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Biomedical subjects

W Ruan

Publications and source records attributed to W Ruan.

17 recordsLinked to original sources
PubMed2001

Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor.

Hematopoietic cytokine receptors, such as the erythropoietin receptor (EpoR), are single membrane-spanning proteins. Signal transduction through EpoR is crucial for the formation of mature erythrocytes. Structural evidence shows that in the unliganded form EpoR exists as a preformed homodimer in an open scissor-like conformation precluding the activation of signaling. In contrast to the extracellular domain of the growth hormone receptor (GHR), the structure of the agonist-bound EpoR extracellular region shows only minimal contacts between the membrane-proximal regions. This evidence suggests that the domains facilitating receptor dimerization may differ between cytokine receptors. We show that the EpoR transmembrane domain (TM) has a strong potential to self interact in a bacterial reporter system. Abolishing self assembly of the EpoR TM by a double point mutation (Leu 240-Leu 241 mutated to Gly-Pro) impairs signal transduction by EpoR in hematopoietic cells and the formation of erythroid colonies upon reconstitution in erythroid progenitor cells from EpoR(-/-) mice. Interestingly, inhibiting TM self assembly in the constitutively active mutant EpoR R129C abrogates formation of disulfide-linked receptor homodimers and consequently results in the loss of ligand-independent signal transduction. Thus, efficient signal transduction through EpoR and possibly other preformed receptor oligomers may be determined by the dynamics of TM self assembly.

Amino Acid Sequence↗
PubMed2000

brakeless is required for photoreceptor growth-cone targeting in Drosophila.

The R1-R6 subclass of photoreceptor neurons (R cells) in the Drosophila compound eye form specific connections with targets in the optic ganglia. In this paper, we report the identification of a gene, brakeless (bks), that is essential for R1-R6 growth cone targeting. In brakeless mutants, R1-R6 growth cones frequently fail to terminate migration in their normal target, the lamina, and instead project through it and terminate in the second optic ganglion, the medulla. Genetic mosaic analysis and transgene rescue experiments indicate that bks functions in R cells and not within the lamina target region. bks encodes a nuclear protein. We propose that it participates in a gene expression pathway regulating one or more growth cone components controlling R1-R6 targeting.

Amino Acid Sequence↗
PubMed2000

An object-oriented design for automated navigation of semantic networks inside a medical data dictionary.

In this paper we present a data dictionary server for the automated navigation of information sources. The underlying knowledge is represented within a medical data dictionary. The mapping between medical terms and information sources is based on a semantic network. The key aspect of implementing the dictionary server is how to represent the semantic network in a way that is easier to navigate and to operate, i.e. how to abstract the semantic network and to represent it in memory for various operations. This paper describes an object-oriented design based on Java that represents the semantic network in terms of a group of objects. A node and its relationships to its neighbors are encapsulated in one object. Based on such a representation model, several operations have been implemented. They comprise the extraction of parts of the semantic network which can be reached from a given node as well as finding all paths between a start node and a predefined destination node. This solution is independent of any given layout of the semantic structure. Therefore the module, called Giessen Data Dictionary Server can act independent of a specific clinical information system. The dictionary server will be used to present clinical information, e.g. treatment guidelines or drug information sources to the clinician in an appropriate working context. The server is invoked from clinical documentation applications which contain an infobutton. Automated navigation will guide the user to all the information relevant to her/his topic, which is currently available inside our closed clinical network.

Automation↗
PubMed2000

IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis.

