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PubMed2006

Integrated analysis of regulatory and metabolic networks reveals novel regulatory mechanisms in Saccharomyces cerevisiae.

We describe the use of model-driven analysis of multiple data types relevant to transcriptional regulation of metabolism to discover novel regulatory mechanisms in Saccharomyces cerevisiae. We have reconstructed the nutrient-controlled transcriptional regulatory network controlling metabolism in S. cerevisiae consisting of 55 transcription factors regulating 750 metabolic genes, based on information in the primary literature. This reconstructed regulatory network coupled with an existing genome-scale metabolic network model allows in silico prediction of growth phenotypes of regulatory gene deletions as well as gene expression profiles. We compared model predictions of gene expression changes in response to genetic and environmental perturbations to experimental data to identify potential novel targets for transcription factors. We then identified regulatory cascades connecting transcription factors to the potential targets through a systematic model expansion strategy using published genome-wide chromatin immunoprecipitation and binding-site-motif data sets. Finally, we show the ability of an integrated metabolic and regulatory network model to predict growth phenotypes of transcription factor knockout strains. These studies illustrate the potential of model-driven data integration to systematically discover novel components and interactions in regulatory and metabolic networks in eukaryotic cells.

Chromatin Immunoprecipitation↗

PubMed1996

Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor.

Mutant cDNAs coding for dominant-negative forms of the fibroblast growth factor receptors 1 (FGFR-1) and 2 (FGFR-2) that lack tyrosine kinase activity were ligated to a 2.2 kb DNA fragment containing the bovine rhodopsin promoter and used to generate transgenic mice. Six independent lines were generated with the FGFR-1 construct, and five were generated with the FGFR-2 construct. Five of the six FGFR-1 mutant lines and all five FGFR-2 mutant lines showed transgene expression in the retina by reverse transcription-PCR. By both in situ hybridization and immunohistochemistry, mutant FGFRs were found to be expressed specifically in photoreceptors of transgene-positive FGFR-1 and FGFR-2 mice. Lines expressing the FGFR-2 mutant showed progressive photoreceptor degeneration; the retinas showed minimal or no abnormalities at 1 month, but by 2 months they showed focal areas of thinning of the outer nuclear layer and disruption of photoreceptors. By 2-4 months, areas of complete loss of photoreceptors were seen. These abnormalities were not seen in control littermates not expressing the transgene. Mice from two FGFR-1 mutant lines showed focal areas of thinning of the outer nuclear layer and numerous photoreceptors with fragmented chromatin, whereas the other FGFR-1 lines showed minimal or no abnormalities. These data indicate that perturbation of FGF signaling in photoreceptors is associated with progressive photoreceptor degeneration, suggesting that one or more of the FGFs may act as a survival factor for photoreceptor cells.

Animals↗

PubMed2003

Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice.

Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1-/- mice phenocopy those of the existing bl (blebbed) mouse mutants, which have been considered a model for the human genetic disorder Fraser syndrome. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.

Animals↗

PubMed2006

Orientation of the crotonaldehyde-derived N2-[3-Oxo-1(S)-methyl-propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5'-CpG-3' sequence.

The conformation of the crotonaldehyde-derived N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct in the oligodeoxynucleotide 5'-d(G(1)C(2)T(3)A(4)G(5)C(6)X(7)A(8)G(9)T(10)C(11)C(12))-3'.5'-d(G(13)G(14)A(15)C(16)T(17)C(18)G(19)C(20)T(21)A(22)G(23)C(2)(4))-3', where X = N(2)-[3-oxo-1(S)-methyl-propyl]-dG, is reported. This adduct arises from opening of the cyclic N(2)-(S-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct when placed opposite dC in duplex DNA. This oligodeoxynucleotide contains the 5'-CpG-3' sequence in which the N(2)-(R-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG but not the N(2)-(S-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct preferentially formed an interstrand carbinolamine cross-link [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61; Cho, Y.-J., Wang, H., Kozekov, I. D., Kurtz, A. J., Jacob, J., Voehler, M., Smith, J., Harris, T. M., Lloyd, R. S., Rizzo, C. J., and Stone, M. P. (2006) Chem. Res. Toxicol. 19, 195-208]. Analysis of (1)H NOE data, chemical shift perturbations, and deoxyribose pseudorotations and backbone torsion angles suggested the presence of a stable and ordered DNA conformation at pH 9.3 and 30 degrees C, with minimal conformational perturbation. The spectral line widths of the adduct protons were comparable to those of the oligodeoxynucleotide, suggesting that the correlation times of these protons were similar to those of the overall duplex. The crotonaldehydic-derived methyl protons showed NOEs in the 5'-direction to C(18) H1', G(19) H1', and G(19) H4' in the complementary strand of the duplex. The aldehyde proton of the adduct exhibited NOEs in the 3'-direction to A(8) H1' and A(8) H4' in the modified strand. All of these NOEs involved DNA protons facing the minor groove. Molecular dynamics calculations, restrained by distances and torsion angles derived from the NMR data, revealed that within the minor groove, the aldehyde of the N(2)-[3-oxo-1(S)-methyl-propyl]-dG adduct oriented in the 3'-direction, while the 1(S) methyl group oriented in the 5'-direction. This positioned the aldehyde distal to the G(19) exocyclic amine and provided a rationale as to why the N(2)-(S-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct generated interstrand cross-links less efficiently than did the N(2)-(R-alpha-CH(3)-gamma-OH-1,N(2)-propano-2')-dG adduct.

