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PubMed1992

[Effect of mutations in the genes su(Hw) and mod(mdg4) on transvection between alleles of the Yellow locus in Drosophila melanogaster].

A typical example of transvection is a complementation between alleles in the yellow locus: y2 (mdg4 insertion inactivating certain y-enhancers) and y1 (deletion of the y-promoter but not of the enhancer). Transvection was explained by trans-activation of promoter in y2-allele by enhancer of y1-allele. Here we found that the mutation mod(mdg4)1u1 in the modifier of mdg4 locus (a regulatory gene controlling, together with suppressor of Hairy wing) expression of (mdg4) completely suppress the complementation. Removal of an acidic domain from su(Hw) protein product in su(Hw)j mutation partially suppress the complementation. We also have found that mod(mdg4)1u1 mutation trans-inactivates the yellow allele with a wild type phenotype (y+2MC) in heterozygote with the y2 allele, i.e. the negative transvection takes place. In this case, deletion removing an acidic domain even in one copy of su(Hw) suppresses the effect of mod(mdg4)1u1 mutation.

Alleles↗
PubMed2006

Osteosarcoma: preliminary results of in vivo assessment of tumor necrosis after chemotherapy with diffusion- and perfusion-weighted magnetic resonance imaging.

PURPOSE: We sought to evaluate diffusion and perfusion weighted 1.5 T magnetic resonance imaging (MRI) in detecting tumor necrosis with histologic correlation after preoperative chemotherapy. MATERIALS AND METHODS: Eight patients (ages 11-19 years) with histologic proven osteosarcoma of the limbs underwent T1- and fat-suppressed T2-weighted spin echo and diffusion-weighted EPI sequences (b value = 700) after 5 cycles of standard chemotherapy. Tumor volume and apparent diffusion coefficients (ADC) were calculated. Tumor signal intensities were measured in dynamic contrast enhanced T1-weighted fast gradient echo-sequences obtained every 3 seconds after an intravenous injection of gadolinium-DTPA. Perfusion parameters of first-pass tracing of contrast medium (time-to-peak, slope of contrast enhancement curve) were calculated, and perfusion maps were established. After MRI, all patients underwent limb resection, and the specimens were investigated macroscopically and histologically. The degree of tumor necrosis was assessed using the histologic Salzer-Kuntschik classification (grades 1-6) after chemotherapy. RESULTS: Necrotic areas, which were confirmed by macroscopic/histologic examination, showed ADC values up to 2.7 (mean, 2.3 +/- 0.2). Viable tumor areas revealed lower apparent diffusion coefficients (mean, 0.8 +/- 0.3). The differences in ADC between viable and necrotic tumor were highly significant (paired t test; P = 0.01). Slopes of necrotic areas ranged from 0.1 up to 5.2%/min (mean, 1.5%/min) and those of viable tumor areas from 2.8 to 31.5%/min (mean, 16.1%/min). The time-to-peak-values (TTPs) ranged from 40 to 210 seconds (mean, 131 seconds, SD 60 seconds) in necrotic tumors and from 30 to 96 seconds (mean, 55 seconds, SD 21) in viable areas of sarcomas. The differences in slope and TTP between viable and necrotic tumor were highly significant. In necrotic areas, the linear correlation between slope (%/min) and ADC (mm/s) and between TTP (s) and ADC were weak, respectively. CONCLUSION: Both dynamic contrast-enhanced MRI and diffusion-weighted MRI permit recognition of tumor necrosis induced by chemotherapy in osteosarcomas. We hypothesized that diffusion-weighted imaging is correlated directly with tumor necrosis. Perfusion-weighted imaging is correlated with microvessel density, vascular permeability, local blood volume, and flow. Therefore, perfusion weighed MRI depicts areas of tumor cell necrosis indirectly.

Adolescent↗
PubMed1993

DNase-I-hypersensitive sites located far upstream of the human c-sis/PDGF-B gene comap with transcriptional enhancers and a silencer and are preceded by (part of) a new transcription unit.