Growth hormone (GH) is essential for rodent mammary gland development during puberty. It binds to GH receptors in the stromal compartment of the mammary gland and stimulates IGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locally produced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structures that lead the process of mammary gland development during puberty. Subsequent studies have in large measure proven this hypothesis. They include the observations that mammary development was grossly impaired in female mice deficient in IGF-I (IGF-I(-/-) knockout mice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammary development while treatment with GH + E2 did not. Thus, the full phenotypic action of GH in mammary gland development is mediated by IGF-I. We have demonstrated one effect of GH on the mammary gland that does not appear to be mediated by the action of IGF-I. GH increased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammary fat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis during pubertal mammary development, other data suggest that IGF-I might also be of importance during pregnancy and lactation. In summary, the earliest phase of pubertal mammary development (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormones have been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-induced IGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for later stages of mammary development, as well.

Animals↗
PubMed2000

A dictionary server for supplying context sensitive medical knowledge.

The Giessen Data Dictionary Server (GDDS), developed at Giessen University Hospital, integrates clinical systems with on-line, context sensitive medical knowledge to help with making medical decisions. By "context" we mean the clinical information that is being presented at the moment the information need is occurring. The dictionary server makes use of a semantic network supported by a medical data dictionary to link terms from clinical applications to their proper information sources. It has been designed to analyze the network structure itself instead of knowing the layout of the semantic net in advance. This enables us to map appropriate information sources to various clinical applications, such as nursing documentation, drug prescription and cancer follow up systems. This paper describes the function of the dictionary server and shows how the knowledge stored in the semantic network is used in the dictionary service.

Decision Support Systems, Clinical↗
PubMed1999

The SH2/SH3 adaptor protein dock interacts with the Ste20-like kinase misshapen in controlling growth cone motility.

Recent studies suggest that the SH2/SH3 adaptor Dock/Nck transduces tyrosine phosphorylation signals to the actin cytoskeleton in regulating growth cone motility. The signaling cascade linking the action of Dock/Nck to the reorganization of cytoskeleton is poorly understood. We now demonstrate that Dock interacts with the Ste20-like kinase Misshapen (Msn) in the Drosophila photoreceptor (R cell) growth cones. Loss of msn causes a failure of growth cones to stop at the target, a phenotype similar to loss of dock, whereas overexpression of msn induces pretarget growth cone termination. Physical and genetic interactions between Msn and Dock indicate a role for Msn in the Dock signaling pathway. We propose that Msn functions as a key controller of growth cone cytoskeleton in response to Dock-mediated signals.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development.

Previous studies from this laboratory have emphasized the essential role of GH in pubertal mammary development and shown that insulin-like growth factor I (IGF-I) was capable of substituting for GH in this process in rats and mice. The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present. IGF-I(-/-) null female animals were found to have significantly less mammary development than age matched wild-type controls (P <0.006) using several endpoints including the number of terminal end buds or TEBs (1.3 vs. 7.3), percent of the fat pad occupied by glandular elements (6.5 vs. 100), and number of ducts (15 vs. too numerous to count). That the deficiency in mammary gland development was related to the absence of IGF-I was underscored by the observation that des (1-3) IGF-I administration to IGF-I(-/-) null animals for 5 days caused significant mammary gland development as measured by TEB formation and branching of ducts. The number of TEBs rose from a mean of 1.3 in controls to 20.5 without added E2 (P < 0.009), and from 1.7 to 21 when des (1-3) IGF-I was given together with E2 (P < 0.006). The number of ducts increased significantly from a mean of 12 to 27 in response to IGF-I and E2, and from 15 to 24.5 with IGF-I alone. In contrast, administration of human GH with E2 had no stimulatory effect on mammary development in these animals, indicating that the full effect of GH in this process is mediated by IGF-I. To determine whether IGF-I was also responsible for further ductal morphogenesis, we administered des (1-3) IGF-I + E2 to the knockout animals for 14 days and compared the effects of this combination of hormones on mammary development with those observed after 5 days. We found that there was a significant increase from 5 to 14 days in the number of TEBs (mean: 21 vs. 41) and the area of the mammary fat pad occupied by glands (mean: 10 vs. 20%). There was elongation and thickening of the ducts which accounted for the increased area that was occupied by ductal structures. There was no significant increase in the number of ducts. However, there was the appearance of a large number of buds along the length of the ductal structures, suggesting the beginning of side branching. These results suggest that IGF-I, when given along with E2, is responsible for ductal morphogenesis.

