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PubMed1990

Effect of sodium chloride on the structure of tubulin assemblies.

By use of a taxol-containing assembly medium, it has been demonstrated that the mean protofilament number of microtubule populations is significantly lower at elevated NaCl concentrations. Assembly of microtubule protein, i.e. tubulin plus microtubule-associated proteins (MAPs), at 80 and 580 mM NaCl results in microtubule populations with mainly 13 and 10 protofilaments whereas microtubules formed from tubulin alone have 12 and 10 protofilaments, respectively. Moreover, when MAPs are prevented from assembly, the formation of taxol-induced aberrant assemblies (C- and S-shaped protofilament ribbons) is suppressed at high NaCl concentrations in favour of microtubules. The described effects are obviously caused by both weakening of MAP binding to tubulin and alterations in tubulin-tubulin association.

Actin Cytoskeleton↗

PubMed1980

Genetic mapping of an H-2-associated antigen expressed on regulatory T cells.

T lymphocytes that serve regulatory functions in the generation of effector T cells to alloantigen and to altered syngeneic cells express a distinguishing H-2-associated cell surface marker that we have termed Ha. Genetic mapping studies with the B10.A(2R), B10.A(4R), B10.A(5R), and LG/Ckc lines of mice have delineated the locus determining the expression of Ha to the right of H-2K and left of H-2IB or within the I-A region. Thus these regulatory T lymphocytes express Ia antigens.

Absorption↗

PubMed1992

Interactions of bacterial lipopolysaccharide with microtubule proteins.

Bacterial LPS is a potent stimulator of immune cells, but its mechanisms are unknown. A possible role for microtubules in LPS actions has been indicated by previous findings that the microtubule-active agent, taxol, can mimic some effects of LPS in macrophages from normal strains of mice, but not from genetically LPS-hyporesponsive strains. In this report we demonstrate that isolated microtubules from mouse brain can bind LPS in vitro. LPS and tubulin coeluted through a gel filtration column, and LPS was cross-linked to microtubule proteins with an iodinatable, photoreactive agent, sulfosuccinimidyl 2-(p-azidosalicylamido) ethyl-1,3'-dithiopropionate. beta-Tubulin and microtubule-associated protein-2 (MAP), a predominant MAP in the brain, bound LPS specifically. Cross-linking was inhibited by an excess of unlabeled LPS or partially by unlabeled lipid A, but not by 2 M NaCl. Under the same conditions, neither myosin nor soybean trypsin inhibitor was labeled by the photoaffinity LPS probe, nor did these proteins compete for binding of LPS to beta-tubulin. These findings support the hypothesis that the microtubule network could be an intracellular target for LPS, and suggest further that a beta-tubulin-associated MAP could have an important role in LPS actions.

Affinity Labels↗

PubMed2001

Cerebral ischemia/reperfusion injury in rat brain: effects of naloxone.

The pathogenesis of cerebral ischemia/reperfusion (I/R) involves cytokine/chemokine production, inflammatory cell influx, astrogliosis, cytoskeletal protein degradation and breakdown of the blood-brain barrier. (-)-Naloxone is able to reduce infarct volume and has been used as a therapeutic agent for cerebral I/R injuries. However, its effects on the mentioned pathophysiologic changes have scarcely been addressed. Cerebral I/R was produced by occluding and opening bilateral common carotid artery and unilateral middle cerebral artery in Sprague-Dawley rats. After cerebral I/R, the degradation of neuronal microtubule-associated protein-2 (MAP-2) was strongly associated with astrogliosis, inflammatory cell infiltration, cytokine/chemokine overproduction, and matrix metalloproteinase-9 activation. (-)-Naloxone pretreatment suppresses post-ischemic activation and preserves more MAP-2 protein. Therefore, (-)-naloxone administration might be an effective therapeutic intervention for reducing ischemic injuries.

Animals↗

PubMed2005

Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study.

