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PubMed1992

A temperature-sensitive CHO-K1 cell mutant (tsTM13) defective in chromosome decondensation and spindle deconstruction in M phase.

A temperature-sensitive CHO-K1 cell mutant, tsTM13, exhibited a delayed cell cycle progression from metaphase to telophase at a nonpermissive temperature and was finally arrested from anaphase to telophase. Metaphase chromosomes were overcondensed and chromosome disjunction in anaphase was uncoordinated. In telophase, sister chromatids were segregated and cytokinesis was completed, but chromosome structure remained in a condensed state and the spindle was not deconstructed. The level of phosphorylation of histones H1 and H3 remained high in the later stages of mitosis and the activity of histone H1 kinase was also maintained at a high level. These results strongly suggest that the pleiotropic defects of tsTM13 cells in mitosis are associated with a lack of inactivation of activated histone H1 kinase.

Amino Acid Sequence↗

PubMed1987

A mechanism for the RNA-catalyzed formation of 5'-phosphates. The origin of nucleases.

Processes involved in RNA metabolism can be distinguished by the nature of the sugar phosphate substitution (5' or 3') in intermediates or products. Although it is known that 3'-phosphates are produced via a 2',3'-cyclic phosphate intermediate, formed by nucleophilic attack on the phosphodiester bond by the adjacent 2'-OH, little is known about the production of 5'-phosphate products. We attribute 5'-phosphate intermediates and products to a preferred configuration of the pentavalent phosphorus intermediate resulting from the attack of a distant nucleophile. This intermediate is favored, since its formation is possible without major conformational changes in the molecule. Based on the two products of nucleic acid hydrolysis we define: the conjunct and disjunct nucleophile mechanisms, each of which would have independent origins. Indeed, the products of an overwhelming number of nucleases and RNases are consistent with one of these mechanistic models demonstrating that the origin of these enzymes are deeply rooted in the intrinsic chemistry of phosphate esters.

Catalysis↗

PubMed1991

T-lymphocyte dysfunctions occurring together with apical gut epithelial cell autoantibodies.

Gut epithelial cell autoantibodies have been considered a hallmark of autoimmune enteropathy, a disorder occurring in children with protracted diarrhea of unknown etiology. Four patients (two male and two female) with such autoantibodies were studied. Immunofluorescence analysis showed two different disjunctive staining patterns: complement-fixing apical (three of four) and cytoplasmic (the remaining fourth one), which are shown to be directed against different structures. All three patients positive for complement-fixing apical gut epithelial cell autoantibodies had abnormal T-cell responses in vitro, one of them with an immunoglobulin G2 immunoglobulin deficiency and another with an immunoglobulin A deficiency. An immunoglobulin A deficiency without T-cell alterations was also diagnosed in the cytoplasmic gut epithelial cell autoantibody-positive patient. These findings suggest that different immunologic alterations (either a T-cell abnormality or immunoglobulin deficiency) may favor the appearance of gut epithelial cell autoantibodies (complement-fixing apical or cytoplasmic, respectively). Furthermore, these autoantibodies should not be considered a specific marker of autoimmune enteropathy, because they may not always be associated with such a disease: two patients with apical gut epithelial cell autoantibodies showed no signs of intestinal lesion or diarrhea.

Adult↗

PubMed1977

Regression of arteriosclerotic lesions in rhesus monkey aortas after regression diet. Scanning and transmission electron microscope observations of the endothelium.

Scanning and transmission microscopy were used to study aortic intima atherosclerotic lesions in Rhesus monkeys during both progression and regression phases. Scanning micrographs of severely atherosclerotic lesions showed areas of disjunctive endothelium and discontinuous basement membranes, frequently accompanied by red blood cells and other circulating elements adhering to the surface. Transmission micrographs also showed occasional areas of endothelial cell damage and loss with lipid-laden smooth muscle cells and foam cells beneath. Regressed lesions (affected by low-fat, low-cholesterol diet with or without cholestyramine) showed endothelial changes suggestive of reparative processes. Scanning micrographs showed flattened residual lesions with continous endothelial lining, while transmission microscopy disclosed interdigitated intercellular tight junctions and frequently reduplicated basement membranes.

