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PubMed2005

Functional differentiation and organization of feline midlumbar commissural interneurones.

Interneurones interconnecting the two sides of the spinal cord (commissural interneurones) are critically important for interlimb coordination, but little is known about their organization. We have examined the inputs to commissural interneurones located in the midlumbar segments with projections to contralateral motor nuclei, aiming to determine whether they form distinct subpopulations. Based on intracellular records from 78 interneurones, two major non-overlapping subpopulations were identified: one monosynaptically excited by group II muscle afferents (n=10), the other monosynaptically excited by reticulospinal neurones (n=52). Monosynaptic input from group I muscle afferents and/or from vestibulospinal tract neurones was found in those with monosynaptic reticulospinal, but not group II input, and in a few other neurones (n=6). Only disynaptic input from these sources was found in the remaining 10 interneurones. Disynaptic excitatory input from ipsilateral and contralateral muscle afferents and from descending tracts was distributed less selectively and might mediate coexcitation of interneurones with monosynaptic afferent or descending input. The dominant disynaptic and polysynaptic input was, however, inhibitory. IPSPs were evoked from the descending tracts in a high proportion of the commissural interneurones that were monosynaptically excited by group II afferents (55%) and from group II afferents in a high proportion of the commissural interneurones that were monosynaptically excited by reticulospinal fibres (78%). This distribution suggests that the two subpopulations are activated differentially, rather than being coactivated, in either centrally initiated movements or reflex adjustments. This would be consistent with the previous demonstration that noradrenaline differentially affects commissural neurones of the two subpopulations.

Animals↗
PubMed1996

Identification and functional differentiation of two type I fatty acid synthases in Brevibacterium ammoniagenes.

The fatty acid synthase (FAS) from Brevibacterium ammoniagenes is a homohexameric multienzyme complex that catalyzes the synthesis of both saturated and unsaturated fatty acids. By immunological screening of a B. ammoniagenes expression library, an fas DNA fragment was isolated and subsequently used to clone the entire gene together with its flanking sequences. Within 10,525 bp of sequenced DNA, the 9,189-bp FAS coding region was identified, corresponding to a protein of 3,063 amino acids with a molecular mass of 324,910 Da. This gene (fasA) encodes, at its 5' end, the same amino acid sequence as is observed with purified B. ammoniagenes FAS. A second reading frame encoding another B. ammoniagenes FAS variant (FasB) had been identified previously. Both sequences are colinear and exhibit 61 and 47% identity at the DNA and protein levels, respectively. By using specific antibodies raised against a unique peptide sequence of FasB, this enzyme was shown to represent only 5 to 10% of the cellular FAS protein. Insertional inactivation of the FasB coding sequence causes no defective phenotype, while fasA disruptants require oleic acid for growth. Correspondingly, oleate-dependent B. ammoniagenes cells obtained by ethyl methanesulfonate mutagenesis were complemented by transformation with fasA DNA but not with fasB DNA. The data indicate that B. ammoniagenes contains two related though differently expressed type I FASs. FasA represents the bulk of cellular FAS protein and catalyzes the synthesis of both saturated and unsaturated fatty acids, while the minor variant, FasB, cannot catalyze the synthesis of oleic acid.

Adhesins, Escherichia coli↗
PubMed1993

Differential function and expression of Saccharomyces cerevisiae B-type cyclins in mitosis and meiosis.

We have studied the patterns of expression of four B-type cyclins (Clbs), Clb1, Clb2, Clb3, and Clb4, and their ability to activate p34cdc28 during the mitotic and meiotic cell cycles of Saccharomyces cerevisiae. During the mitotic cell cycle, Clb3 and Clb4 were expressed and induced a kinase activity in association with p34cdc28 from early S phase up to mitosis. On the other hand, Clb1 and Clb2 were expressed and activated p34cdc28 later in the mitotic cell cycle, starting in late S phase and continuing up to mitosis. The pattern of expression of Clb3 and Clb4 suggests a possible role in the regulation of DNA replication as well as mitosis. Clb1 and Clb2, whose pattern of expression is similar to that of other known Clbs, are likely to have a role predominantly in the regulation of M phase. During the meiotic cell cycle, Clb1, Clb3, and Clb4 were expressed and induced a p34cdc28-associated kinase activity just before the first meiotic division. The fact that Clb3 and Clb4 were not synthesized earlier, in S phase, suggests that these cyclins, which probably have a role in S phase during the mitotic cell cycle, are not implicated in premeiotic S phase. Clb2, the primary mitotic cyclin in S. cerevisiae, was not detectable during meiosis. Sporulation experiments on strains deleted for one, two, or three Clbs indicate, in agreement with the biochemical data, that Clb1 is the primary cyclin for the regulation of meiosis, while Clb2 is not involved at all.

