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M van den Heuvel

Publications and source records attributed to M van den Heuvel.

At least 19 recordsLinked to original sources
PubMed2006

Mechanisms regulating immune cell contributions to spiral artery modification -- facts and hypotheses -- a review.

Early during murine, human and porcine pregnancy, endometrium associated with developing placentae is enriched for uterine Natural Killer (uNK) cells. A shared role for uNK cells in each of these species is production of angiogenic growth factors. Many uNK cells are located in close proximity to or structurally integrated within the walls of endometrial vessels. In mice, uNK cells have been found essential for the initiation of pregnancy-associated spiral arterial modification through their production of interferon-gamma. Unique aspects of uNK cell interactions with decidual endothelium are being defined using cell and tissue transfer into pregnant, alymphoid mice, adhesion of viable lymphocytes to frozen uterine tissue sections under shear forces, laser capture microdissection of uNK cells for quantitative RNA analyses and intravital microscopy. These studies indicate that uterine lymphocytes have a fundamental and major importance in promotion of angiogenesis within implantation sites that is regulated by the reproductive hormone cycle. Further, this work suggests that the pro-inflammatory endometrial cytokine response seen when peri-implantation conceptuses arrest has, as its target for destruction, newly developed endometrial vasculature rather than fetal trophoblast.

Animals↗
PubMed2005

Using 15N to determine a budget for effluent-derived nitrogen applied to forest.

Using stable N isotopes, the fate of effluent-derived N has been determined within a land based municipal effluent irrigation scheme. Over 900 metric tonnes(t) of effluent-derived N have been applied to 192 ha of production conifer forest near Rotorua (NZ) over the past 11 years. The effluent N has a natural isotopic signal, generated by the treatment process, allowing it to be traced into various components of the system. Using this isotopic signal, a realistic approximation of storage capacity of various components of the system has been generated, including a calculation of the contribution of effluent N exiting the catchment via stream flow. Forest storage accounts for 50% of the applied N with a considerable proportion of that immobilized in wood and soil. The wetland, although not intensively sampled, retains 115 t, (13%) of the applied N. Denitrification, including that occurring within the wetland, accounts for 23 t (3%). Nitrogen isotope data confirm that the rise in NO3 concentrations is directly attributable to effluent N. Currently 88% of NO3-N in the stream is effluent-derived. Using current N isotope values for the stream and extrapolating over the discharge period, export of effluent N via the stream is estimated as 263 t (29%) of the applied N. Overall the forest and wetland ecosystem has intercepted or denitrified 65% of applied N, with 29% lost to the stream, and 50 t (5%) unaccounted for. The forest ecosystem is currently over-supplied with N and a number of management implications flows from these findings. In the long term the continued application of effluent N to the current irrigation area is not sustainable.

Biomass↗
PubMed2003

Stromal cell-derived receptor 2 and cytochrome b561 are functional ferric reductases.

Iron has a variety of functions in cellular organisms ranging from electron transport and DNA synthesis to adenosine triphosphate (ATP) and neurotransmitter synthesis. Failure to regulate the homeostasis of iron can lead to cognition and demyelination disorders when iron levels are deficient, and to neurodegenerative disorders when iron is in excess. In this study we show that three members of the b561 family of predicted ferric reductases, namely mouse cytochrome b561 and mouse and fly stromal cell-derived receptor 2 (SDR2), have ferric reductase activity. Given that a fourth member, duodenal cytochrome b (Dcytb), has previously been shown to be a ferric reductase, it is likely that all remaining members of this family also exhibit this activity. Furthermore, we show that the rat sdr2 message is predominantly expressed in the liver and kidney, with low expression in the duodenum. In hypotransferrinaemic (hpx) mice, sdr2 expression in the liver and kidney is reduced, suggesting that it may be regulated by iron. Moreover, we demonstrate the presence of mouse sdr2 in the choroid plexus and in the ependymal cells lining the four ventricles, through in situ hybridization analysis.

Animals↗
PubMed2003

Adaptation of a sandwich enzyme-linked immunosorbent assay to determine the concentration of bovine leukemia virus p24 and optimal conditions for p24 expression in short-term cultures of peripheral blood mononuclear cells.

