NLS sequence or a strong NES sequence or both to Tob. The obtained results have demonstrated that the strong NLS-added Tob has a much weaker activity to inhibit cell cycle progression from G0/G1 to S phase. These results suggest that cytoplasmic localization or nucleocytoplasmic shuttling is important for the antiproliferative function of Tob.

3T3 Cells↗
PubMed2003

Localization of orexins and their receptors in the rat olfactory system: possible modulation of olfactory perception by a neuropeptide synthetized centrally or locally.

Orexin-A and -B, also known as hypocretins, are two neuropeptides acting on feeding and sleep. They are specific ligands for two different receptors belonging to the G-protein coupled receptors family. Orexin fibers and orexin receptor neurons have been previously described in the forebrain olfactory system. Using immunocytochemistry, we showed that both orexin-A and -B as well as their receptors were present at different levels of the olfactory system, from the nasal mucosa to nuclei of the amygdala. A punctuated staining for orexins and their receptors was detected at the apical part of the olfactory epithelium; in the lamina propria of the mucosa, the staining was localized around olfactory nerves. At the ultrastructural level, olfactory neurons and supporting cells were found immunoreactive for orexins and their receptors. The labeling was localized in dendritic knobs and cilia of neurons, in the apical part and microvilli of supporting cells. The finding of immunolabeled cisternae of reticulum strongly suggests a local synthesis of both peptides and receptors, confirmed by RT-PCR experiments. In forebrain and amygdala regions, we detected numerous orexin fibers. Orexin receptors were present in mitral-tufted cells of the bulb and in many neuronal perikarya in the anterior olfactory nuclei, piriform cortex and amygdala nuclei. Altogether, these results show that orexins and their receptors are present at all levels of the olfactory system, from cilia where odors bind to their receptors to central regions where integration of olfactory signals occurs. They suggest a possible modulation of olfactory perception by these neuropeptides.

Amygdala↗
PubMed2002

Radiation and hormonal therapy for locally advanced and clinically localized prostate cancer.

Patients with locally advanced prostate cancer (TNM clinical stage T3, T4) who were treated using external-beam radiotherapy (EBRT) and 3 years of androgen deprivation therapy (ADT) were compared with patients treated with EBRT alone and were shown to have a survival benefit. Studies that address the same question for patients with clinically localized disease (stage T1, T2) have been completed and are awaiting follow-up study. A rate of decrease in the serum hemoglobin level of > or =1 g/dL during the first month of neoadjuvant ADT predicted for a significantly worse disease-free survival outcome, as defined by the prostate-specific antigen, for patients with intermediate- and high-risk clinically localized disease who were undergoing EBRT and ADT. Validation of this predictive factor by others is needed.

Androgen Antagonists↗
PubMed2000

Short-course intensity-modulated radiotherapy for localized prostate cancer with daily transabdominal ultrasound localization of the prostate gland.