High density lipoprotein cholesterol (HDL-C) is inversely associated with coronary heart disease and has a genetic component; however, linkage to HDL-C is not conclusive. Subfractions of HDL, such as HDL(3)-C, may be better phenotypes for linkage studies. Using HDL(3)-C levels measured on 907 Framingham Heart Study subjects from 330 families around 1987, we conducted a genome-wide variance components linkage analysis with 401 microsatellite markers spaced approximately 10 centimorgan (cM) apart. Nine candidate genes were identified and annotated using a bioinformatics approach in the region of the highest linkage peak. Twenty-eight single nucleotide polymorphisms (SNPs) were selected from these candidate genes, and linkage and family-based association fine mapping were conducted using these SNPs. The highest multipoint log-of-the-odds (LOD) score from the initial linkage analysis was 3.7 at 133 cM on chromosome 6. Linkage analyses with additional SNPs yielded the highest LOD score of 4.0 at 129 cM on chromosome 6. Family-based association analysis revealed that SNP rs2257104 in PLAGL1 at approximately 143 cM was associated with multivariable adjusted HDL(3) (P = 0.03). Further study of the linkage region and exploration of other variants in PLAGL1 are warranted to define the potential functional variants of HDL-C metabolism.

Adult↗

PubMed2000

Encephalitozoon cuniculi (Microspora) genome: physical map and evidence for telomere-associated rDNA units on all chromosomes.

A restriction map of the 2.8-Mb genome of the unicellular eukaryote Encephalitozoon cuniculi (phylum Microspora), a mammal-infecting intracellular parasite, has been constructed using two restriction enzymes with 6 bp recognition sites (Bss HII and Mlu I). The fragments resulting from either single digestions of the whole molecular karyotype or double digestions of 11 individual chromosomes have been separated by two-dimensional pulsed field gel electrophoresis (2D-PFGE) procedures. The average distance between successive restriction sites is approximately 19 kb. The terminal regions of the chromosomes show a common pattern covering approximately 15 kb and including one 16S-23S rDNA unit. Results of hybridisation and molecular combing experiments indicate a palindromic-like orientation of the two subtelomeric rDNA copies on each chromosome. We have also located 67 DNA markers (clones from a partial E. cuniculi genomic library) by hybridisation to restriction fragments. Partial or complete sequencing has revealed homologies with known protein-coding genes for 32 of these clones. Evidence for two homologous chromosomes III, with a size difference (3 kb) related to a subtelomeric deletion/insertion event, argues for diploidy of E.cuniculi. The physical map should be useful for both the whole genome sequencing project and studies on genome plasticity of this widespread parasite.

Animals↗

PubMed1998

Mapping of the natural resistance-associated macrophage protein 1 (NRAMP1) gene to pig chromosome 15.

The natural resistance-associated macrophage protein 1 (NRAMP1) was mapped in the pig for study as a potential candidate gene in controlling pig resistance to Salmonella infection. Primers were designed from the pig cDNA to amplify a 1.6 kb fragment between exons 1 and 3. By using a pig-rodent somatic cell hybrid panel, NRAMP1 was mapped to pig chromosome 15 (SSC15) with 100% probability, and the regional assignment was SSC15q23-26 with 87% concordance. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) marker was developed by using the HinfI enzyme and three alleles were identified from a population including 11 breeds. Linkage analysis confirmed the physical assignment by using the PiGMaP reference families. Pig NRAMP1 was linked to SSC15 markers S0088, S0149 and S0284 (LOD > 3). A small population study revealed large allele frequency differences among tested breeds. An A allele is only observed in dam (white) lines whereas a similar exclusivity of the C allele was seen in sire (colored) breeds.

Alleles↗

PubMed1981

Calcium lability of cytoplasmic microtubules and its modulation by microtubule-associated proteins.