Animals↗
PubMed1999

Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development.

Insulin-like growth factor I (IGF-I) has been implicated as a factor that may predispose one to prostate cancer. However, no specific relationship between IGF-I and prostate development or cancer in vivo has been established. To determine whether IGF-I was important in prostate development, we examined prostate architecture in IGF-I(-/-) null mice and wild-type littermates. Glands from 44-day-old IGF-I-deficient animals were not only smaller than those from wild-type mice, but also had fewer terminal duct tips and branch points and deficits in tertiary and quaternary branching (P < 0.0001), indicating a specific impairment in gland structure. Administration of des(1-3)-IGF-I for 7 days partially reversed the deficit by increasing those parameters of prostate development (P < 0.006). That IGF-I production probably mediates an effect of GH in this process was indicated by the observations that GH antagonist transgenic mice also had significantly impaired prostate development (P < 0.0002) and that bovine GH had no independent effect on stimulating prostate development in IGF-I null animals. The data indicate that IGF-I deficiency is the proximate cause of impaired prostate development and give credence to the idea that, like testosterone, GH and IGF-I may be involved in prostate cancer growth as an extension of a normal process.

Animals↗
PubMed1999

The effect of GH on estrogen receptor expression in the rat mammary gland.

Both GH and insulin-like growth factor I (IGF-I) synergize with estrogen to induce normal mammary gland development. However, the nature of this synergy has not been explored. To gain insight into the mechanism of these interactions we have examined the effects of these substances on the estrogen receptor (ER). ER levels in the mammary gland cytosols from hypophysectomized and oophorectomized rats, were measured using two assay systems: a dextran-coated charcoal procedure to measure binding to radiolabeled steroid, and an immunologic assay employing a specific antibody to the receptor. In both assays, levels of ER were at or near baseline detection (approximately 1-2 ng/mg protein). Treating animals with either bovine or human GH significantly increased ER activity (P<0.001), whereas prolactin (PRL) and/or estradiol treatment had no effect. That this increase was at the level of transcription was demonstrated by reverse transcriptase/polymerase chain reaction. Following a single injection of GH (50 microgram), a substantial increase in ER mRNA was observed by 10 h, with levels returning to baseline within 24 h; a concomitant increase in ER itself was also observed at the 10 h time point. The effect of GH appeared to occur mainly in the mammary stroma, because there were no differences in GH stimulation of ER between gland-free and gland containing mammary fat pads. Furthermore, analysis of mammary gland ER by immunocytochemistry demonstrated that while ER was present in the epithelial cells of non-treated animals, only GH treated animals had ER clearly visible in both glandular and fat cells of the tissue. In contrast, treating animals with des(1-3)-IGF-I did not result in reproducible increases in ER, nor in the staining of fat cell nuclei for ER. These data demonstrate a specific GH effect on the ER in the mammary fat cell.

Animals↗
PubMed1998

Evidence that the mammary fat pad mediates the action of growth hormone in mammary gland development.