PURPOSE: To present our initial observations on the clinical feasibility of the technique of short-course intensity-modulated radiotherapy (SCIM-RT) in the treatment of localized prostate cancer coupled with daily transabdominal ultrasound localization of the prostate. The proposed regimen consists of a hypofractionated course delivering 70.0 Gy in 28 fractions. METHODS AND MATERIALS: The treatment data of the first 51 patients treated with SCIM-RT at the Cleveland Clinic Foundation are presented in this report. The technique consisted of intensity-modulated radiotherapy using 5 static fields (anterior, 2 laterals, and 2 anterior obliques). Inverse plans were generated by the Corvus treatment-planning system. The treatment delivery was performed with a Varian Dynamic Multileaf Collimator. The target was the prostate only in patients with low-risk disease (stage T1-T2, pretreatment PSA < or =10, and biopsy Gleason < or =6). The target was the prostate and seminal vesicles in patients with high-risk disease (stage T3 or pretreatment PSA > 10 or biopsy Gleason > or =7). In the Corvus planning system, the margins for the planning target volume (PTV) were 4 mm posteriorly, 8 mm laterally, and 5 mm in all other directions. A total of 70.0 Gy (mean prostate dose approximately 75 Gy) was prescribed in all cases at 2.5 Gy per fraction to be delivered in 28 fractions over 5 1/2 weeks. Prior to treatment delivery, the patients were minimally immobilized on the treatment table, only using lasers and skin marks. The location of the prostate gland was verified daily with the BAT transabdominal ultrasound system and patient position adjustments were performed accordingly. Fifty-one patients completed therapy between October 1998 and May 1999. RESULTS: The dose was prescribed to an isodose line ranging from 82.0% to 90.0% (mean: 87.2%). The range of the individual prostate mean doses was 73.5 to 78.5 Gy (average: 75.3 Gy). The range of the maximum doses was 77.4 to 84.5 Gy (average: 80.2 Gy). The range of the minimum doses was 64.3 to 69.2 Gy (average: 67.5 Gy). The average time for the prostate position verification and alignment of the prostate using the BAT system was 5 minutes. The entire localization/alignment process was performed by the radiation therapists. The daily alignment images were automatically saved and reviewed by the radiation oncologist, a process similar to port film checks. The total treatment (beam-on) time was around 6 minutes using the 5 static intensity-modulated fields. The mean and standard deviation (SD) of bladder volumes irradiated to 50, 60, and 70 Gy were as follows: 24 +/- 11 cc, 16 +/- 8 cc, and 8 +/- 6 cc. The mean and SD of rectal volumes irradiated to 50, 60, and 70 Gy were as follows: 22 +/- 11 cc, 15 +/- 8 cc, and 7 +/- 5 cc. The RTOG acute bladder toxicity scores were as follows: 0 in 3 (6%), 1 in 38 (74%), and 2 in 10 (20%). The RTOG acute rectal toxicity scores for SCIM-RT cases were as follows: 0 in 10 (20%), 1 in 33 (65%), and 2 in 8 (16%). No Grade 3 or 4 acute toxicities were observed. CONCLUSION: The delivery of our proposed hypofractionated-schedule SCIM-RT in combination with daily target localization/alignment with the BAT transabdominal ultrasound system is clinically feasible. It is an alternative method of dose escalation in the treatment of localized prostate cancer. The proposed schedule would significantly increase convenience to patients due to the decrease in overall treatment time. Preliminary acute toxicity results are extremely encouraging. Long-term follow-up is needed to assess late complications and treatment efficacy.

Dose Fractionation, Radiation↗
PubMed1998

[Current studies of combined radiotherapy-hormone therapy in localized and locally advanced prostatic cancers].

In locally advanced prostate cancer three clinical randomized trials have shown that external irradiation combined with LHRH analogue with or without antiandrogen improved survival: disease-free survival, local recurrence-free survival, metastasis-free survival (P < 0.001). EORTC trial 22863 alone has shown a significant improvement of overall survival (P = 0.001), with an LHRH analogue (goserilin acetate, zoladex) started the first day of irradiation and followed every 4 weeks for 3 years; for RTOG trial 85-31 the same LHRH analogue started during the last week of irradiation and given until relapse increases survival of patients with poor differentiated tumours with gleason score ranging from 8 to 10 (P = 0.03). In locally confined prostate carcinoma randomized trials are ongoing to assess the impact of conventional irradiation or three dimensional conformal radiotherapy with or without adjuvant hormonotherapy.

Antineoplastic Agents, Hormonal↗
PubMed2001

Local structure and local compressibilities around Co2+ impurity in ZnSiF6.6H2O crystal determined from electron paramagnetic resonance data.