Detergent-extracted BSC-1 monkey cells have been used as a model system to study the Ca(2+) sensitivity of in vivo polymerized microtubules under in vitro conditions. The effects of various experimental treatments were observed by immunofluorescence microscopy. Whereas microtubules are completely stable at Ca(2+) concentrations below 1 muM, Ca(2+) at greater than 1-4 muM induces microtubule disassembly that begins in the cell periphery and proceeds towards the cell center. At concentrations of up to 500 muM, both the pattern and time course of disassembly are not markedly altered, suggesting that, within this concentration range, Ca(2+) effects are catalytic rather than stoichiometric. Higher (millimolar) Ca(2+) concentration results in rapid destruction of microtubules. Of other divalent cations, only Sr(2+) has a slight depolymerizing effect, whereas millimolar Ba(2+), Mg(2+), or Mn(2+) is ineffective. Disassembly induced by micromolar Ca(2+) is inhibited by pharmacological agents known to bind to calmodulin and inhibit its function, suggesting that calmodulin mediates Ca(2+) effects. Both the addition of exogenous brain microtubule-associated proteins (MAPs) after lysis and the retention of endogenous cellular MAPs normally extracted during the lysis step stabilize microtubules against the depolymerizing effect of micromolar Ca(2+). The results indicate that, in this model system, microtubules are sensitive to physiological Ca(2+) concentrations and that this sensitivity may be conferred by calmodulin associated with the microtubules. MAPs appear to have a modulating effect on microtubular Ca(2+) sensitivity and thus may function as a discriminating factor in cellular functions performed by calmodulin. It is hypothesized that Ca(2+)-stimulated microtubule disassembly depends on the relative amount of MAPs.

Animals↗

PubMed1985

In vivo proteolytic activity of the mammary gland. Contribution to the origin of secretory component, beta 2-microglobulin and bovine-associated mucoprotein (BAMP) in cows milk.

Milk samples were collected from Holstein-Friesian cows at various times after milking (10-30 min; 30 min-10 hr) and treated with a protease inhibitor or control solution. Samples were then fractionated into whole, skimmed and cell-free skimmed milk aliquots. Some animals were treated with E. coli endotoxin prior to sample collection. The concentrations of three membrane-associated proteins (MAP), beta 2-microglobulin (beta 2M), secretory component (SC) and bovine-associated mucoprotein (BAMP) as well as albumin were measured in each aliquot to determine if in vivo proteolysis of milk elements could explain the origin of these MAP in milk. All three MAP could be localized on milk fat globules (MFG) and alveolar epithelial cells of the gland. Data revealed that all BAMP in milk can be accounted for by in vivo proteolytic degradation of MFG while most beta 2M is derived by similar degradation, from cellular elements in milk, presumably monocytes. Experiments with endotoxin which elevate PMN levels, failed to influence the release of any MAP while elevating albumin levels by greater than 10-fold. Based on these studies, SC release into milk cannot be ascribed to a protease-dependent mechanism.

Animals↗

PubMed2006

Differential recruitment of the splicing machinery during transcription predicts genome-wide patterns of mRNA splicing.

The splicing machinery associates with genes to facilitate efficient cotranscriptional mRNA processing. We have mapped these associations by genome localization analysis to ascertain how splicing is achieved and regulated on a system-wide scale. Our data show that factors important for intron recognition sample nascent mRNAs and are retained specifically at intron-containing genes via RNA-dependent interactions. Spliceosome assembly proceeds cotranscriptionally but completes posttranscriptionally in most cases. Some intron-containing genes were not bound by the spliceosome, including several developmentally regulated genes. On this basis, we predicted and verified regulated splicing and observed a role for nuclear mRNA surveillance in monitoring those events. Finally, we present evidence that cotranscriptional processing events determine the recruitment of specific mRNA export factors. Broadly, our results provide mechanistic insights into the coordinated regulation of transcription, mRNA processing, and nuclear export in executing complex gene expression programs.

Adenosine Triphosphatases↗

PubMed1998

Changes in mRNA abundance of microtubule-associated proteins in the rat brain following electroconvulsive shock.