Aldehydes↗

PubMed2001

Serpin protein CrmA suppresses hypoxia-mediated apoptosis of ventricular myocytes.

BACKGROUND: In this study, we ascertain whether caspase 8 activation and mitochondrial defects underlie apoptosis of ventricular myocytes during hypoxia. As an approach to circumvent the potential shortcomings surrounding the limited permeability and short half-life of the synthetic peptide inhibitors designed to block caspase activation, we constructed a replication-defective adenovirus encoding the serpin caspase inhibitor protein CrmA to ensure efficient and continual inhibition of caspase 8 activity during chronic hypoxia. METHODS AND RESULTS: In contrast to normoxic cells, oxygen deprivation of postnatal ventricular myocytes for 24 hours resulted in a 9-fold increase (P<0.05) in apoptosis as determined by Hoechst 33258 staining and nucleosomal DNA laddering. Moreover, hypoxia provoked a 1.5-fold increase (P<0.01) in caspase 8-like activity. Furthermore, hypoxia provoked perturbations to mitochondria consistent with the mitochondrial death pathway, including permeability transition pore (PT) opening, loss of mitochondrial membrane potential ((m)), and cytochrome c release. Importantly, CrmA suppressed caspase 8 activity, PT pore changes, loss of (m), and apoptosis but had no effect on hypoxia-mediated cytochrome c release. Furthermore, Bongkrekic acid, an inhibitor of PT pore, prevented hypoxia-induced PT pore changes, loss of (m), and apoptosis but had no effect on hypoxia-mediated cytochrome c release. CONCLUSIONS: To our knowledge, we provide the first direct evidence for the operation of CrmA as an antiapoptotic factor in ventricular myocytes during prolonged durations of hypoxia. Furthermore, our data suggest that perturbations to mitochondria including PT pore changes and (m) loss are caspase-regulated events that appear to be separable from cytochrome c release.

Adenoviridae↗

PubMed1987

Time, a quality-control parameter in flow cytometry.

Time has been used as a quality-control parameter in our flow cytometer. This parameter was automatically incorporated into the list-mode data base by hooking the computer clock directly into the acquisition logic. Quality control can then be checked by "replaying" fluorescence or light scatter data vs. time and any instrumental drift can be observed and degraded data can be excised. The technique is illustrated with a number of DNA data sets from a tissue culture cell line in which artificial perturbations were introduced during data acquisition to simulate potential causes of instrumental drift.

Cell Line↗

PubMed2004

SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins.

High molecular weight serpins are members of a large superfamily of structurally conserved proteins that inactivate target proteinases by a suicide substrate-like mechanism. In vertebrates, different clades of serpins distribute predominantly to either the intracellular or extracellular space. Although much is known about the function, structure, and inhibitory mechanism of circulating serpins such as alpha(1)-antitrypsin (SERPINA1) and antithrombin III (SERPINC1), relatively little is known about the function of the vertebrate intracellular (clade B) serpins. To gain a better understanding of the biology of the intracellular serpins, we initiated a comparative genomics study using Caenorhabditis elegans as a model system. A screen of the C. elegans genomic and cDNA databases revealed nine serpin genes, tandemly arrayed on chromosome V. Although the C. elegans serpins represent a unique clade (L), they share significant functional homology with members of the clade B group of intracellular serpins, since they lack typical N-terminal signal peptides and reside intracellularly. To determine whether nematode serpins function as proteinase inhibitors, one family member, srp-2, was chosen for further characterization. Biochemical analysis of recombinant SRP-2 protein revealed SRP-2 to be a dual cross-class inhibitor of the apoptosis-related serine proteinase, granzyme B, and the lysosomal cysteine proteinases, cathepsins K, L, S, and V. Analysis of temporal and spatial expression indicated that SRP-2 was present during early embryonic development and highly expressed in the intestine and hypoderm of larval and adult worms. Transgenic animals engineered to overexpress SRP-2 were slow growing and/or arrested at the first, second, or third larval stages. These data suggest that perturbations of serpin-proteinase balance are critical for correct postembryonic development in C. elegans.