The perturbation formulas of g-factors gparallel, gperpendicular and hyperfine structure constants Aparallel, Aperpendicular for 3d7 ion in trigonal octahedral crystal field are established on the basis of a cluster approach. These formulas consist of the contributions from configuration interaction and covalency effect and the parameters related to both effects can be estimated from the optical spectra and the structural data of the system under study. According to these formulas, the local trigonal distortion angle beta at pressure P = 0 and the local compressibilities d ln beta/dP in two pressure regions around Co2+ impurity in ZnSiF6.6H2O crystal are estimated by fitting the calculated electron paramagnetic resonance parameters gi, Ai and their pressure coefficients to the observed values. The results show that these local values are different from those of the host crystal because of the influence of impurity.

Cations, Divalent↗
PubMed1985

Influence of gamma-hydroxybutyrate on the relationship between local cerebral glucose utilization and local cerebral blood flow in the rat brain.

The relationship between local cerebral glucose utilization (LCGU) and local CBF (LCBF) was examined during the action of gamma-hydroxybutyrate (GHB) (900 mg/kg i.v.) in conscious rats. GHB induced discrepant effects on blood flow and metabolism. LCGU was markedly depressed in all structures examined, whereas LCBF was differently affected in that no related changes were observed. Global glucose utilization was markedly depressed (-51%), whereas global blood flow was not significantly altered. The marked dissociation between the changes in global glucose utilization and global blood flow induced by GHB is reflected only to a minor degree in the local values inasmuch as the correlation between LCGU and LCBF was only slightly weakened and its heterogeneity was increased.

Animals↗
PubMed2006

The importance of including local correlation times in the calculation of inter-proton distances from NMR measurements: ignoring local correlation times leads to significant errors in the conformational analysis of the Glc alpha1-2Glc alpha linkage by NMR spectroscopy.

The experimental determination of oligosaccharide conformations has traditionally used cross-linkage 1H-1H NOE/ROEs. As relatively few NOEs are observed, to provide sufficient conformational constraints this method relies on: accurate quantification of NOE intensities (positive constraints); analysis of absent NOEs (negative constraints); and hence calculation of inter-proton distances using the two-spin approximation. We have compared the results obtained by using 1H 2D NOESY, ROESY and T-ROESY experiments at 500 and 700 MHz to determine the conformation of the terminal Glc alpha1-2Glc alpha linkage in a dodecasaccharide and a related tetrasaccharide. For the tetrasaccharide, the NOESY and ROESY spectra produced the same qualitative pattern of linkage cross-peaks but the quantitative pattern, the relative peak intensities, was different. For the dodecasaccharide, the NOESY and ROESY spectra at 500 MHz produced a different qualitative pattern of linkage cross-peaks, with fewer peaks in the NOESY spectrum. At 700 MHz, the NOESY and ROESY spectra of the dodecasaccharide produced the same qualitative pattern of peaks, but again the relative peak intensities were different. These differences are due to very significant differences in the local correlation times for different proton pairs across this glycosidic linkage. The local correlation time for each proton pair was measured using the ratio of the NOESY and T-ROESY cross-relaxation rates, leaving the NOESY and ROESY as independent data sets for calculating the inter-proton distances. The inter-proton distances calculated including the effects of differences in local correlation times give much more consistent results.

Acetylglucosamine↗
PubMed2001

Local lung responses following local lung challenge with recombinant lungworm antigen in systemically sensitized sheep.

