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W Bender

Publications and source records attributed to W Bender.

At least 37 records · Page 2Linked to original sources
PubMed1998

The transcriptional effects and DNA-binding specificities of 17beta-estradiol after dimethyldioxirane activation.

It was found recently that 17beta-estradiol (E2) could be activated by the epoxide-forming oxidant dimethyldioxirane (DMDO) resulting in the inhibition of rat liver nuclear and nucleolar RNA synthesis in vitro (Carcinogenesis, 17, 1957-1961, 1996). To further study the mechanism of this inhibition, several synthetic DNAs with different base content and sequence were used to study the transcriptional effects and binding specificities of E2 after DMDO activation in vitro. The results show: (1) E2 after activation had a strong inhibitory effect on the template function of both A-T and G-C containing double-stranded DNAs, e.g. poly[d(A-T)], polydG x polydC and poly[d(I-C)], and only a weak inhibition on the single-stranded DNA template, polydC. The inhibition was dose-dependent, and only after DMDO activation. (2) 3H-labeled E2, after DMDO activation, was able to bind DNAs containing both A-T and G-C bases. The order of the binding preference was: calf thymus DNA > poly[d(A-T)] > poly[d(G-C)]. (3) The covalent binding nature of E2 to DNA after activation was further confirmed by 32P-post-labeling analysis using calf thymus DNA. (4) The absorption spectrum of E2 changed, after DMDO treatment, from a peak around 280-290 nm to 260-270 nm with a shoulder appearing around 300-320 nm. These studies have not only confirmed our earlier observation that E2, after DMDO activation, can inhibit DNA-dependent RNA synthesis, but also provided new insights into the DNA-binding properties after activation. Additionally, since epoxidation is often required for the activation of chemical carcinogens to bind DNA, these studies lend further support to our proposed hypothesis that E2 epoxidation may play an initiation role in estrogen carcinogenesis.

Animals↗
PubMed1997

Report of an international summer school--oncology for medical students--in 1996 in Groningen, The Netherlands.

An international summer school session, Oncology for Medical Students, was held in 1996 at Groningen University Hospital in The Netherlands. It was sponsored and organized by the WHO Collaborating Centre for Cancer Education-Groningen. The central focus of the two-week course was cancer in general health care. Various teaching techniques were used, but interaction between students and patients, and students and faculty, was considered a prerequisite. The approach was multidisciplinary, with a variety of clinical disciplines participating, including patient organizations and the Comprehensive Cancer Center North Netherlands. The students, from all over the world, presented posters about oncology topics in their countries. Evaluation showed that the course was highly appreciated by the students; in particular, the students felt they had benefitted from the multidisciplinary approach, the patient encounters, the psychosocial concern, the poster sessions, the quality of the teaching, and meeting other students from all over the world.

Curriculum↗
PubMed1997

A comparison of the Dutch Blueprint standards (theory) with the experiences of students in clerkships in Groningen (practice).

BACKGROUND: A comparison was made between the Dutch national objectives for the education of medical doctors (in terms of clinical experiences and skills) which are stated in the Blueprint, and the extents to which the objectives were realized in six clerkships at the Faculty of Medical Sciences in Groningen. METHODS: From each clerkship, 40 complete logbooks were analyzed. RESULTS: On the average, the clerkships did not fully meet the national objectives, but they did offer clinical experiences and skills that are not mentioned in the formal objectives. Students varied significantly in their clinical experiences. CONCLUSIONS: The design of the clerkships should be improved to make them more concordant with national goals. This relates to both cancer education and medical education in general.

Clinical Clerkship↗
PubMed1997

Interactions of Drosophila Ultrabithorax regulatory regions with native and foreign promoters.

The Ultrabithorax (Ubx) gene of the Drosophila bithorax complex is required to specify parasegments 5 and 6. Two P-element "enhancer traps" have been recovered within the locus that contain the bacterial lacZ gene under the control of the P-element promoter. The P insertion that is closer to the Ubx promoter expresses lacZ in a pattern similar to that of the normal Ubx gene, but also in parasegment 4 during embryonic development. Two deletions have been recovered that remove the normal Ubx promoter plus several kilobases on either side, but retain the lacZ reporter gene. The lacZ patterns from the deletion derivatives closely match the normal pattern of Ubx expression in late embryos and imaginal discs. The lacZ genes in the deletion derivatives are also negatively regulated by Ubx and activated in trans by Contrabithorax mutations, again like the normal Ubx gene. Thus, the deleted regions, including several kilobases around the Ubx promoter, are not required for long range interactions with Ubx regulatory regions. The deletion derivatives also stimulate transvection, a pairing-dependent interaction with the Ubx promoter on the homologous chromosome.