Animals↗

PubMed1986

Computer-averaged views of the 70 S monosome from Escherichia coli.

The prokaryotic (70 S) monosome, composed of a roughly hemispherical 50 S large subunit and an elongate 30 S small subunit, appears in the electron micrograph in only a few common views representing the small number of preferred orientations assumed by the particle. Two of these, termed O and L views, have previously been characterized as the overlap and non-overlap projections; a third view, which we term the R view, represents the other endpoint of a rotational continuum with the overlap or O view. Tilt studies enabled us to calibrate this range as spanning approximately 50 degrees. The disjunct set of L views was averaged, and the reproducible resolution was determined to be 1/3.5 nm-1. The combined sets of O and R views were analyzed by correspondence analysis, and a continuous "rotation series" of subaverages was obtained. Interpretation of the views in the light of what is known about the morphologies of the individual subunits allows a general picture of the mutual fit of the subunits in the monosome to be conceived.

Computers↗

PubMed1988

Reaction time in ambulant multiple sclerosis patients. Part I. Influence of prolonged cognitive effort.

Reaction times (RT) were measured in 39 multiple sclerosis (MS) patients and 25 healthy controls, before and after comprehensive neuropsychological assessment lasting at least 4 h. The assessment required prolonged mental effort, which was assumed to induce fatigue. Simple and disjunctive RT were measured for visual and auditory stimuli. RT before and after prolonged effort were significantly longer in MS than in control subjects (with exception of auditory RT). This effect was related to disease duration and to simultaneous presence of brainstem, cerebellar and/or pyramidal signs. Age did not significantly contribute to the explanation of RT increase. In female patients, increasing distribution of functional lesions in the central nervous system was related with greater RT increase than in male patients. RT of MS and controls changed after prolonged mental effort and effort-related fatigue was experienced subjectively. Yet no differences in direction or degree of change in RT were found between controls and ambulant patients with stable MS who apparently had resources to overcome fatigue.

Adolescent↗

PubMed1994

Severe radicular pathology in rats with longstanding diabetes.

There few pathological abnormalities in nerves from animals with diabetes. Reported changes consist of mild distal axonal atrophy, axoglial disjunction and minimal segmental demyelination and remyelination. These changes are seen in distal nerves but no studies of radicular pathology in diabetic animals have been reported. We therefore studied peripheral nerve and radicular pathology in rats with longstanding, severe, chemically-induced diabetes. We found marked interstitial edema and severe changes of myelin in the roots of diabetic rats, particularly in the dorsal root. The earliest changes consist of myelin splitting, occurring at the intraperiod line. This progresses to myelin ballooning, accompanied by both tubulovescicular myelin degeneration and macrophage stripping, all of which tend to predominate in large myelinated fibers. There is minimal axonal degeneration. Despite these severe changes in nerve roots, the distal peripheral nerves show no discernible edema and only minimal myelin splitting without demyelination or axonal degeneration. The radicular changes are almost identical to those seen in much older nondiabetic animals. This suggests that they may represent an acceleration of the normal aging process, perhaps related to increased glycation of myelin proteins induced by accumulation of glucose rich interstitial endoneurial edema.

Animals↗

PubMed1994

A standardized protocol for flow cytometric analysis of cells isolated from cerebrospinal fluid.

Flow cytometry (FC) is an useful tool for the analysis of subpopulations in complex cell suspensions. When applying this method to the cerebrospinal fluid (CSF), some characteristic properties of this cell type must be taken into consideration: there are only few cells which decay rapidly in their native medium and during centrifugation. One aim of the immunostaining procedure preceding flow cytometric analysis must be to minimize cell loss in order to get an undistorted picture of 'true' CSF cell populations. Consequently, morphological flow cytometric plots of high resolution are an indispensable precondition for reliable determination of subpopulations defined by monoclonal antibody (Mab) binding. We describe a standardized protocol for the flow cytometric examination of CSF cells which minimizes undesired cell loss. By the use of a 'quality control' the extent of cell loss could be monitored. Examples of morphological flow cytometric plots are given. The subsequent determination of Mab binding subpopulations is critical when fluorescence intensities of antigen positive and negative cells are non-disjunct. A statistical test was developed for these cases often seen when cell surface determinants are expressed at low levels only.