CDC28 Protein Kinase, S cerevisiae↗
PubMed1994

Induction versus progression of brain tumor development: differential functions for the pRB- and p53-targeting domains of simian virus 40 T antigen.

The ability of simian virus 40-encoded large T antigen to disrupt the growth control of a variety of cell types is related to its ability to interfere with certain cellular proteins, such as p53 and the retinoblastoma susceptibility gene product (pRB). We have used wild-type and mutant forms of T antigen in transgenic mice to dissect the roles of pRB, p53, and other cellular proteins in tumorigenesis of different cell types. In this study, using a cell-specific promoter to target expression specifically to brain epithelium (the choroid plexus) and to B and T lymphoid cells, we characterize the tumorigenic capacity of a T-antigen fragment that comprises only the amino-terminal 121 residues. This fragment (dl1137) retains the ability to interact with pRB and p107 but lacks the p53-binding domain. While loss of the p53-binding region results in loss of the capacity to induce lymphoid abnormalities, dl1137 retains the ability to induce choroid plexus tumors that are histologically indistinguishable from those induced by wild-type T antigen. Tumors induced by dl1137 develop much more slowly, however, reaching an end point at around 8 months of age rather than at 1 to 2 months. Analysis of tumor progression indicates that tumor induction by dl1137 does not require secondary genetic or epigenetic events. Rather, the tumor growth rate is significantly slowed, indicating that the T-antigen C-terminal region contributes to tumor progression in this cell type. In contrast, the pRB-binding region appears essential for tumorigenesis as mutation of residue 107, known to disrupt pRB and p107 binding to wild-type T antigen, abolishes the ability of the dl1137 protein to induce growth abnormalities in the brain.

Animals↗
PubMed1974

Functional differentiation of human jejunum and ileum: a comparison of the handling of glucose, peptides, and amino acids.

The characteristics of glucose, glycine, L-alanine, and glycyl-L-alanine absorption from the jejunum and ileum have been compared in normal human subjects. A perfusion technique has been used, and correct positioning of the perfusion tube has been confirmed by measuring the differential jejunal and ileal handling of bicarbonate. Glucose and glycine were absorbed faster from the jejunum than from the ileum of all subjects studied, and L-alanine was absorbed faster from the jejunum than from the ileum in five out of six subjects studied. In contrast, the dipeptide glycyl-L-alanine was absorbed at comparable rates from the jejunum and ileum. Higher concentrations of free amino acids were detected in the luminal contents aspirated during the ileal dipeptide perfusions.These results emphasize the importance of oligopeptide transport in the absorption of protein digestion products, especially in the human ileum, and the practical implications of these findings are discussed.

Adult↗
PubMed2003

Expression of P-cadherin, but not E-cadherin or N-cadherin, relates to pathological and functional differentiation of breast carcinomas.

AIMS: To compare the expression of the cell adhesion molecules P-cadherin, N-cadherin, and E-cadherin in invasive and in situ breast carcinomas relative to clinicopathological features (size, node status, type, grade, and receptors) to determine whether expression patterns relate to specific tumour characteristics. METHODS: Using immunohistochemistry, 110 invasive and in situ breast carcinomas were examined for the presence, extent, and localisation of all three cadherins. Findings were related to tumour size, type, grade, node status, oestrogen (ER), progesterone, and epidermal growth factor receptor (EGFR) expression for invasive carcinomas and to grade and receptors for in situ carcinomas. RESULTS: P-cadherin was detected in 40% of invasive carcinomas, N-cadherin in 30%, and E-cadherin in 81%. For invasive carcinomas, the presence of P-cadherin significantly correlated with high grade, lack of ER and presence of EGFR, but not tumour size or node status. Carcinomas containing P-cadherin could be put into three categories dependent upon receptor and E-cadherin profile. There were no correlations between E/N-cadherin and size, grade, node status, or receptors. Three of 16 infiltrating lobular carcinomas expressed cytoplasmic but none membranous E-cadherin, and P-cadherin and N-cadherin were present in four carcinomas of this type. E-cadherin was found in all ductal carcinomas in situ, P-cadherin in a proportion of high grade tumours, and N-cadherin in a mixture of grades. CONCLUSION: P-cadherin but not E/N-cadherin expression in breast carcinomas shows a strong correlation with higher grade (poorer differentiation), lack of ERs, and presence of EGFR, and its expression may aid in the further subdivision of high grade carcinomas.