Microtubule-associated proteins (MAPs) are involved in the maintenance of mature neuronal morphology, neurite outgrowth and neuronal plasticity. Alteration in MAP expression may underlie neuronal structural changes in response to seizure activity. The aim of the present study was to investigate whether electroconvulsive shock (ECS), an animal model of electroconvulsive therapy (ECT) in clinical treatment of depression, affected gene expression of MAPs in the rat brain. Using in situ hybridization, we studied the expression of encoding mRNA for MAPs in the brains of rats treated with ECS 5 times over 10 days. The abundance of mRNA encoding microtubule-associated protein 2 (MAP2), a dendritic MAP, was significantly increased (142% compared with controls) in the dentate gyrus 6 and 24 h after the last shock, and had returned to baseline levels within 48 h. These changes were confined to the dentate gyrus no significant changes were observed in CA1 and CA3 of the hippocampus. The increase in MAP2 expression was accompanied by an increase in MAP2 immunoreactivity in the molecular layer of the dentate gyrus. The abundance of mRNA encoding for tau, an axon-specific MAP, and MAP1B, an embryonic MAP, was unaffected by ECS. These data demonstrate that ECS specifically altered the mRNA and protein expression of MAP2 but had no effect on tau or MAP1B, and suggest that changes in MAP2 expression may be related to morphological changes in the dentate gyrus, particularly in the dendrites.

Animals↗

PubMed1993

Okadaic acid induces spindle lengthening and disrupts the interaction of microtubules with the kinetochores in metaphase II-arrested mouse oocytes.

The cell cycle is regulated by phosphorylation events via a cascade of protein kinases and phosphatases, but many of their substrates remain unknown. To study whether proteins of the metaphase II-arrested mouse oocyte meiotic spindle are substrates for phosphorylation events, we used okadaic acid (OA), a potent phosphatase inhibitor, upon fully mature spindles. Incubation of oocytes for 3 hr with 1 microM OA led to a dramatic lengthening of the spindle and a disorganization of the metaphase plate. Electron microscope studies revealed that this was due to a disruption of the interactions between the microtubules and the kinetochores. Biochemical analysis including MPM-2 immunoblotting and [32P]phosphate labeling of whole oocytes revealed several changes in the phosphorylation pattern following the OA treatment. Moreover, meiotic spindle purification or microtubule-associated proteins (MAPs) isolation showed that some of these phosphorylations occur on proteins associated with the microtubules or with structures closely related to the spindle. These results suggest that the changes occurring in the microtubule network during the cell cycle are partly due to the phosphorylation of some proteins associated with the microtubules.

Animals↗

PubMed2004

Randomized comparison of anatomical versus voltage guided ablation of the cavotricuspid isthmus for atrial flutter.

OBJECTIVES: The purpose of this prospective study was to compare radiofrequency catheter ablation of the cavotricuspid isthmus using a strictly anatomic approach to an approach guided by a bipolar voltage map to avoid high voltage zones in the cavotricuspid isthmus. BACKGROUND: It is not clear whether local atrial electrogram amplitude influences the achievement of complete cavotricuspid isthmus block during radiofrequency catheter ablation for atrial flutter. METHODS: Thirty-two patients with atrial flutter were randomized to cavotricuspid isthmus ablation using an anatomical approach (group I, 16 patients) or guided by a bipolar voltage map (group II, 16 patients). A 3-dimensional electroanatomic mapping system and an 8-mm-tip ablation catheter were used in all patients. With the anatomical approach, an ablation line was created in the cavotricuspid isthmus at a 6 o'clock position in the 45 degree left anterior oblique projection. During voltage-guided ablation, a high-density bipolar voltage map of the cavotricuspid isthmus was created, and then contiguous applications of radiofrequency energy were delivered to create an ablation line through the cavotricuspid isthmus sites with the lowest bipolar voltage. RESULTS: Complete cavotricuspid isthmus conduction block was achieved in 100% of patients in each group. The mean maximum voltages along the line were 3.6 +/- 1.5 mV in group I, and 1.2 +/- 0.9 mV in group II (P < .01). Creating a high-density voltage map was associated with approximately 15-minute increase in the total procedure time (P = .2). During a mean follow-up of 177 +/- 40 days, there were no recurrences of atrial flutter in either group. There were no complications in either group. CONCLUSIONS: When cavotricuspid isthmus ablation for atrial flutter is performed with an 8-mm-tip catheter, complete block can be achieved in all patients regardless of local voltage. Ablation of high voltage zones is not associated with a higher recurrence rate. Therefore, anatomic ablation without voltage mapping is the preferred initial approach for cavotricuspid isthmus ablation.