Amino Acid Sequence↗

PubMed2000

Decrease in trunk muscular response to perturbation with preactivation of lumbar spinal musculature.

STUDY DESIGN: An experimental study of healthy subjects' trunk muscle responses to force perturbations at differing angles and steady state efforts. OBJECTIVES: To determine whether increased preactivation of muscles was associated with decreased likelihood of muscular activation in response to a transient force perturbation. SUMMARY OF BACKGROUND DATA: Trunk stability (ability to return to equilibrium position after a perturbation) requires the stiffness of appropriately activated muscles to prevent buckling and consequent "self-injury." Therefore, greater trunk muscle preactivation might decrease the likelihood of reflex muscle responses to small perturbations. METHODS: Each of 13 subjects stood in an apparatus with the pelvis immobilized. A harness around the thorax provided a preload and a force perturbation by a horizontal cable and a movable pulley attached to one of five anchorage points on a wall track surrounding the subject at angles of 0 degrees, 45 degrees, 90 degrees, 135 degrees, and 180 degrees to the forward direction. Subjects first equilibrated with a preload effort of nominally 20% or 40% of their maximum extension effort. Then a single full sine-wave force perturbation pulse of nominal amplitude, 7.5% or 15% of maximum effort, duration 80 milliseconds or 300 milliseconds, was applied at a random time, with three repeated trials of each test condition. The applied force (via a load cell) and the electromyographic activity of six right and left pairs of trunk muscles were recorded. Muscle responses were detected by two methods. 1) Shewhart method: electromyographic signal greater than "baseline" values by more than three standard deviations, and 2) Mean Electromyographic Difference method: mean electromyographic signal in a time window 25 to 150 milliseconds after the force perturbation greater than that in a 25- to 150-millisecond window before the perturbation. RESULTS: Lower preload efforts were associated with more muscle responses (overall mean response detection rate = 33% at low preload and 25% at high preload). Using the Shewhart method, there were significant differences by effort (P<0.05) for all abdominal muscles and for all left dorsal muscles except multifidus. Using the Mean Electromyographic Difference method, there were significant differences by effort (P<0.05) for the same dorsal muscles, but only for one of the abdominal muscles. CONCLUSIONS: Findings are consistent with the hypothesis that the spine can be stabilized by the stiffness of activated muscles, obviating the need for active muscle responses to perturbations.

Adult↗

PubMed2005

Stepping stability: effects of sensory perturbation.

BACKGROUND: Few tools exist for quantifying locomotor stability in balance impaired populations. The objective of this study was to develop and evaluate a technique for quantifying stability of stepping in healthy people and people with peripheral (vestibular hypofunction, VH) and central (cerebellar pathology, CB) balance dysfunction by means a sensory (auditory) perturbation test. METHODS: Balance impaired and healthy subjects performed a repeated bench stepping task. The perturbation was applied by suddenly changing the cadence of the metronome (100 beat/min to 80 beat/min) at a predetermined time (but unpredictable by the subject) during the trial. Perturbation response was quantified by computing the Euclidian distance, expressed as a fractional error, between the anterior-posterior center of gravity attractor trajectory before and after the perturbation was applied. The error immediately after the perturbation (Emax), error after recovery (Emin) and the recovery response (Edif) were documented for each participant, and groups were compared with ANOVA. RESULTS: Both balance impaired groups exhibited significantly higher Emax (p = .019) and Emin (p = .028) fractional errors compared to the healthy (HE) subjects, but there were no significant differences between CB and VH groups. Although response recovery was slower for CB and VH groups compared to the HE group, the difference was not significant (p = .051). CONCLUSION: The findings suggest that individuals with balance impairment have reduced ability to stabilize locomotor patterns following perturbation, revealing the fragility of their impairment adaptations and compensations. These data suggest that auditory perturbations applied during a challenging stepping task may be useful for measuring rehabilitation outcomes.