The human c-sis gene encodes the B chain of platelet-derived growth factor (PDGF), a potent mitogen for cultured cells of mesenchymal origin. PDGF is stored in the alpha-granules of blood platelets, which are derived from bone marrow megakaryocytes and lack transcriptional machinery. Human myeloid leukemia cell line K562 can be used as a model for megakaryocytes. Phorbol-ester-mediated megakaryocytic differentiation of K562 cells is accompanied by more than 200-fold increase in the c-sis mRNA level. We have now localized transcriptional enhancers at -8.6 kb and -9.9 kb relative to the human c-sis gene transcription start site. The enhancer at -8.6 kb increases activity of the c-sis promoter by 40-60-fold specifically in K562 cells and comaps with a DNase-I-hypersensitivity (DH) site. The enhancer at -9.9 kb increases c-sis promoter activity by 5-10-fold in K562 cells and DH at that site accompanies phorbol-ester-induced megakaryocytic differentiation. In phorbol-ester-treated K562 cells the two enhancers may be negatively influenced by a silencer that comaps with DH at -10.7/-11.0 kb. Reporter gene analysis predicted that combined activity of the upstream enhancers and the c-sis promoter may result in 100-1000-fold higher promoter activity in phorbol-ester-treated K562 cells compared with untreated cells, which can fully explain the more than 200-fold increase in c-sis mRNA level. DH at -8.6 kb and -9.9 kb was also detected in human fibroblasts and in the carcinoma cell lines HeLa and PC3, which express, respectively, undetectable, low and high levels of c-sis mRNA. Although the individual DH sites displayed 4-10-fold enhancer activity in all these cells, they lost most of their biological activity when combined in a larger fragment. In addition we localized (part of) a new transcription unit at approximately 13 kb upstream of the c-sis transcription start site. The corresponding 0.45-kb sis upstream region (sur) transcript is constitutively expressed in all cell lines examined. The expression of the sur transcript is independent of the expression of c-sis mRNA and of the pattern of DH sites far upstream of the c-sis gene. Thus, at present, there is no indication that the upstream DH sites are involved in regulation of expression of the sur gene.

Cell Line↗
PubMed1999

Ethanol potentiates the mitogenic effects of sphingosine 1-phosphate by a zinc- and calcium-dependent mechanism in fibroblasts.

In mouse embryo NIH 3T3 fibroblasts, ethanol (60-80 mM) was found to enhance the stimulatory effects of sphingosine 1-phosphate (S1P) on both DNA synthesis and cell proliferation. Well-detectable potentiating effects of ethanol on S1P-induced mitogenesis required the presence of calcium (>1 mM) and zinc (20-40 microM) in the incubation medium. The amphibian tetrapeptide bombesin, which is known to mobilize intracellular calcium in fibroblasts, had no effect alone, but it approximately doubled the combined stimulatory effects of ethanol and S1P on DNA synthesis. The synergistic mitogenic effects of ethanol and S1P were also slightly enhanced, rather than inhibited, by the alcohol dehydrogenase inhibitor 4-methylpyrazole (5 mM). Of the various growth regulatory enzymes examined, ethanol detectably enhanced the stimulatory effects of S1P on the phosphosphorylation (activation) of p42/p44 mitogen-activated protein (MAP) kinases, but not of p38 MAP kinase. Cotreatment of fibroblasts with ethanol for 10 min also enhanced the stimulatory effects of S1P on the activities of c-Raf-1 kinase and p70 S6 kinase, but neither S1P nor ethanol had effects on phosphatidylinositol 3'-kinase and Akt/PKB kinase activities. Ethanol-plus-S1P-induced DNA synthesis was partially inhibited by both PD 98059 (50 microM) and rapamycin (10 nM), inhibitors of p42/p44 MAP kinase kinase and mTOR/p70 S6 kinases, respectively. The results indicate that in NIH 3T3 fibroblasts, ethanol can enhance the mitogenic effects of S1P by a zinc- and calcium-dependent mechanism involving both the rapamycin-sensitive p70 S6 kinase-dependent and the c-Raf-1/MAP kinase-dependent growth regulatory pathways.

3T3 Cells↗
PubMed2004

Asymmetric Nodal expression in the mouse is governed by the combinatorial activities of two distinct regulatory elements.