Animals↗
PubMed1997

Feeding the future.

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Conservation of Natural Resources↗
PubMed1996

Probes of chromatin accessibility in the Drosophila bithorax complex respond differently to Polycomb-mediated repression.

The Polycomb group (PcG) of genes are required for maintenance of the repressed state of the homeotic genes in Drosophila. There are similarities between the PcG repression and mating-type silencing in yeast or heterochromatic position effect in Drosophila, which suggest that PcG repression may involve a highly compacted chromatin structure. To test for such a structure, heterologous DNA- binding proteins were used as probes for DNA accessibility in Drosophila embryos. Binding sites for the yeast transcriptional activator GAL4 and for bacteriophage T7 RNA polymerase were inserted into the bithorax (bx) regulatory region of the endogenous Ultrabithorax (Ubx) gene, which is regulated by the PcG. Ubiquitously expressed GAL4 protein directs transcription through its binding sites only in the posterior segments where the bx region is active. The block to GAL4 activation in the more anterior segments is dependent on Polycomb (Pc) function. In contrast, T7 RNA polymerase can transcribe from its target promoter in all segments of the embryo. Thus, Pc-mediated repression blocks activated polymerase II transcription, but does not simply exclude all proteins.

Animals↗
PubMed1996

Neurological soft signs in schizophrenia: assessment and correlates.

A German version of the Neurological Evaluation Scale (NES) was administered to 143 schizophrenic patients, 45 of them being severly chronic and disabled. Seventy-eight alcohol-dependent inpatients and 57 healthy volunteers were tested as control groups. Neurological soft signs (NSS) were rated with convincing agreement. Schizophrenic patients are more impaired on all scales than healthy controls. The chronic, severly disabled schizophrenic patients are more impaired compared with the main group of schizophrenic patients and both control groups. A significant difference between the main group of schizophrenic patients and alcohol-dependent patients was only found for the subscale "Motor Coordination". Compared with healthy controls the alcohol-dependent patients show a higher NES total score. The NES total score was related to the relative width of the third ventricle. Total score and subscales were correlated consistently with the level of cognitive functioning as measured by the Raven Standard Progressive Matrices and various neuropsychological tests presumably sensitive to dysfunctions of the prefrontal cortex. The NSS were related to positive as well as to negative symptoms, the correlations with negative symptoms being confined to items of "Cognitive Disorganization". This close association of psychomotor and cognitive dysfunctions may be seen as related to the frequently discussed dysfunctions of the prefrontal cortex or the neurointegrative deficit postulated by Meehl.

Adult↗
PubMed1996

Activation of 17beta-estradiol and estrone by dimethyldioxirane and inhibition of rat liver nuclear and nucleolar RNA synthesis in vitro.

17beta-estradiol (E2), estrone and diethylstilbestrol (DES) had no effect on nuclear and nucleolar RNA synthesis in vitro. However, after reacting with dimethyldioxirane (DMDO), a versatile epoxide-forming oxidant, these estrogens were able to inhibit and in a dose-dependent manner nuclear and nucleolar RNA synthesis in vitro. It was also found that the time required for the maximal activation of these chemicals by DMDO varied: estrone, 10 min; E2, 30 min; DES, 60 min. Tamoxifen (TAM) was also able to inhibit nuclear and nucleolar RNA synthesis in a dose-dependent manner, but the mechanism of this inhibition was more complex. Control experiments clearly indicated, unlike E2, estrone and DES, TAM per se was able to directly inhibit RNA synthesis in vitro. TAM after activation by DMDO was able to further inhibit RNA synthesis contributing part of the total observed inhibition. These data show for the first time that E2, estrone, DES and TAM can be activated by DMDO and possibly to epoxides. We propose that epoxidation of E2 and estrone may be the underlying mechanism of carcinogenesis for these estrogens in vivo.

Animals↗
PubMed1995

Psychomotor disturbances in psychiatric patients as a possible basis for new attempts at differential diagnosis and therapy. Part VI. Evaluation of psychomotor training programs in schizophrenic patients.