Journal Article↗

PubMed1996

Remodeling the shape of the skeleton in the intact red cell.

The role of the membrane skeleton in determining the shape of the human red cell was probed by weakening it in situ with urea, a membrane-permeable perturbant of spectrin. Urea by itself did not alter the biconcave disk shape of the red cell; however, above threshold conditions (1.5 M, 37 degrees C, 10 min), it caused an 18% reduction in the membrane elastic shear modulus. It also potentiated the spiculation of cells by lysophosphatidylcholine. These findings suggest that the contour of the resting cell is not normally dependent on the elasticity of or tension in the membrane skeleton. Rather, the elasticity of the skeleton stabilizes membranes against deformation. Urea treatment also caused the projections induced both by micropipette aspiration and by lysophosphatidylcholine to become irreversible. Furthermore, urea converted the axisymmetric conical spicules induced by lysophosphatidylcholine into irregular, curved and knobby spicules; i.e., echinocytosis became acanthocytosis. Unlike controls, the ghosts and membrane skeletons obtained from urea-generated acanthocytes were imprinted with spicules. These data suggest that perturbing interprotein associations with urea in situ allowed the skeleton to evolve plastically to accommodate the contours imposed upon it by the overlying membrane.

Biomechanical Phenomena↗

PubMed1994

Point estimates of cancer risk at low doses.

There has been considerable discussion regarding the conservativeness of low-dose cancer risk estimates based upon linear extrapolation from upper confidence limits. Various groups have expressed a need for best (point) estimates of cancer risk in order to improve risk/benefit decisions. Point estimates of carcinogenic potency obtained from maximum likelihood estimates of low-dose slope may be highly unstable, being sensitive both to the choice of the dose-response model and possibly to minimal perturbations of the data. For carcinogens that augment background carcinogenic processes and/or for mutagenic carcinogens, at low doses the tumor incidence versus target tissue dose is expected to be linear. Pharmacokinetic data may be needed to identify and adjust for exposure-dose nonlinearities. Based on the assumption that the dose response is linear over low doses, a stable point estimate for low-dose cancer risk is proposed. Since various models give similar estimates of risk down to levels of 1%, a stable estimate of the low-dose cancer slope is provided by ŝ = 0.01/ED01, where ED01 is the dose corresponding to an excess cancer risk of 1%. Thus, low-dose estimates of cancer risk are obtained by, risk = ŝ x dose. The proposed procedure is similar to one which has been utilized in the past by the Center for Food Safety and Applied Nutrition, Food and Drug Administration. The upper confidence limit, s., corresponding to this point estimate of low-dose slope is similar to the upper limit, q1., obtained from the generalized multistage model. The advantage of the proposed procedure is that ŝ provides stable estimates of low-dose carcinogenic potency, which are not unduly influenced by small perturbations of the tumor incidence rates, unlike q1.

Humans↗

PubMed2004

Perturbation of NgTRF1 expression induces apoptosis-like cell death in tobacco BY-2 cells and implicates NgTRF1 in the control of telomere length and stability.

Telomeres are specialized nucleoprotein complexes that are essential for preserving chromosome integrity in eukaryotic cells. Several potential telomere binding proteins have recently been identified in higher plants, but nothing is known about their in vivo functions. We previously identified NgTRF1 as a double-stranded telomeric repeat binding factor in tobacco (Nicotiana tabacum) and here show that the binding of NgTRF1 to telomeric repeats inhibits telomerase-mediated telomere extension. To determine whether NgTRF1 is involved in telomere length regulation, we established transgenic tobacco BY-2 cell lines that overexpress or suppress NgTRF1. Pulsed-field gel electrophoresis showed that 35S::NgTRF1 cells exhibited significantly shortened telomeres (45 to 10 kb), whereas 35S::antisense-NgTRF1 cells contained longer telomeres (80 to 25 kb) compared with wild-type and 35S::GUS control cells (65 to 15 kb), indicating that telomere length inversely correlates with the amount of functional NgTRF1 in BY-2 cells. 35S::NgTRF1 cells with shorter telomeres displayed a progressive reduction in cell viability and stopped dividing after 25 to 40 successive rounds of 12-d batch subculture, in sharp contrast with control cells, which have an unlimited capacity for division. Internucleosomal DNA fragmentation, mitochondrial release of cytochrome c, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling positive nuclei were detected in 35S::NgTRF1 cells during prolonged subculture, indicating that enhanced cell death was attributable to an apoptosis-like mechanism. 35S::antisense-NgTRF1 cells containing low levels of NgTRF1 also exhibited a progressive decrease in cell viability and apoptotic cell death, but less so than did 35S::NgTRF1 cells, suggesting that the level of NgTRF1 is critically associated with cell viability. Taken together, these data indicate that perturbation of NgTRF1 expression results in changes in telomere length and stability, which in turn causes apoptotic cell death in transgenic BY-2 cells. These results are discussed in light of the suggestion that NgTRF1 is involved in the mechanism by which telomere length and stability are maintained. We further suggest that the structural stability of telomeres, in addition to length maintenance, is essential for their function and for the immortality of BY-2 cells.