Biomarkers, Tumor↗
PubMed1989

Functional differentiation of long bones in lorises.

The external dimensions of the limb bones and the geometry of their midshaft cross-sections were determined for Loris tardigradus and Nycticebus coucang. Relative cortical thickness, cortical area, and second moment of area were calculated and contrasted with locomotor stresses. The difference in shape-related strength of the bones between the smaller- and the larger-bodied species is more pronounced than can be expected from stresses acting during normal locomotion. The Nycticebus skeleton has a much higher safety margin overall and seems to be dimensioned for infrequent but critical stresses of high magnitude. Lorisine gaits in general are characterized by low ground reaction forces, great mobility in all joints, and a nearly equal share in propulsion and weight-bearing by the fore- and hindlimb. Accordingly, the long bones of lorises (especially those of L. tardigradus) tend to be less rigid than those of other mammalian species (including other primates), they lack a preferential plane of higher bending strength, and femur and humerus do not differ markedly in their capacity to withstand mechanical stresses. External dimensions of the humerus and femur of the two African lorisine species parallel and corroborate these results. Some more general implications for the relationships between bone shape and locomotor stresses are also discussed.

Animals↗
PubMed1994

Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones.

Matrix metalloproteinases are a highly regulated family of enzymes, that together can degrade most components of the extracellular matrix. These proteins are active in normal and pathological processes involving tissue remodeling; however, their sites of synthesis and specific roles are poorly understood. Using in situ hybridization, we determined cellular distributions of matrix metalloproteinases and tissue inhibitor of metalloproteinase-1, an inhibitor of matrix metalloproteinases, in endometrium during the reproductive cycle. The mRNAs for all the metalloproteinases were detected in menstrual endometrium, but with different tissue distributions. The mRNA for matrilysin was localized to epithelium, while the others were detected in stromal cells. Only the transcripts for the 72-kD gelatinase and tissue inhibitor of metalloproteinases-1 were detected throughout the cycle. Transcripts for stromelysin-2 and the 92-kD gelatinase were only detected in late secretory and menstrual endometrium, while those for matrilysin, the 72-kD gelatinase, and stromelysin-3 were also consistently detected in proliferative endometrium. These data indicate that matrix metalloproteinases are expressed in cell-type, tissue, and reproductive cycle-specific patterns, consistent with regulation by steroid hormones, and with specific roles in the complex tissue growth and remodeling processes occurring in the endometrium during the reproductive cycle.

Adult↗
PubMed2002

Differential functional magnetic resonance imaging language activation in twins discordant for a left frontal tumor.

Eight-year-old twins, one with a left frontal tumor and aphasic seizures, the other neurologically normal, underwent serial assessment of expressive language with functional magnetic resonance imaging and neuropsychology. The affected twin showed a significant amount of right hemisphere activation coincident with behavioral deterioration in expressive language and late growth in the tumor. This pattern of language dysfunction and the left language dominance of her co-twin suggested that the affected twin was also left dominant for language, and the significance of her right activation is discussed. We postulate that the right hemisphere activation represents a stabilizing mechanism in the context of a developmental and progressive lesion in language cortex rather than language transfer per se.

Brain Neoplasms↗
PubMed1983

Epidermal growth factor stimulates cell proliferation and inhibits functional differentiation of mouse mammary epithelial cells in culture.