In all vertebrates, invariant left/right (L/R) positioning and organization of the internal viscera is controlled by a conserved pathway. Nodal, a member of the TGFbeta superfamily is a critical upstream component responsible for initiating L/R axis determination. Asymmetric Nodal expression in the node preceeds and foreshadows morphological L/R asymmetry. Here we address the mechanism of Nodal activation in the left LPM by studying the function of a novel enhancer element, the AIE. We show this element is exclusively active in cells of the left lateral plate mesoderm (LPM) and is not itself responding to Nodal asymmetry. To test the hypothesis that this element may initiate asymmetric Nodal expression in the LPM, we deleted it from the mouse germ line. Mice homozygous for the AIE deletion (Nodal(deltaaie/deltaaie)) show no defects. However, we find that the AIE contributes to regulating the level of asymmetric Nodal activity; analysis of transheterozygous embryos (Nodal(deltaaie/null)) shows reduced Nodal expression in the left LPM associated with a low penetrance of L/R defects. Our findings point to the existence of two independent pathways that control Nodal expression in the left LPM.

Alleles↗
PubMed2002

[ECG mapping in clinical practice].

First the authors present a review of important cornerstones in the history of the electrocardiogram (ECG) and ECG mapping. The first to describe the electric cardiac field based on twenty ECGs was A.D. Waller in 1889. The decisive cornerstone for practical use was the introduction of a string galvanometer in 1901 by W. Einthoven and his triaxial lead system. Another very important cornerstone in the development of ECG were the findings of F.N. Wilson. Merits as regards the development and application of ECG mapping are due to B. Taccardi. Workers of the Second Medical Clinic in Prague enhanced after 15 years of studies and comparison of ECG maps with coronarographic findings in subjects with ischaemic heart disease (IHD) and microvascular coronary dysfunction (syndrome X--SyX) substantially the specificity of this method in impaired myocardial vascularization. Better diagnosis was achieved by introduction of diagnostic tests which influence coronary vascularization such as e.g. hyperventilation, as well as other tests. After their application progression of chronic myocardial ischaemia occurs, e.g. by the mechanism of the "steal phenomenon" or restriction of the microcirculation after hyperventilation in patients with SyX. Furthermore the authors present examples of ECG maps after PTCA, after application of diagnostic tests in IHD and SyX and also regression of myocardial ischaemia after marked reduction of total cholesterol.

Adult↗
PubMed1997

The developmental activation of the chicken lysozyme locus in transgenic mice requires the interaction of a subset of enhancer elements with the promoter.

The complete chicken lysozyme locus is expressed in a position independent fashion in macrophages of transgenic mice and forms the identical chromatin structure as observed with the endogenous gene in chicken cells. Individual lysozyme cis -regulatory elements reorganize their chromatin structure at different developmental stages. Accordingly, their activities are developmentally regulated, indicating a differential role of these elements in locus activation. We have shown previously that a subset of enhancer elements and the promoter are sufficient to activate transcription of the chicken lysozyme gene at the correct developmental stage. Here, we analyzed to which grade the developmentally controlled chromatin reorganizing capacity of cis -regulatory elements in the 5'-region of the chicken lysozyme locus is dependent on promoter elements, and we examined whether the lysozyme locus carries a dominant chromatin reorganizing element. To this end we generated transgenic mouse lines carrying constructs with a deletion of the lysozyme promoter. Expression of the transgene in macrophages is abolished, however, the chromatin reorganizing ability of the cis -regulatory elements is differentially impaired. Some cis -elements require the interaction with the promoter to stabilize transcription factor complexes detectable as DNase I hypersensitive sites in chromatin, whereas other elements reorganize their chromatin structure autonomously.

Animals↗
PubMed2006

3T MR imaging of the brain.

The advent of very high field clinical scanners that operate at 3T is taking structural and functional imaging to new levels and is reinvigorating clinical spectroscopy, fMR imaging, and noncontrast-enhanced methods of MRA. Most of the challenges that are related to 3T imaging have been addressed to facilitate routine clinical imaging. An awareness of the complexities that underlie the solutions to these challenges is important to the continued improvements to the 3T platform so that its maximal potential can be reached. The development of the multichannel-head coils and the improvement in the design of body coils, concurrently with the development of multichannel capabilities that enable parallel imaging, have benefited all field platforms. Perhaps the added value of parallel imaging has been greatest at 3T where the additional signal can be exploited. The definition of very high field is a moving target, and may be well on its way to 7.0 T, although in terms of the current clinical state of the art, 3T is our current reference.