Recent evidence from our laboratory suggests that GH and insulin-like growth factor I (IGF-I) mediate glandular mammary development together with estrogen. It has also been well established that both stromal and epithelial elements must interact for mammary glandular development to occur. To determine whether the effect of GH is mediated by the stromal or epithelial tissue, we set up the following experiment. Bovine GH (bGH; 100 microg) or BSA (as a control), without or with estradiol (E2), was injected i.p. into sexually immature female rats that were hypophysectomized and oophorectomized. Mammary glands and subscapular fat pads were removed from the animals. The mammary glands were divided into two parts: a gland-free fat pad and remaining glandular tissue. The end point of bGH activity was induction of IGF-I messenger RNA (mRNA). This was determined quantitatively by solution hybridization and also by RT-PCR. We found that the effects of GH on stimulation of IGF-I mRNA in the gland-free mammary fat pad and the remainder of the mammary gland were similar (3.6- vs. 3.9-fold, respectively; P < 0.001). In both sorts of mammary tissue, bGH was found to synergize with E2 in the induction of IGF-I mRNA (5.8- vs. 5.3-fold; P < 0.001). There was also an increase in IGF-I mRNA in subscapular fat pads in response to 100 microg bGH (5.3-fold; P < 0.001); however, no synergism between bGH and E2 was found. These data indicate that bGH works as well on mammary stromal tissue as on tissue with glands and suggests that GH acts on the stromal compartment of the mammary gland to induce IGF-I mRNA and possibly IGF-I itself, which, in turn, causes differentiation of epithelial ducts into terminal end buds. These data also might explain why mammary epithelium is also able to differentiate in nonmammary fat pads when transplanted there.

Adipose Tissue↗
PubMed1998

The effect of environmental conditions and glucose feeding in shaking flask on glutathione (GSH) production.

The effects of pH, broth volume, initial sugar concentration, ratio of carbon to nitrogen and phosphorus, and the glucose feeding method on GSH production in a shaking flask were investigated. The results showed that the proper pH and broth content for GSH production were 6.0 and 60 ml broth per 500 ml flask, respectively. The initial glucose concentration distinctly affected the GSH production; the intracellular GSH content of yeast would decrease when the initial glucose concentration was beyond 12 g/L. A glucose feeding strategy with the purpose of controlling the specific growth rate at an expected value was developed and applied to a 12 hour fermentation with the total glucose concentration 26.2 g/L; the final cell concentration (DCW) and the intracellular GSH content could reach 8.78 g/L and 13.6 mg/g, respectively, while the total GSH in the broth was 119.4 mg/L and the yield of cell to glucose was 0.335 g/g.

Carbon↗
PubMed1998

On the way to a Web based hospital information system: concepts for the use of a medical data dictionary to present context sensitive information in an intranet environment.

Many authors have promoted the www-paradigm to build modern hospital information systems. However currently web-based applications are better suited to information "browsing" than to build complex data entry features. This prompted us to start with our first web based developments inside the Giessen University Hospital Information System in the field of pure presentation of stored knowledge and information. This article describes the concepts which will be used in Giessen to convert available information sources to the www paradigm and to implement context-sensitive knowledge presentation mechanisms inside the clinical information system. The approach is based upon a web-based medical data dictionary server. The data dictionary is used to map terms of interest, chosen from the clinical user during work with a HIS-application, to a semantic network of relationships. The dictionary server will follow those semantic links in order to find and display the webpages, which are linked to the subject.

Dictionaries as Topic↗
PubMed1995

Estradiol enhances the stimulatory effect of insulin-like growth factor-I (IGF-I) on mammary development and growth hormone-induced IGF-I messenger ribonucleic acid.