Mouse mammary epithelial cells cultured on collagen gels multiplied and produced casein and alpha-lactalbumin in response to insulin, cortisol, and PRL. The addition of epidermal growth factor (EGF) at 50 ng/ml increased the total number of epithelial cells by 30-40% and thymidine incorporation into DNA 4.7-fold after 5 days of culture. In contrast, EGF inhibited hormonal induction of the synthesis of casein and alpha-lactalbumin in those cells by about 45% and 55%, respectively, without inhibiting total protein synthesis. Furthermore, EGF decreased casein mRNA activity by 55% and increased total mRNA activity by 66% in cells cultured with the three hormones. These effects of EGF were apparent at 0.1 ng/ml and were maximal at 50-100 ng/ml and could be reversed by its removal from the medium, followed by the addition of anti-EGF antibody. The inhibition of casein synthesis by EGF was unaffected by the concentrations of insulin, cortisol, and PRL. Other growth factors, such as fibroblast growth factor, multiplication-stimulating activity, nerve growth factor, and platelet-derived growth factor, did not simulate the effects of EGF. Cytarabine (1 microgram/ml), which inhibited thymidine incorporation into DNA by 94%, did not block the inhibitory action of EGF on casein synthesis. These results suggest that EGF serves as a regulator of hormone-dependent growth and differentiation of mammary epithelial cells.

Animals↗
PubMed1985

Modulation of differentiated function in cultured thyroid cells: thyrotropin control of thyroid peroxidase activity.

The activity of thyroid peroxidase (TPO) in primary dog thyroid cell cultures was measured by both guaiacol oxidation and iodide oxidation assays. Whether cultures were initiated in the absence or presence of 50 mU/ml TSH, TPO activity fell in the first 24 h of culture to approximately 10% of the activity in freshly isolated follicles. After 5 days in culture, TPO activity almost completely disappeared in the absence of TSH, whereas in the presence of TSH, TPO activity rebounded to approximately 30% of that in freshly isolated follicles. TSH similarly induced TPO activity in cells that had lost this activity during a 1- to 6-day preincubation period in the absence of hormone. The half-time for the induction of TPO activity was approximately 3 days. Whether TSH was present from the start of culture or added after 5 days of culture without TSH, the half-maximal dose for reinduction of TPO activity was 0.3-0.4 mU TSH/ml. (Bu)2cAMP, 8-bromo-cAMP, forskolin, and cholera toxin all mimicked, either completely or in part, the ability of TSH to induce TPO activity in cells preincubated without hormone. We conclude that, in cultured dog thyroid cells, TPO activity is modulated by chronic TSH stimulation, and that this effect is mediated by cAMP. However, even though TSH stimulates TPO activity in cultured thyroid cells, the fact that there is no comparable restoration of organic iodine formation (as found in previous studies) makes it likely that other aspects of the iodide organification mechanism are altered.

Animals↗
PubMed1988

Fibroblast growth factor stabilizes ribonucleic acid and regulates differentiated functions in a multipeptide-secreting neuroendocrine cell line.

A clonal cell line (44-2C) which synthesizes and secretes somatostatin, neurotensin, calcitonin (CT), and CT gene-related peptide and transiently expresses c-fos was used to characterize the mechanism of action of basic fibroblast growth factor (bFGF). bFGF had two modes of action: 1) short term incubation of 44-2C cells with bFGF increased the cellular content of neurotensin, somatostatin, and CT; and 2) bFGF enhanced the response of the cells to rat hypothalamic GRF-mediated cAMP efflux. The long term action of bFGF was manifested by the permissive effect of the molecule. bFGF had a sustained effect on RNA synthesis, and pretreatment with bFGF for 24 h altered the time course of response of the cells to rat GRF. In this cell line the cellular action of bFGF was not mediated via protein kinase-C action. bFGF was not mitogenic in 44-2C cells. bFGF stimulated uridine incorporation without affecting thymidine incorporation. Results obtained with actinomycin-D and alpha-amanitin suggest that the above effects of bFGF can be correlated with increased RNA stability produced by bFGF.

Amanitins↗
PubMed1991

Ovarian actions of tumor necrosis factor-alpha (TNF alpha): pleiotropic effects of TNF alpha on differentiated functions of untransformed swine granulosa cells.