Artifacts↗
PubMed1992

Enhanced heterologous gene expression in novel rpoH mutants of Escherichia coli.

Extragenic temperature-resistant suppressor mutants of an rpoD800 derivative of Escherichia coli W3110 were selected at 43.5 degrees C. Two of the mutants were shown to have a phenotype of enhanced accumulation of heterologous proteins. Genetic mapping of the two mutants showed that the mutation conferring temperature resistance resided in the rpoH gene. P1-mediated transduction of the rpoD+ gene into both of the rpoD800 rpoH double mutants resulted in viable rpoH mutants, MON102 and MON105, that retained temperature resistance at 46 degrees C, the maximum growth temperature of W3110. The complete rpoH gene, including the regulatory region, from MON102, MON105, and the parental W3110 was cloned and sequenced. Sequencing results showed that a single C----T transition at nucleotide 802 was present in both MON102 and MON105, resulting in an Arg(CGC)----Cys(TGC) substitution at amino acid residue 268 (R-268-C; this gene was designated rpoH358). Heterologous protein accumulation levels in both MON102 and MON105, as well as in rpoH358 mutants constructed in previously unmanipulated W3110 and JM101, were assessed and compared with parental W3110 and JM101 levels. Expression studies utilizing the recA or araBAD promoter and the phage T7 gene 10L ribosome-binding site (g10L) showed that increased accumulation levels of a number of representative heterologous proteins (i.e., human or bovine insulin-like growth factor-1, bovine insulin-like growth factor-2, prohormone of human atrial natriuretic factor, bovine placental lactogen, and/or bovine prolactin) were obtained in the rpoH358 mutants compared with the levels in the parental W3110 and JM101. The mechanism of enhanced heterologous protein accumulation in MON102 and MON105 was unique compared with those of previously described rpoH mutants. Pulse-chase and Northern (RNA) blot analyses showed that the enhanced accumulation of heterologous proteins was not due to decreased proteolysis but was instead due to increased levels of the respective heterologous mRNAs accompanied by increased synthesis of the respective heterologous proteins. The plasmid copy number remained unaltered.

Base Sequence↗
PubMed2001

HIV Nef increases T cell ERK MAP kinase activity.

The human immunodeficiency regulatory protein Nef enhances viral replication and is central to viral pathogenesis. Although Nef has displayed a capacity to associate with a diverse assortment of cellular molecules and to increase T cell activity, the biochemical activity of Nef in T cells remains poorly defined. In this report we examine the bioactivity of Nef in primary CD4 T cells and, in particular, focus on the biochemical pathways known to be central to T cell activity. The extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway was dramatically affected by Nef expression with increases in ERK, MEK, and Elk induction. The capacity of Nef to increase the MAP kinase pathway activity was dependent on T cell receptor stimulation. By increasing ERK MAP kinase activity, Nef is functionally associated with a kinase known to affect T cell activity, viral replication, and viral infectivity.

CD4-Positive T-Lymphocytes↗
PubMed1991

Determination of local myocardial electrical activation for activation sequence mapping. A statistical approach.

Electrical activation sequence mapping requires accurate identification of local activation, but because extracellular recordings do not exclusively reflect local events, complex electrograms may be difficult to interpret. In such cases, the assignment of local activation is subject to error that could affect interpretation of the resulting activation maps. The purpose of this investigation was to develop an approach that would provide quantitative indexes of error in the determination of local activation. An electrode array with 64 closely spaced unipolar electrodes was used to record from the left ventricular surface during open heart surgery. Electrograms with multiple deflections were recorded from four patients with scarred myocardium; two other patients with normal myocardial function served as controls. Each of 784 deflections was scored on the basis of three features: evidence for propagation, the configuration of the bipolar signal, and the effect of changing from the chest to an average reference. Local activation was considered probable if evidence for all three features was present and improbable if none of the three features was present. Deflections that were ambiguous with respect to this standard were excluded. Of over 30 test variables analyzed, the three with the greatest power to discriminate signals due to local activation from those due to distant activity were 1) a linear combination of the extracellular potential plus the ratio of the second derivative and the extracellular potential, 2) the second derivative, and 3) the minimum (greatest negative) first derivative. For each of these variables, the threshold value providing the greatest performance was identified by the maximum quality of efficiency, an index of agreement. This statistical approach provides an objective basis for determining local activation and provides a quantitative assessment of error that could enhance interpretation of electrical activation sequence maps.