Parts I-III of this series established signs of disturbed motor performance--the "psychotic motor syndrome" (PMS)--in schizophrenic and endogenous depressed patients, which was not found in neurotic/reactive depressed nor healthy persons. Part IV yielded EEG signs of concomitant brain dysfunction in these patients, which were demonstrated by other (SPECT/PET) neuroimaging methods also. In part V we engaged in the development of motor-training programs applied both actively and mentally, using the PMS as target syndrome in depressed patients. We hypothesized that motor training would not only improve disturbed motor behaviour, but ameliorate other symptoms of psychopathology additionally, which was supported for these patients. Part VI is the final paper of this series demonstrating favourable results of our motor-training programs in 96 schizophrenic inpatients in two separate investigations. A general discussion to the whole series attempts to link motor symptoms to neuroimaging findings of brain dysfunction during motor challenge and to modern three- and four-factor models of schizophrenic symptomatology. A final version of our complete training programs will be published as an appendix to this paper along with information regarding the abbreviated test battery.

Adolescent↗
PubMed1995

Studies on the isolated transcriptionally active and inactive chromatin fractions from rat liver nuclei.

Using mild sonication, nucleoplasmic, nucleolar, and subnucleolar P-3 and S-3 chromatin fractions are isolated from rat liver nuclei. These fractions differ widely (over 80-fold) from each other in transcriptional activity as measured by the chromatin bound engaged RNA polymerases. Chemical analyses indicate that the active chromatin, e.g. P-3 and nucleolar fractions, are rich in RNA and protein as compared to the inactive chromatin, e.g. nucleoplasmic, and S-3 fractions. However, the DNA base content are all the same, showing 40% GC and 60% AT, including P-3 which is enriched in rDNA. Polyacrylamide gel electrophoresis of the 0.25 N HCl extracted proteins shows that all five histones are present in active chromatin. Additionally, the gel reveals two protein bands, one ahead of histone H2B and another ahead of histone H4, that are diminished or missing from the inactive chromatin. On the other hand, there is a fast moving protein band ahead of H4 in the inactive chromatin that is almost absent in the active chromatin. Transcriptional tests using E. coli RNA polymerase and several synthetic DNA templates of known base content and sequence indicate that the 0.25 N HCl soluble protein extracts from active chromatin contain activator proteins which are capable of countering the histone suppressors present in the extracts in a DNA base and sequence specific manner. The data show that although the histone suppressors are able to strongly inhibit the template function of poly[d(A-T)], the protein activators are able to overcome the suppressor activity and stimulate RNA synthesis several-fold when poly(dA).poly(dT) or poly(dT) is used.

Animals↗
PubMed1995

Comparison of germline mosaics of genes in the Polycomb group of Drosophila melanogaster.

The genes of the Polycomb group (PcG) repress the genes of the bithorax and Antennapedia complexes, among others. To observe a null phenotype for a PcG gene, one must remove its maternal as well as zygotic contribution to the embryo. Five members of the PcG group are compared here: Enhancer of Polycomb [E(Pc)], Additional sex combs (Asx), Posterior sex combs (Psc), Suppressor of zeste 2 [Su (z) 2] and Polycomblike (Pcl). The yeast recombinase (FLP) system was used to induce mitotic recombination in the maternal germline. Mutant embryos were analyzed by staining with antibodies against six target genes of the PcG. The loss of the maternal component leads to enhanced homeotic phenotypes and to unique patterns of misexpression. E(Pc) and Su(z) 2 mutations had only subtle effects on the target genes, even when the maternal contributions were removed. Asx and Pcl mutants show derepression of the targets only in specific cell types. Psc shows unusual effects on two of the targets, Ultrabithorax and abdominal-A. These results show that the PcG genes do not act only in a common complex or pathway; they must have some independent functions.

Animals↗
PubMed1995

Dorsal wing, a locus that affects dorsoventral wing patterning in Drosophila.