Pubertal mammary development in the rat is largely dependent upon GH and estrogen. We recently showed that insulin-like growth factor-I (IGF-I) can substitute for GH in inducing mammary development in male rats, suggesting that IGF-I mediates GH action. The present study investigated whether IGF-I, like GH, required estradiol (E2) to act or whether IGF-I could substitute for both GH and E2. The effects of IGF-I were tested in the presence and absence of E2. Elvax pellets containing IGF-I or des(1-3) IGF-I were implanted into right lumbar mammary glands of sexually immature, hypophysectomized, oophorectomized female rats, with control BSA-containing pellets in the contralateral glands. After 5 days, both lumbar mammary glands were removed and examined in whole mounts for mammary development by counting terminal end buds and alveolar structures. E2, administered in SILASTIC brand capsules, had no independent effect on mammary development. In the absence of E2, des(1-3) IGF-I had a small, but significant, independent effect on mammary development; native IGF-I was ineffective. The addition of E2 significantly enhanced the effects of IGF-I and des(1-3) IGF-I on mammary development, similar to that noted when E2 was given along with GH. We also studied the effects of E2 and/or hGH on mammary gland IGF-I messenger RNA (mRNA) in hypophysectomized castrated male animals. E2 alone did not increase mammary gland IGF-I mRNA concentrations, but E2 enhanced the effect of hGH on IGF-I mRNA by 4- to 6-fold. These studies indicate that IGF-I can have a small independent effect on mammary development, but like GH, E2 is required for a full effect. They also indicate that E2 is capable of synergizing with GH in the production or expression of IGF-I mRNA, and that the action of E2 on mammary development may take place at multiple sites. If locally produced IGF-I does indeed mediate the action of GH in mammary development, then although E2 is capable of enhancing the effect of GH on IGF-I mRNA, its major effect in mammary development occurs after IGF-I is produced.

Animals↗
PubMed1993

Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland.

We have shown that nonlactogenic rat (r) GH is far more potent than rPRL in inducing rat mammary development. To determine the relative roles of GH and PRL in mammary development and their mechanisms of action, we have compared the abilities of a group of native and mutant GHs, PRLs, and placental lactogens (PLs) to induce mammary development, bind to GH receptors, and activate lactogenic receptors. Mammary development was assessed histologically by counting terminal end buds and alveolar structures in glands from sexually immature, hypophysectomized, castrated, estradiol-treated rats. Hormones were implanted, in Elvax pellets, into the lumbar mammary gland. Significant increases in terminal end buds (P < 0.03) over internal control values were obtained with rGH, recombinant human GH (rhGH), rbGH, and one of two mutant rhGHs. These four hormones were also found to bind to GH receptors with high affinity. In contrast, little development occurred with hPRL, rPRL, rhPL, ovine PRL, mutant forms of rhPRL and rhPL, and a mutant of rhGH altered to reduce binding to GH and PRL receptors. All of these substances are more than 50-fold reduced in binding to the GH receptor, yet can bind and activate lactogenic receptors. Thus, only those natural or mutant pituitary or placental hormones with high binding affinity to GH receptors induce mammary development, suggesting that GH receptors play a central role in this process.

Animals↗
PubMed1992

Intact and amino-terminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development.

Growth hormone (GH) plays a role in regulating growth and differentiation of immature glandular structures in the mammary gland, but the mechanisms by which the hormone exerts these effects are unknown. We have previously found that GH stimulates insulin-like growth factor I (IGF-I) I mRNA production within the mammary glands of hypophysectomized rats. In this study we set out to determine if IGF-I administration could mimic the action of GH in initiating mammary gland differentiation and development. Two forms of IGF-I, intact and amino-terminally shortened [des-(1-3)-IGF-I], were found to induce the development of terminal end buds and the formation of alveolar structures in the mammary glands of hypophysectomized, castrated, and estradiol-treated sexually immature male rats. The effect of both forms of IGF-I was similar to that obtained with human GH, but the truncated form was at least 5 times more potent than intact IGF-I. These findings suggest that the inductive effect of GH on glandular differentiation is mediated by the GH-induced production of IGF-I or a related molecule within the mammary gland itself.

Animals↗
PubMed1990

Non-lactogenic effects of growth hormone on growth and insulin-like growth factor-I messenger ribonucleic acid of rat mammary gland.

In contrast to established dogma that PRL is central in mammary development, and GH mimics PRL in affecting growth because of structural similarities, we found that both hGH, which is lactogenic, and rGH, which is non-lactogenic, were significantly more potent than hPRL and rPRL in stimulating mammary growth in rats. Additionally, hGH was more potent than hPRL in increasing mammary IGF-I mRNA content. These data indicate that GH has separate effects on parameters of mammary gland growth, suggesting an independent role for GH in mammary growth.

Animals↗