Differential Threshold↗
PubMed1990

Cooperative enhancement at the Drosophila Sgs-3 locus.

The Drosophila glue gene Sgs-3 is specifically expressed in the secretory cells of the salivary glands of third instar larvae. We have assayed the expression of gene fusions to determine the role of cis-acting Sgs-3 sequences in conferring this pattern of expression. These experiments define two regulatory regions required for expression of reporter genes from the Sgs-3 promoter. One region, between 106 and 56 bp upstream of the Sgs-3 mRNA 5' end is sufficient for low but correct tissue- and stage-specific expression. A second region, lying between 629 and 130 bp 5' of the RNA start site is functionally equivalent; that is, it alone will also direct low level, specific expression. These two regions act synergistically to give high level expression. More distant upstream regions function to further increase levels of expression. These two regulatory elements can confer a salivary gland-specific pattern of expression on a heterologous promoter and are also sufficient to drive gene expression in other Drosophila species, implying conservation of regulators.

Animals↗
PubMed2006

Mapping of treatment-induced apoptosis in normal structures: 99mTc-Hynic-rh-annexin V SPECT and CT image fusion.

PURPOSE: The purpose of this study was to map treatment-induced (99m)Tc-Hynic-rh-annexin V uptake in normal tissues using co-registration of SPECT and CT. METHODS: Nineteen patients (11 male, 8 female, mean age 57 years) with various malignant tumours (12 lymphomas, four non-small cell lung cancers and three head and neck squamous cell carcinomas) underwent (99m)Tc-Hynic-rh-annexin V scintigraphy and CT before and within 48 h after the start of anticancer therapy. SPECT and CT were performed separately, with the patient in a reproducible position. Volume-based automated and manual methods were used to match functional and anatomical data. SPECT/CT co-registration was used to evaluate treatment-induced changes in the normal structures. RESULTS: A significant radiation field-related increase in early post-treatment (99m)Tc-Hynic-rh-annexin V uptake in salivary glands and bone marrow was detected in eight of nine patients. Radiation field-related increase in bone marrow activity above the baseline value was detected in all 13 irradiated patients. A minimal, symmetrical increase in activity in the salivary glands was detected after the initial course of platinum-based chemotherapy, and a diffuse prominent increase in (99m)Tc-Hynic-rh-annexin V in the bone marrow was detected in all cases. Precise delineation between the tumour and normal tissue tracer accumulation was accomplished in all cases using SPECT/CT co-registered volumes, enhanced by the "colourwash" technique. CONCLUSION: Mapping of early treatment-related changes in annexin V uptake by SPECT/CT co-registration permits accurate evaluation of tracer distribution in normal structures and precise delineation from tumour uptake. The associations between tracer distribution in the normal tissues and treatment regimen found in this study may contribute to the evaluation of dose-effect relations in various treatment schedules.

Adult↗
PubMed2002

Isochronal difference mapping: an approach for mapping dynamic changes during reentrant ventricular tachycardia.

During clinical electrophysiological study for treatment of reentrant ventricular tachycardia, activation maps constructed from the acquired electrophysiological data can be difficult to interpret when the reentrant circuit is changing from one cardiac cycle to the next. Reduction of complexity would be beneficial but has been difficult. A new technical method termed isochronal difference mapping (IDM) was devised to reduce complexity and enhance distinctive conduction patterns present in the data. Electrograms were acquired from 196 sites using a canine model of a reentrant ventricular tachycardia circuit with a figure eight conduction pattern occurring in the epicardial border zone. Activation maps were constructed for all cardiac cycles during episodes of tachycardia in five experiments. IDM maps were then created, which are subtractive comparisons of the activation maps from two different cardiac cycles during a given tachycardia episode. In each map the electrical activation occurring for only one or for both of the cardiac cycles was separately highlighted in distinct spatial areas of the border zone during an isochronal interval. Based on the mappings, areas of conduction velocity change, regions of breakthrough of the wavefront across functional lines of block, regions with coherent activation, and regions with irregular activation became readily apparent. IDM maps showed that when cycle length prolonged due to deceleration of conduction within the reentrant circuit isthmus, conduction velocity increased elsewhere in the circuit. IDM accentuates cycle-to-cycle differences in multi-channel electrophysiological data and can be used to reduce complexity and enhance distinctive conduction patterns.