Antibodies, Monoclonal↗

PubMed1988

The pathogenesis and prevention of diabetic neuropathy and nephropathy.

The chronic complications of diabetes are thought to be caused by an interaction between hyperglycemia, or other metabolic consequences of insulin deficiency, and independent genetic or environmental factors that are poorly defined. Several potentially relevant biochemical sequelae to hyperglycemia have been identified in tissue susceptible to diabetic complications. Among these, a rise in tissue sorbitol secondary to concentration-dependent activation of polyol pathway activity by glucose, and an accompanying fall in tissue myo-inositol and Na-K-ATPase activity have recently been linked to a self-reinforcing cyclic metabolic defect that accounts for rapidly reversible slowing of conduction in peripheral nerve in diabetes. Impaired Na-K-ATPase activity also appears to be responsible for intracellular Na+ accumulation and resultant localized axonal paranodal swelling that characterizes diabetic neuropathy in both humans and laboratory animals. These swellings are thought to be responsible for the subsequent disruption of the nodal apparatus (axo-glial disjunction) and some component of the loss of large and small myelinated fibers. Recent studies have suggested that microvascular insufficiency may also contribute to diabetic neuropathy, especially in non-insulin-dependent diabetes. Aldose reductase activity is concentrated in endoneurial vessels, and similar biochemical mechanisms (ie, sorbitol accumulation, myo-inositol deficiency, and impaired Na-K-ATPase activity) are thought to be operative in the endoneurial microvessels in diabetes. Administration of an aldose reductase inhibitor to patients with diabetic neuropathy is associated with repair of damaged nerve fibers and the appearance of newly generated fibers, presumably secondary to metabolic correction within the nerve fibers themselves or their supporting microvasculature.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗

PubMed1975

The mutagenicity of azathioprine in mice, Drosophila melanogaster and Neurospora crassa.

The chemotherapeutic coumpound azathioprine was tested for possible mutagenicity in Swiss Albino mice, Drosophila melanogaster and Neurospora crassa. Utilizing the dominant-lethal assay it was found that acute oral doses of azathioprine (2 times 25 mg/kg body weight), induced dominant-lethal mutations in mouse spermatocytes. Chronic oral doses of azathioprine (2 times 25 mg/kg body weight/week for 10 weeks) resulted in a greater rate of dominant-lethality. This increase was not permanent, and by week 4 of gamete sampling there was no significant increase in dominant-lethal mutations. Histological sections showed that chronic treatment of male mice with azathioprine caused pyknosis of spermatocyte nuclei and depletion of the spermatid population. Both acute and chronic doses of azathioprine caused a temporary reduction in sperm viability. Oral treatment of male Canton-S, D. melanogaster with azathioprine caused an increase in dominant-lethality in broods assumed to correspond to spermatid and spermaotcyte stages. Azathioprine also increased the rate of non-disjunction of the X and Y chromosomes, loss of the long arm of the Y chromosome, and loss of the X or Y chromosome in treated male R(I)2, vf/BsYy+D. melanogaster. Since sex-ratio deviation did not occur in progeny from treated rod-X (yv/B2Yy+) male D. melanogaster, it was concluded that the observed sex-ration deviation in the treated ring-X stock was the result of induced ring-X lethality. Azathioprine induced recessive-lethal mutations in the ad-3 region of a N. crassa heterokaryon. In the host-mediated assay using this same heterokaryon and male Swiss Albino mice as host, the mutagenic activity of azathioprine did not appear to be potentiated or detoxified by the host. The results show that azathioprine has a deleterious effect on reproduction in mice and probably induces mutational events in mice, D. melanogaster and N. crassa.

Animals↗

PubMed1976

The capacity of Drosophila for detecting relevant genetic damage.