Apoptosis↗

PubMed1987

T-cell subsets and natural killer cell function with squamous cell carcinoma of the head and neck.

Twenty-two patients with squamous cell carcinoma of the head and neck were studied to assess potential abnormalities in total T lymphocytes, T4/T8 ratios, and natural killer cell function. Total T-cell counts were reduced for the entire group with the greatest reduction occurring in individuals with hypopharyngeal tumors and/or stage IV disease. Helper to suppressor ratios were within the norm for the total group, but specific site variances were detected in patients with oral cavity and hypopharyngeal primary carcinomas. Similarly altered T4/T8 ratios were noted with stage III disease. Substantive differences in natural killer cell activity were not observed. These data suggest that perturbations in T-lymphocyte subsets can be associated with decreased survival.

Adult↗

PubMed2001

Apoptosis in normal and neoplastic mammary gland development.

Apoptosis plays important roles in mammary development from early embryonic formation of the mammary gland to the regression that follows cessation of cycling. The most dramatic occurrence of apoptosis is found during mammary involution. Most of the secretory epithelium in the lactating breast undergoes apoptosis as the mammary gland regresses and is reorganized for another cycle of lactation. We used the morphology, biochemical changes, and gene expression detected in apoptotic mammary epithelium during involution as a model for studying cell death during other stages of mammary development and for approaching the failure of apoptosis found in mammary hyperplasia. Morphological studies and gene expression have suggested that apoptosis during involution is comprised of two phases: an early limited apoptosis in response to hormone ablation and later protease promoted widespread apoptosis in response to altered cell-matrix interactions and loss of anchorage. We examined protein expression during involution for changes associated with loss of hormone stimulation and altered cell-matrix interactions. One of the proteins whose expression is able to inhibit apoptosis, and is altered during mammary epithelial cell was the serine-threonine protein kinase, Akt 1. Akt 1 activation is common to hormone, growth factor, and anchorage-mediated survival of epithelial cells. We found regulated expression of activated Akt 1 in the mammary gland during involution. Akt 1 activation peaked in pregnancy and lactation, and decreased significantly during apoptosis in mammary involution. Mechanisms of Akt 1 action include modulation of the ratio bcl-2 family members implicated in control of apoptosis. Bcl-2 family proteins were also expressed in pattern consistent with Akt 1 regulation. These observations led us to examine expression of activated Akt 1 and bcl-2 family proteins in premalignant hyperplasias. Akt 1 activation was increased; expression of anti-apoptotic proteins bcl-2 and bcl-x was strongly increased while pro-apoptotic bax was greatly diminished in three different lines of transplantable premalignant mammary hyperplasia. This data suggest that activation of Akt 1 by hormone- or anchorage-mediated pathways regulates survival of mammary epithelium and can contribute to initiation of neoplasia. These data suggest that perturbation of normal cell turnover can contribute to initiation of neoplasia.

Animals↗

PubMed1980

The kinetics of the formation of a G2 block from tritiated thymidine in phytohemagglutinin-stimulated human lymphocytes.

Flow cytometry (FCM) was used to monitor the radiation effects promoted by incorporated tritiated thymidine (3H-TdR) on phytohemagglutinin (PHA)-stimulated human peripheral blood lymphocytes stained with propidium iodide (PI). Lymphocyte microcultures were continuously labeled or pulse-labeled for various periods of time with different 3H-TdR concentrations. Two types of DNA histogram analyses were performed on unperturbed and 3H]TdR perturbed lymphocytes. The data analyses consisted of statistical analyses between averaged groups of histograms (nonparametric analysis) and cell cycle analyses (parametric analysis) to determine the percentages of cells in G0 + G1, S and G2 + M. The results showed that (a) 3H-TdR when added to proliferating lymphocytes under certain conditions (both short-term continuous and pulse-labeling) caused a highly significant increase in the proportion of tetraploid (4C) cells by FCM, (b) the increase in the proportion of 4C cells represented a block in G2 and (c) the relative increase in the percentage of 4C cells was proportional to 3H-TdR incorporation which was proportional to labeling time and concentration. Therefore, it was concluded that short labeling times be used to minimize adverse radiation effects when 3H-TdR is used to assay substances affecting lymphocyte proliferation or in the estimation of cell cycle time.