BACKGROUND: Chronic mast cell-mediated inflammation may contribute significantly towards the extensive tissue remodelling that is a feature of lungworm infection in ruminants. Understanding the factors that control tissue remodelling is a necessary step toward effective management and treatment of conditions that feature such pathology. OBJECTIVE: We sought to define in a novel ovine model system, the cellular, immune and mast cell phenotypic events that occur following local lung challenge with a recombinant protein antigen, DvA-1, derived from the ruminant lungworm nematode, Dictyocaulus viviparus. METHODS: Two spatially disparate lung segments in systemically sensitized sheep were challenged on three occasions with DvA-1 (3xDVA) and two further segments were challenged with saline (3xSAL). Two months after the third challenge, one of the two segments previously repeatedly challenged with DvA-1 was challenged again with DvA-1 (3xDVA:DVA) whilst the other was challenged with saline (3xDVA:SAL). A similar protocol was followed with the saline challenged segments (3xSAL:SAL and 3xSAL:DVA). Bronchoalveolar lavage fluid (BALF) (n = 16) and tissue (n = 3) were collected after the last challenge. RESULTS: Cellular changes 24 h after the fourth challenge were characterized by an increase in the absolute numbers of neutrophils and eosinophils in BALF from 3xDVA:DVA and 3xSAL:DVA segments. Local antibody production was implied through increased levels of antibody in both 3xDVA:DVA and 3xDVA:SAL segments, with the latter being unaffected by inflammation. Levels of active transforming growth factor beta-1 (TGF-beta(1)) were significantly increased in 3xDVA:SAL segments and a trend towards an increase was apparent in 3xDVA:DVA segments. Total TGF-beta1 levels were significantly correlated with eosinophil counts in all except the 3xDVA:SAL segments. Such changes in the bronchoalveolar space were complemented by increased ratios of sheep mast cell proteinase-1 expressing cells and tryptase expressing cells, to toluidine blue positive cells in airways from 3xDVA:DVA segments. CONCLUSION: Mast cell phenotypic events occurring as a consequence of antigen challenge were limited to segments in which changes in BALF were characterized by neutrophil influx and increased local antibody production.

Animals↗
PubMed2002

Localized melanosis in an immunocompromised patient with local metastatic melanoma.

BACKGROUND: Melanosis is a rare, but well recognized late complication of some cases of metastatic melanoma. The precise pathogenesis is unclear. Most described cases report diffuse metastases and diffuse melanosis. OBJECTIVE: To present a case of localized melanosis secondary to locally metastatic melanoma without evidence of systemic involvement in a renal transplant patient. METHODS: Case report and literature review. RESULTS: We describe a case of localized melanosis in an immunocompromised patient without evidence of systemic metastases. The patient underwent limb perfusion and her immunosuppressive therapy has been stopped. The melanosis has not regressed; however, there has been no systemic involvement and her transplanted kidney is still functioning well. CONCLUSION: To our knowledge this is the first report of this phenomenon in an immunocompromised host.

Aged↗
PubMed1992

[Localization disorders in squint amblyopia: horizontal line bisection and relative vertical localization].

We used two different procedures for the evaluation of spatial localization errors in strabismic and anisometropic amblyopes, strabismic alternators and normal control subjects: partitioning of horizontal lines and vertical alignment. We found defective spatial localization in the amblyopic eyes of squinters with both procedures. However, in the horizontal partitioning experiment, the control subjects also showed asymmetries between the two hemifields. Thus, there is no good baseline under these conditions for the results of the amblyopic eyes of squinters. Our results show that vertical alignment is the more appropriate procedure to quantify defective spatial localization in strabismic amblyopes.

Discrimination Learning↗
PubMed2006

Dynamically screened local correlation method using enveloping localized orbitals.

In this paper we present a local coupled cluster approach based on a dynamical screening scheme, in which amplitudes are either calculated at the coupled cluster level (in this case CCSD) or at the level of perturbation theory, employing a threshold driven procedure based on MP2 energy increments. This way, controllable accuracy and smooth convergence towards the exact result are obtained in the framework of an a posteriori approximation scheme. For the representation of the occupied space a new set of local orbitals is presented with the size of a minimal basis set. This set is atom centered, is nonorthogonal, and has shapes which are fairly independent of the details of the molecular system of interest. Two slightly different versions of combined local coupled cluster and perturbation theory equations are considered. In the limit both converge to the untruncated CCSD result. Benchmark calculations for four systems (heptane, serine, water hexamer, and oxadiazole-2-oxide) are carried out, and decay of the amplitudes, truncation error, and convergence towards the exact CCSD result are analyzed.

Journal Article↗
PubMed1995

Fibroblast growth factor receptors (FGFRs) localize in different cellular compartments. A splice variant of FGFR-3 localizes to the nucleus.