For the detection and study of mutagenic agents, Drosophila offers many advantages. It is a higher organism with a short generation time that is cheap and easy to breed in large numbers. The simple genetic testing methods provide unequivocal answers about the whole spectrum of relevant genetic damage. A comparison of the detection capacity of assays sampling different kinds of genetic damage revealed that various substances are highly effective in inducing mutations, but do not produce chromosome breakage effects at all, or only at much higher concentrations than those required for mutation induction. Of the different assay systems available, the classical sex-linked recessive lethal test thus deserves priority, in view of its superior capacity to detect mutagens. Of practical importance is also its high sensitivity, because a large number of loci in one-fifth of the genome is tested for newly induced forward mutations, including small deletions. Drosophila is capable of carrying out the same metabolic activation reactions as the mammalian liver. An additional advantage, in this respect, is the capacity of Drosophila for detecting short-lived activation products, because intracellular activation occurs within the spermatids ans spermatocytes. These properties make the test for recessive sex-linked lethals a useful tool for verifying results obtained in the pre-screening of potential mutagens with fast microbial assay systems. In studies on non-disjunction, detailed genetic analysis of the induced changes is possible, and these may shed light on the mechanisms involved. A new adaptation of the bithorax transvection method by Mendelson permits the recovery of high yields of chromosome aberrations in a fast one-generation test.

Animals↗

PubMed1978

The ratio of de novo unbalanced translocation to 47, trisomy 21 Down syndrome. A new method for human mutation surveillance and an apparent recent change in mutation rate resulting in human interchange trisomies in one jurisdiction.

The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.

Down Syndrome↗

PubMed1979

The effect of exposure fractionation on the yield of nondisjunctional segregation involving compound X and free 4-chromosomes in Drosophila.

This paper describes the effect of fractionation of an exposure of 2000-R X-rays into two 1000-R exposures separated by a 3-h interval on the frequency of various segregation products following chromatoid interchange between a compound X and the 4th chromosome. It was observed that fractionation leads to a decrease of all exceptional progeny, the result being significant at the 0.05-probability level for both classes of detachments; i.e., with or without a 4th chromosome. The finding that the same effect of fractionation was observed for numerical aberration (non-disjunction) and detachment supports the idea that these reflect different consequences of the same primary effect, radiation-induced rearrangement. Furthermore, alternative recoveries were observed to occur at equal frequencies. Following C(1)-4 interchange, the univalent 4 does not segregate at random, but assorts apart from its homologue 1.5 as frequently as it moves to the same pole.

Animals↗

PubMed1980

Chromosomal aberrations induced by caffeine in somatic ganglia of Drosophila melanogaster.

Nerve ganglia of third-instar larvae were treated with various doses of caffeine (5 X 10(-4), 10(-3), 5 X 10(-3), 10(-2) and 2 X 10(-2) M) for 2 h at 25 +/- 1 degrees C. The ganglia were fixed at set time intervals after treatment so that the effect of caffeine in different stages of the cell cycle could be observed. Chromatid aberrations were induced only when the caffeine was administered in G2 or approaching mitosis. No aberrations were observed after treatment in S or early G2. In relation to the different doses administered, a threshold effect was evidenced, the number of aberrations increasing in a marked way at doses exceeding 5 X 10(-3) M. These data indicate that the effect observed in Drosophila melanogaster is similar to that described by Kihlman in animals and plants treated with caffeine at temperatures below 30 degrees C. Results obtained in non-cytological tests (non-disjunction, chromosome loss, lethal recessives, dominant lethals) have so far given incomplete indications as to the mutagenicity of caffeine in Drosophila. The results we have obtained with the cytological test seem to contribute to a better definition of the mutagenicity.

Animals↗

PubMed1981

Increment kinetics of recessive lethal mutations and dominant lethals in offspring of Drosophila melanogaster on storage of methyl-methanesulfonate-treated sperm in females.

The frequencies of sex-linked recessive lethal mutations in F1 males after feeding adult male Drosophila melanogaster with 0.25 and 0.5 mM methyl methanesulfonate (MMS) orally for 24 h increased approximately linearly with storage of the treated spermatozoa in females, whereas the number of hits of dominant lethals in the sperm after feeding 0.3 and 0.5 mM MMS increased approximately with the square of the storage time. Chromosome losses and mosaics in F1 males also increased with the dose of MMS to males, but their yields were too low to be analyzed quantitatively, only indicating a slight increase of chromosome loses and a slight decrease of mosaics with the time of storage of sperm. Maternal non-disjunctions (or chromosome losses), detected in F1 males, decreased with the dose of MMS to spermatozoa and their yield decreased with the time of storage of sperm of both MMS-treated and the control groups. A unitary model is proposed to explain the effect of storage on the dominant lethals and recessive lethal mutations.