We have examined interactions between tumor necrosis factor-alpha (TNF alpha), a product of the immune system, and ovarian cells using serum-free monolayer cultures of untransformed swine granulosa cells. Recombinant human TNF alpha, a potent cytoactive product of activated macrophages, bound specifically and with high affinity to intact granulosa cells. Binding sites had an apparent Kd of 0.17 nM (95% confidence interval, 0.065-0.31), and a binding capacity of 80 nmol/micrograms DNA (95% confidence interval, 52-110). The binding capacity of granulosa cells for TNF alpha (but not the binding affinity) was increased approximately 2-fold by treatment with FSH and insulin. The biological effects of TNF alpha on pig granulosa cells were expressed after 48 and 96 h in culture. At the latter time, TNF alpha significantly suppressed insulin- and insulin- plus FSH-stimulated progesterone accumulation, with respective ID50 values of 0.08 +/- 0.008 and 0.06 +/- 0.014 nM, but did not affect basal progesterone accumulation or DNA content. TNF alpha also significantly attenuated the stimulatory effect of combined treatment with FSH and insulin on cAMP generation during 48-96 h of culture. TNF alpha inhibited the stimulatory effects of forskolin, cholera toxin, and the cAMP analog 8-bromo-cAMP on progesterone accumulation, indicating multiple sites of action of this immune modulator. Inhibition of progestin biosynthesis was observed even in the presence of 25-hydroxycholesterol, a soluble oxygenated sterol substrate for the cholesterol side-chain cleavage reaction, and was accompanied by decreased concentrations of specific cellular mRNA encoding cholesterol side-chain cleavage enzyme. There were no changes in the amounts of a constitutively expressed enzyme, phosphoglyceraldehyde dehydrogenase. Inhibitory actions of TNF alpha were specific to de novo steroid hormone biosynthesis, since nanomolar concentrations of this cytokine stimulated accumulation of prostaglandin E2 and prostaglandin F2 alpha basally and during treatment with FSH, cholera toxin, or 8-bromo-cAMP. In contrast, prostaglandin accumulation was not enhanced by interferon-gamma or interleukin-2. In summary, untransformed porcine granulosa cells exhibit specific, high affinity, low capacity saturable binding sites for TNF alpha, and the number of such binding sites can be regulated by combined treatment with insulin and FSH. Granulosa cells are susceptible to the inhibitory actions of TNF alpha on FSH- and insulin-supported progesterone biosynthesis and cAMP accumulation. One important locus of TNF alpha action is blockade of hormonally stimulated increases in specific mRNA encoding the cholesterol side-chain cleavage cytochrome P450 enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Functional differentiation of placental syncytiotrophoblasts during baboon pregnancy: developmental expression of chorionic somatomammotropin messenger ribonucleic acid and protein levels.

The objective of the present study was to determine whether, in addition to the onset of chorionic somatomammotropin (CS) production previously shown to result from the morphological differentiation of cytotrophoblasts into syncytiotrophoblasts, there is a further developmental increase in the capacity of syncytiotrophoblasts to produce CS with advancing stages of baboon pregnancy. Placentas were obtained from baboons in early (days 48-62), mid (days 97-110), and late (days 161-175) gestation (term = 184 days), and CS messenger ribonucleic acid (mRNA) and protein levels were determined in a syncytiotrophoblast-rich cell fraction isolated by Percoll gradient centrifugation. CS mRNA levels in syncytiotrophoblasts, expressed as a ratio of beta-actin, exhibited a progressive increase from early (0.04 +/- 0.04 relative arbitrary units) to mid (2.37 +/- 0.33; P < 0.001) to late (3.66 +/- 0.39; P < 0.05) gestation. Levels of the 22-kDa CS protein were very low on days 48-55 (0.83 +/- 0.09 arbitrary units), increased 10-fold (P < 0.001) on days 57-60 (8.11 +/- 0.68), and increased (P < 0.001) to a maximum of 14.58 +/- 0.58 near term. CS mRNA levels in whole placental villous tissue increased (P < 0.05) between early (0.89 +/- 0.48) and mid (2.97 +/- 0.47) gestation, then remained constant. CS protein exhibited a similar increase (P < 0.001) in villous tissue between early (2.32 +/- 0.40) and mid (6.07 +/- 0.24) gestation, then remained constant. The increase in mRNA and protein levels of CS in the placenta was accompanied by a progressive (P < 0.001) rise in serum CS. We conclude that in addition to the morphological differentiation of cytotrophoblasts into syncytiotrophoblasts that has been well established to result in the onset of CS biosynthesis, villous syncytiotrophoblasts undergo functional/biochemical differentiation thereafter, manifested as an increase in the capacity for the synthesis of CS.

Animals↗