Atrial Flutter↗

PubMed2004

Integrating linkage and radiation hybrid mapping data for bovine chromosome 15.

BACKGROUND: Bovine chromosome (BTA) 15 contains a quantitative trait loci (QTL) for meat tenderness, as well as several breaks in synteny with human chromosome (HSA) 11. Both linkage and radiation hybrid (RH) maps of BTA 15 are available, but the linkage map lacks gene-specific markers needed to identify genes underlying the QTL, and the gene-rich RH map lacks associations with marker genotypes needed to define the QTL. Integrating the maps will provide information to further explore the QTL as well as refine the comparative map between BTA 15 and HSA 11. A recently developed approach to integrating linkage and RH maps uses both linkage and RH data to resolve a consensus marker order, rather than aligning independently constructed maps. Automated map construction procedures employing this maximum-likelihood approach were developed to integrate BTA RH and linkage data, and establish comparative positions of BTA 15 markers with HSA 11 homologs. RESULTS: The integrated BTA 15 map represents 145 markers; 42 shared by both data sets, 36 unique to the linkage data and 67 unique to RH data. Sequence alignment yielded comparative positions for 77 bovine markers with homologs on HSA 11. The map covers approximately 32% of HSA 11 sequence in five segments of conserved synteny, another 15% of HSA 11 is shared with BTA 29. Bovine and human order are consistent in portions of the syntenic segments, but some rearrangement is apparent. Comparative positions of gene markers near the meat tenderness QTL indicate the region includes separate segments of HSA 11. The two microsatellite markers flanking the QTL peak are between defined syntenic segments. CONCLUSIONS: Combining data to construct an integrated map not only consolidates information from different sources onto a single map, but information contributed from each data set increases the accuracy of the map. Comparison of bovine maps with well annotated human sequence can provide useful information about genes near mapped bovine markers, but bovine gene order may be different than human. Procedures to connect genetic and physical mapping data, build integrated maps for livestock species, and connect those maps to more fully annotated sequence can be automated, facilitating the maintenance of up-to-date maps, and providing a valuable tool to further explore genetic variation in livestock.

Animals↗

PubMed2001

Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells.

Vinca alkaloids are used extensively in the treatment of childhood acute lymphoblastic leukemia (ALL) and despite their usefulness, drug resistance remains a serious clinical problem. Vinca alkaloids bind to the beta-tubulin subunit of the alpha/beta-tubulin heterodimer and inhibit polymerization of microtubules. Recent studies have implicated altered beta-tubulin isotype expression and mutations in resistance to microtubule-stabilizing agents. Microtubule-associated protein (MAP) MAP4 binds to and stabilizes microtubules, and increased expression is associated with decreased sensitivity to microtubule-depolymerizing agents. To address the significance of beta-tubulin and MAP4 alterations in childhood ALL, two CCRF-CEM-derived Vinca alkaloid resistant cell lines, VCR R (vincristine) and VLB100 (vinblastine), were examined. Decreased expression of class III beta-tubulin was detected in both VCR R and VLB100 cells. VCR R cells and to a lesser extent VLB100 cells expressed increased levels of MAP4 protein. Increased microtubule stability was observed in these VCR R cells as identified by the high levels of polymerized tubulin (45.6 +/- 2.6%; P < 0.005) compared with CEM and VLB100 cells (24.7 +/- 3.3% and 24.7 +/- 2.5%, respectively). Expression was associated with a single MAP4 isoform in the polymerized microtubule fraction in CEM and VCR cells. In contrast, VLB100 cells expressed a lower molecular weight isoform in the polymerized fraction. Two-dimensional-PAGE and immunoblotting revealed marked posttranslational changes in class I beta-tubulin in VCR R cells not evident in CEM cells. Sequencing of the beta-tubulin (HM40) gene identified a point mutation in VCR R cells in nucleotide 843 (CTC-->ATC; Leu(240)-->Ile) that was not present in CEM or VLB100 cells. This mutation resides in a region of beta-tubulin that lies in close proximity to the alpha/beta tubulin interface. Multiple alterations related to normal microtubule function were identified in ALL cells selected for resistance to Vinca alkaloids, and these alterations may provide important insight into mechanisms mediating resistance to Vinca alkaloids.