The wing imaginal disc is subdivided into a dorsal and a ventral compartments. A new dominant homeotic mutation, Dorsal wing1 (Dlw1), transforms ventral into dorsal compartment in heterozygotes. This phenotype is similar to one of the dominant phenotypes of Polycomb (Pc) mutants. In Pc Dlw+/Pc+ Dlw1 double mutants, the transformation is greatly enhanced. The recessive phenotype of Dlw1 is the opposite to the dominant phenotype. Dlw1/Dlw1 somatic clones induced at any larval stage differentiate only ventral pattern on both wing surfaces. This effect is one of the somatic clone phenotypes of trithorax (trx) lethals. A similar dorsal-to-ventral transformation is observed in Pc Dlw/Dlw clones. Dlw1/Dlw1 clones have no effect elsewhere, except in the dorsal notum, which may differentiate extra macrochaetes. We propose that: (1) Dlw+ is required for the specification of dorsal compartment; (2) some genes of the Polycomb group act as negative regulators of Dlw+, while some genes of the trithorax group act as positive regulators.

Animals↗
PubMed1995

Discrete Polycomb-binding sites in each parasegmental domain of the bithorax complex.

The Polycomb protein of Drosophila melanogaster maintains the segmental expression limits of the homeotic genes in the bithorax complex. Polycomb-binding sites within the bithorax complex were mapped by immunostaining of salivary gland polytene chromosomes. Polycomb bound to four DNA fragments, one in each of four successive parasegmental regulatory regions. These fragments correspond exactly to the ones that can maintain segmentally limited expression of a lacZ reporter gene. Thus, Polycomb acts directly on discrete multiple sites in bithorax regulatory DNA. Constructs combining fragments from different regulatory regions demonstrate that Polycomb-dependent maintenance elements can act on multiple pattern initiation elements, and that maintenance elements can work together. The cooperative action of maintenance elements may motivate the linear order of the bithorax complex.

Animals↗
PubMed1994

Enhancer point mutation results in a homeotic transformation in Drosophila.

In Drosophila, the misexpression or altered activity of genes from the bithorax complex results in homeotic transformations. One of these genes, abd-A, normally specifies the identity of the second through fourth abdominal segments (A2 to A4). In the dominant Hyperabdominal mutations (Hab), portions of the third thoracic segment (T3) are transformed toward A2 as the result of ectopic abd-A expression. Sequence analysis and deoxyribonuclease I footprinting demonstrate that the misexpression of abd-A in two independent Hab mutations results from the same single base change in a binding site for the gap gene Krüppel protein. These results establish that the spatial limits of the homeotic genes are directly regulated by gap gene products.

Animals↗
PubMed1994

Studies on the binding and transcriptional properties of aflatoxin B1-8,9-epoxide.

[3H]Aflatoxin B1-8,9-epoxide ([3H]AFB1-8,9-epoxide), the putative ultimate carcinogen of AFB1, was synthesized and tested for its binding specificity to and transcriptional effect on several single- and double-stranded DNAs containing cytosine. The test was carried out over a 200-fold concentration range (i.e. 0.1-20 microgram [3H]AFB1-8,9-epoxide per 0.025 A260 units of DNA). The results show: (i) [3H]AFB1-8,9-epoxide bound preferentially to the double-stranded alternating co-polymer poly[d(G-C)] over the double-stranded poly(dG).poly(dC) and single-stranded poly(dG) or poly(dC) homopolymers. (ii) The binding affinity of [3H]AFB1-8,9-epoxide to poly(dC) was essentially the same as the poly(dG). (iii) Under identical conditions, [3H]AFB1-8,9-epoxide bound to poly(dG).poly(dC) 2.5-3 times more than to poly[d(I-C)]; however, poly[d(I-C)]-directed RNA synthesis was clearly more sensitive to [3H]AFB1-8,9-epoxide inhibition than poly(dG).poly(dC). Conversely, the binding affinity of [3H]AFB1-8,9-epoxide to poly(dC) and to poly[d(I-C)] was quite similar, yet poly(dC)-directed RNA synthesis was much more resistant to [3H]AFB1-8,9-epoxide inhibition than poly[d(I-C)]. (iv) After [3H]AFB1-8,9-epoxide was hydrolyzed to [3H]AFB1-8,9-dihydrodiol (0.01 N NaOH, 10 min 23 degrees C), it was no longer able to bind poly[d(G-C)] or to inhibit poly[d(G-C)]-directed RNA synthesis. These results confirm our earlier studies using microsome-activated AFB1 and AFB1-Cl2 that AFB1 after activation is able to bind cytosine in DNA, and the binding is not via AFB1-8,9-dihydrodiol. Furthermore, the results also suggest that AFB1 adducts may not have the same biological effect depending on the base, sequence as well as the conformation of the DNA where the adducts are formed.

Aflatoxin B1↗