Animals↗

PubMed1981

Non-homologue pairing and spontaneous meiotic interchanges in Drosophila melanogaster females.

Spontaneous interchange between the X chromosomes and the C(2L) autosomal compound in their centromeric regions was studied in y/XY;C(2L);C(2R) and In(1)dl-49+BM1/XY;C(2L);C(2R) Drosophila melanogaster females. These females were mated with F(2L)/F(2L);C(2R) males. Interchange occurrence was recorded as the appearance of an F1 individual with a half-translocation of either X . 2L or Y . 2L type. 37 interchanges were recovered in y/XY and 67 in In(1)/XY females. The majority of the interchanges were of meiotic origin. The interchanges were mainly C(2L)-XY; the most frequent type of half-translocation was Y . 2L;dl-49+BM1. Inversion increased about 5-fold the interchange frequency. In the course of C(2L)-XY interchange, the other X chromosome and C(2R) compound regularly paired and disjoined. In y/XY females, 8 crossover half-translocations of meiotic origin were recovered. The results obtained indicate that meiotic pairing between the X's and C(2L) occurred in the females examined. According to our estimates, XY-C(2L) pairing is associated with interchange in the heterochromatic centromeric regions with a frequency of 10(-3). The recovery of crossover half-translocations supports the chromocentral model of non-homologous pairing and allows us to assume that a chromosome may simultaneously pair with a homologue and a non-homologue. The disjunction pattern of this trivalent depends on its structure in each particular case. The chromosome-segregation pattern resulting from spontaneous interchanges was similar to that resulting from radiation-induced interchanges in the immature oocytes described by Parker. This similarity suggests that non-homologue pairing occurs in the immature oocytes too. The non-homologue-pairing pattern established by the interchange test conformed well with that previously established in y/XY and In(1)XY females by the distribution test.

Animals↗

PubMed1981

Investigations on radiosensitive and radioresistant populations of Drosophila melanogaster. XI. The resistance factor rar-3: effects in immature oocytes.

The effects of the radioresistance factor rar-3 on the X-ray induction of various types of genetic damage in immature oocytes (about stage 7) of Drosophila melanogaster were studied. The dose-reduction factors previously postulated for rar-3 with respect to dominant lethals (1.58), sex-linked recessive lethals (1.87), non-disjunction of major chromosomes (1.58), and homologous interchanges (1.58) were confirmed experimentally. It is concluded that all effects attributed arbitrarily to rar-3 are contributed by the single genetic factor rar-3. No differences were found in quality of sex-linked recessive lethals (Y suppression, distribution over the X) induced in either rar-3 or rar-3+. Recombination frequencies were normal in unirradiated rar-3.

Animals↗

PubMed1987

Positive correlation between the occurrence of chromosome breakage and the induction of point mutations associated with male recombination 31.1 MRF system of hybrid dysgenesis in Drosophila melanogaster.

One of the weak singed (snw) mutations, induced by the 31.1 MRF in the X-chromosome of a laboratory strain, is highly unstable, often changing to either a strong expression (snst) or reverting to wild type (sn+). The present study shows that the X-chromosome carrying the (snw) mutation and the X-chromosome carrying one of the snst alleles derived from the snw mutation generate different frequencies of deletions associated with the w locus. Moreover, they produce different frequencies of mutations associated with the w locus in males after the reintroduction of the 31.1 MRF second chromosome. The occurrence of the deletions and the induction of the mutations are positively correlated and increase when flies are raised at a higher temperature. These data indicate that the induction of the w mutations follows the generation of chromosome breaks in the w locus. The break-points of the recovered deletions occurred in specific sites in the 3C subdivision. Furthermore both snw and snst X-chromosomes induce different frequencies of non-disjunction in females depending on the culture temperature and the genetic background. The present data also show that the 23.5 MRF second chromosome which exhibits specific differences in its activities from the 31.1 MRF is unable to induce w mutations. This fact supports our previous indications that the 31.1 MRF and the 23.5 MRF are not identical.

Animals↗