We have raised specific antibodies to the second immunoglobulin-like domain of fibroblast growth factor receptors (FGFRs) and used these to investigate the expression and subcellular localization of FGFR-1, -2, -3, and -4 in breast epithelial cells. All four receptors classes could be detected in breast cell lines; however, FGFR-4 and FGFR-2 appeared to be expressed at a higher level in breast cancer cell lines than in normal epithelial cells. Surprisingly, FGFR-3 localized in the cell nucleus by immunofluorescence. A second antibody to a separate epitope confirmed this finding and showed that the form of FGFR-3 present must contain an intact kinase domain as well as the growth factor binding domain. Western analysis of fractionated cells revealed the presence of two forms of FGFR-3 of 135 and 110 kDa. The 110-kDa form was predominantly found in the nucleus, whereas the 135 kDa form was sometimes found in the nucleus. RT-PCR analysis of FGFR-3 mRNA showed the presence of a splice variant in which exons 7 and 8 are deleted. This results in the translation of FGFR-3 missing the transmembrane domain but with an intact kinase domain, which could be a soluble, intracellular receptor. Transfection experiments showed that FGFR-3 containing this deletion and no signal peptide gave an identical nuclear staining pattern to that seen in breast epithelial cells. We conclude that two forms of FGFR-3 are present in breast epithelial cells; a full-length 135-kDa receptor, which has a conventional membrane localization, and a novel soluble form of 110 kDa.

Alternative Splicing↗
PubMed2004

Janus kinase (Jak) subcellular localization revisited: the exclusive membrane localization of endogenous Janus kinase 1 by cytokine receptor interaction uncovers the Jak.receptor complex to be equivalent to a receptor tyrosine kinase.

The Janus kinases are considered to be cytoplasmic kinases that constitutively associate with the cytoplasmic region of cytokine receptors, and the Janus kinases (Jaks) are crucial for cytokine signal transduction. We investigated Jak1 localization using subcellular fractionation techniques and fluorescence microscopy (immunofluorescence and yellow fluorescent protein-tagged Jaks). In the different experimental approaches we found Jak1 (as well as Jak2 and Tyk2) predominantly located at membranes. In contrast to previous reports we did not observe Jak proteins in significant amounts within the nucleus or in the cytoplasm. The cytoplasmic localization observed for the Jak1 mutant L80A/Y81A, which is unable to associate with cytokine receptors, indicates that Jak1 does not have a strong intrinsic membrane binding potential and that only receptor binding is crucial for the membrane recruitment. Finally we show that Jak1 remains a membrane-localized protein after cytokine stimulation. These data strongly support the hypothesis that cytokine receptor.Janus kinase complexes can be regarded as receptor tyrosine kinases.

Cell Line↗
PubMed2004

Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes.

Endothelial cell migration is promoted by chemoattractants and is accompanied with microtubule extension toward the leading edge. Cytoskeletal microtubules polarize to function as rails for delivering a variety of molecules by motor proteins during cell migration. It remains, however, unclear how directional migration with polarized extension of microtubules is regulated. Here we report that Rap1 controls the migration of vascular endothelial cells. We found that Rap1-associating molecule, RAPL, which belongs to the Ras association domain family (Rassf), localized on microtubules and that activated Rap1 induced dissociation of RAPL from microtubules. A Rap1 activation-monitoring probe based on the fluorescence resonance energy transfer enabled us to demonstrate that local Rap1 activation occurs at the leading edge of the cells under the two types of cell migration, chemotaxis and wound healing. Time lapse imaging of microtubules marked by enhanced green fluorescent protein-RAPL showed the directional growth of microtubules toward the leading edge of the migrating cells. Using adenovirus, inactivation of Rap1 by expression of rap1GAPII inhibited wound healing. In addition, disconnection of Rap1 and RAPL by expression of a RAPL mutant also perturbed wound healing. Collectively, the locally activated Rap1 and its association with RAPL controls the directional migration of vascular endothelial cells.

Adaptor Proteins, Signal Transducing↗