Adolescent↗

PubMed1995

In vivo effects of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) and alpha-difluoromethylornithine (DFMO) on L1210 growth, cell-cycle phase distribution and polyamine contents.

We studied the in vivo effects of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A), alpha-difluoromethylornithine (DFMO) and a combination of CGP 48664A-DFMO on tumor growth, cell-cycle phase distribution and polyamine contents. DBA-2 mice were inoculated i.p. with 10(5) L1210 cells on day 0, treated i.p. on days 1-4 and killed on day 5. As compared to controls, CGP 48664A, DFMO and the CGP 48664A-DFMO combination reduced L1210 cell numbers by 33, 43 and 85%, respectively. CGP 48664A did not affect cell-cycle phase distribution. DFMO and the CGP 48664A-DFMO combination caused a moderate and a heavy accumulation in G0/G1- and G2/M-phases, respectively. Compared with controls, the CGP 48664A-DFMO combination reduced putrescine, spermidine and total polyamines, but did not affect spermine. Compared with CGP 48664A, the CGP 48664A-DFMO combination caused lower putrescine and total polyamines, higher spermine, but no change in spermidine. Compared with DFMO, the CGP 48664A-DFMO combination caused higher putrescine and spermidine, lower spermine, but no change in total polyamine levels. We conclude that CGP 48664A potentiates the cystostatic effect of DFMO in vivo. The resulting growth inhibition is accompanied by an accumulation in G0/G1- and G2/M-phases and a reduction of putrescine and spermidine. The data suggest that perturbed polyamine composition rather than reduced spermidine or total polyamine pool size causes a profound growth inhibition.

Adenosylmethionine Decarboxylase↗

PubMed1994

Handedness and hemispheric differences for feature perturbations.

The influence of handedness on hemispheric differences for feature perturbations was assessed in left- and right-handed normal subjects, with equal numbers of each sex in each group. Stimulus displays consisting of five small squares arranged in a single row were presented tachistoscopically to the left or right of fixation, and the size of the squares was manipulated in different conditions. Subjects were instructed to state in which square a horizontal "tick" mark was located. The handedness of the subjects contributed to the pattern of hemispheric differences for tick mislocations resulting from feature perturbations in the toward-fovea direction. For left-handed subjects, fewer errors occurred when stimuli were presented to the left hemisphere; for right-handed subjects, fewer errors occurred when stimuli were presented to the right hemisphere. Increasing stimulus size tended to enhance the handedness and hemispheric feature perturbation effects. The data suggest that handedness contributes to hemispheric organization of featural extraction processes.

Adult↗

PubMed1984

Adaptation of postural control to weightlessness.

Adaptation of motor control to weightlessness was studied during a 7-day spaceflight. The maintenance of control of upright posture was examined during a voluntary raising movement of the arm and during the voluntary raising on tiptoe. In order to evaluate the contribution of visual cues, three types of visual situations were examined: normal vision, central vision, and without vision. On the basis of cinematographic and mechanographic data, the postural perturbations consecutive to the movement of a body part in conditions of weightlessness were found to be similar to those observed on earth. However, in weightlessness, in contrast to the ground-based situation, erectness of posture was maintained primarily due to the predominant contraction of the ankle flexor muscles. The sequences of postural leg muscle activity associated with the arm or foot movement were well structured and varied slightly in the course of the flight. In addition, the initial posture, that is the erect posture before the movement was executed, changed throughout the flight from an exaggerated oblique position to a terrestrial standing position. Visual information was preponderant at the beginning of the space mission for the recalibration of other sensory cues affected by weightlessness. The findings are indicative of two types of adaptation of the central program of posture regulation to weightlessness: fast, short-term adaptation, characterized by a quasi-instantaneous redistribution of motor commands between ankle flexors and extensors (an "operative process") and slow, long-term adaptation, exemplified by the loss of anticipatory activation of certain muscles by the end of the flight (a "conservative process").

Adaptation, Physiological↗