Animals↗
PubMed1993

The octamer/mu E4 region of the immunoglobulin heavy-chain enhancer mediates gene repression in myeloma x T-lymphoma hybrids.

We have shown previously that the immunoglobulin heavy-chain enhancer acts as a repressor of gene transcription in hybrids between immunoglobulin-producing myelomas and a T-lymphoma line. We have now mapped this repressive activity to a 51-bp enhancer subfragment which contains the octamer and mu E4 protein-binding motifs. Even a single copy of this subfragment will repress gene expression in hybrid cells. Mutational analyses of the repressor fragment suggest that in non-B cells, a strong transcriptional repressor(s) functions through the same motifs important for gene activation in B cells. Changes in chromatin structure that accompany reporter gene repression suggest a general mechanism for prohibiting immunoglobulin heavy-chain locus activation in inappropriate cell types.

Animals↗
PubMed2001

Staging of palpable T1-2 invasive breast cancer with helical CT.

BACKGROUND: The purpose of this study was to evaluate the accuracy of contrast-enhanced high resolution helical computed tomography (CT) for assessing locoregional staging of palpable T1-2 invasive breast cancer. METHODS: Helical CT studies of 156 lesions from 156 patients with invasive breast cancer before breast-conserving surgery were examined. A lesion was defined as positive if focal enhancement was detected by CT within 100 seconds after contrast material administration. After resection, tumors were histopathologically mapped and comparison made with the extent of contrast enhancement. RESULTS: Helical CT enabled detection of all 156 index tumors. CT enabled detection of 28 of 43 multifocal lesions (65%) and five of five multicentric lesions (100%). In 24 of 33 lesions (73%), CT revealed additional cancers not seen on mammography. The extent of tumor significantly correlated with CT measurements (r=0.76, p<0.0001). CONCLUSION: Helical CT of the breast is an accurate preoperative imaging modality for assessing the locoregional staging of T1-2 invasive breast cancer.

Adult↗
PubMed1973

A note on the maternal effect mutants daughterless and abnormal oocyte in Drosophila melanogaster.

Two deficiencies for, and a dominant enhancer of, the second chromosome maternal effect mutant, "daughterless" (da), were induced with X-irradiation. Their properties were studied with respect to both da and the linked maternal effect mutant, "abnormal oocyte" (abo), with the following conclusions. (1) The most probable map positions of da and abo are: J-(1/2)-da-2(1/2)-abo, where J is a dominant marker located at 41 on the standard map. (2) The da locus is in bands 31CD-F on the polytene chromosome map; abo is to the right of 32A. (3) Because homozygous da individuals survive while individuals carrying da and a deficiency for da are lethal, it is concluded that da is hypomorphic. (4) From a weak da-like maternal effect in heterozygous da females induced by an "Enhancer of da," we have confirmed a previous report that (a) the amount of sex chromosome heterochromatin contributed by the father can influence the severity of the da maternal effect, and (b) the sex chromosome heterochromatin which influences the da effect is different from that which influences the abo effect. (5) The possibility that da and abo are in a special region of chromosome 2 concerned with the regulation of sex chromosome heterochromatin is strengthened by the observation that the Enhancer of da appears to rescue abnormal eggs produced by homozygous abo mothers. (6) The Enhancer of da is a translocation between chromosomes 2 and 3 with the second chromosome breakpoint in the basal heterochromatin; because the enhancing effect maps in this region of chromosome 2, it is possible that autosomal, as well as sex chromosomal, heterochromatin interacts with da and abo.

Alleles↗