Antineoplastic Agents, Phytogenic↗

PubMed1997

A dominant B-cell epitope on the 22 kDa tegumental membrane-associated antigen of Schistosoma japonicum maps to an EF-hand calcium binding domain.

The 22 kDA tegumental surface membrane-associated antigen of schistosomes is of recognized importance in immunity to schistosomiasis. Here, we have defined linear B-cell epitopes on the recently cloned and expressed recombinant Schistosoma japonicum 22 kDa antigen (reSj22), using mice immunized with this molecule. Sera from three strains of mice, CBA, C57BL/6 and BALB/c, representing different genetic backgrounds, were reacted with a series of overlapping synthetic peptides in epitope-scanning studies. The predicted hydrophilic N-terminal domain was found to be highly immunogenic, containing several sequences that were strongly recognized by all strains of mice. The most dominant epitope identified, corresponding to peptide 6, was located in a region previously identified as an EF-hand calcium binding domain. In contrast, the more hydrophobic C-terminal region of the molecule was poorly recognized, with the exception of a single peptide encoding residues 121-140 that was recognized by CBA and C57BL/6 but not BALB/c mice, suggesting that the latter epitope was genetically restricted between the strains. The data presented here describing the epitope mapping of this molecule may prove important in research aimed at further defining immune responses to schistosomal antigens.

Amino Acid Sequence↗

PubMed2006

Using self-organizing maps to recognize acoustic units associated with information content in animal vocalizations.

Kohonen self-organizing neural networks, also called self-organizing maps (SOMs), have been used successfully to recognize human phonemes and in this way to aid in human speech recognition. This paper describes how SOMS also can be used to associate specific information content with animal vocalizations. A SOM was used to identify acoustic units in Gunnison's prairie dog alarm calls that were vocalized in the presence of three different predator species. Some of these acoustic units and their combinations were found exclusively in the alarm calls associated with a particular predator species and were used to associate predator species information with individual alarm calls. This methodology allowed individual alarm calls to be classified by predator species with an average of 91% accuracy. Furthermore, the topological structure of the SOM used in these experiments provided additional insights about the acoustic units and their combinations that were used to classify the target alarm calls. An important benefit of the methodology developed in this paper is that it could be used to search for groups of sounds associated with information content for any animal whose vocalizations are composed of multiple simultaneous frequency components.

Animals↗

PubMed2001

The genetic dissection of complex traits in a founder population.

We estimated broad heritabilities (H(2)) and narrow heritabilities (h(2)) and conducted genomewide screens, using a novel association-based mapping approach for 20 quantitative trait loci (QTLs) among the Hutterites, a founder population that practices a communal lifestyle. Heritability estimates ranged from.21 for diastolic blood pressure (DBP) to.99 for whole-blood serotonin levels. Using a multipoint method to detect association under a recessive model we found evidence of major QTLs for six traits: low-density lipoprotein (LDL), triglycerides, lipoprotein (a) (Lp[a]), systolic blood pressure (SBP), serum cortisol, and whole-blood serotonin. Second major QTLs for Lp(a) and for cortisol were identified using a single-point method to detect association under a general two-allele model. The heritabilities for these six traits ranged from.37 for triglycerides to.99 for serotonin, and three traits (LDL, SBP, and serotonin) had significant dominance variances (i.e., H(2) > h(2)). Surprisingly, there was little correlation between measures of heritability and the strength of association on a genomewide screen (P>.50), suggesting that heritability estimates per se do not identify phenotypes that are influenced by genes with major effects. The present study demonstrates the feasibility of genomewide association studies for QTL mapping. However, even in this young founder population that has extensive linkage disequilibrium, map densities <<5 cM may be required to detect all major QTLs.

Adolescent↗