Bovine leukemia virus (BLV) is a common retroviral infection of cattle. Infection is accompanied by integration of BLV into the host cell genome and is persistent for the life of the individual as is the presence of anti-BLV antibodies. Lymphosarcoma occurs in a small fraction of infected adult individuals but otherwise there is little or no associated disease. Viremia is undetectable, however, BLV is expressed readily once infected cells are cultured in vitro. A sandwich enzyme-linked immunosorbent assay (sELISA) was optimized, using murine monoclonal antibodies, to quantify the major internal structural protein (p24) produced in short-term cultures of peripheral blood mononuclear cells (PBMCs). Optimal production of BLV p24 was achieved utilizing RPMI supplemented with 10% fetal bovine serum (FBS), pH 7, and 5 x 10(6) cells per ml. Cultures were terminated at 24 h. The sELISA was linear between 30 and 900 ng/ml and the limit of detection was 1.2 ng/ml. At three concentrations of p24, intra- and inter-assay coefficients of variation (CV) varied between 9.2 and 13.3 and 5.1 and 12.9%, respectively.

Animals↗
PubMed2002

[Acute hepatitis after use of a herbal preparation with greater celandine (Chelidonium majus)].

A 42-year-old woman developed jaundice due to acute hepatitis several weeks after ingestion of a herbal preparation containing greater celandine (Chelidonium majus) and curcuma root, which had been prescribed by an alternative therapist due to a skin complaint. After the medication had been withdrawn, clinical recovery was rapid and the hepatic functions returned to normal within 2 months. The hepatitis was ascribed to the known hepatotoxic effects of C. majus. In view of the increasing popularity of herbal remedies, greater awareness of side effects, such as hepatotoxicity, is needed. Quite a number of herbal preparations carry the risk of liver damage. The supposed clinical effectiveness of herbal remedies does not seem to always outweigh the potential risks. In the event of non-clarified liver function disturbances the ingestion of supposedly harmless, but potentially hepatotoxic, herbal products should be considered.

Acute Disease↗
PubMed2001

Straight or split: signals to transcription.

Since the discovery of substance in serum media that are able to drive cells into proliferation and/or differentiation, investigators have tried to understand how such signalling molecules can influence cells to change their behaviour. The complex nature of the responses to signals, and the equally complex signalling pathway leading to those responses, have made life difficult for the researcher. However, recent evidence obtained in genetic developmental systems indicates that a multiplicity of downstream events can be accomplished by regulation of the activity of just one transcription factor.

Animals↗
PubMed2000

Disruption of SMN function by ectopic expression of the human SMN gene in Drosophila.

Spinal muscular atrophy is a neurodegenerative disorder caused by mutations or deletions in the survival motor neuron (SMN) gene. We have cloned the Drosophila ortholog of SMN (DmSMN) and disrupted its function by ectopically expressing human SMN. This leads to pupal lethality caused by a dominant-negative effect, whereby human SMN may bind endogenous DmSMN resulting in non-functional DmSMN/human SMN hetero-complexes. Ectopic expression of truncated versions of DmSMN and yeast two-hybrid analysis show that the C-terminus of SMN is necessary and sufficient to replicate this effect. We have therefore generated a system which can be utilized to carry out suppressor and high-throughput screens, and provided in vivo evidence for the importance of SMN oligomerization for SMN function at the level of an organism as a whole.

Amino Acid Sequence↗
PubMed2000

Patched represses the Hedgehog signalling pathway by promoting modification of the Smoothened protein.

Hedgehog (Hh) signalling plays a central role in many developmental processes in both vertebrates and invertebrates [1]. The multipass membrane-spanning proteins Patched (Ptc) [2-4] and Smoothened (Smo) [5-7] have been proposed to act as subunits of a putative Hh receptor complex. According to this view, Smo functions as the transducing subunit, the activity of which is blocked by a direct interaction with the ligand-binding subunit, Ptc [8]. Activation of the intracellular signalling pathway occurs when Hh binds to Ptc [8-11], an event assumed to release Smo from Ptc-mediated inhibition. Evidence for a physical interaction between Smo and Ptc is so far limited to studies of the vertebrate versions of these proteins when overexpressed in tissue culture systems [8,12]. To test this model, we have overexpressed the Drosophila Smo protein in vivo and found that increasing the levels of Smo protein per se was not sufficient for activation of the pathway. Immunohistochemical staining of wild-type and transgenic embryos revealed distinct patterns of Smo distribution, depending on which region of the protein was detected by the antibody. Our findings suggest that Smo is modified to yield a non-functional form and this modification is promoted by Ptc in a non-stoichiometric manner.

Animals↗
PubMed2000

A directed mutagenesis screen in Drosophila melanogaster reveals new mutants that influence hedgehog signaling.

The Hedgehog signaling pathway has been recognized as essential for patterning processes in development of metazoan animal species. The signaling pathway is, however, not entirely understood. To start to address this problem, we set out to isolate new mutations that influence Hedgehog signaling. We performed a mutagenesis screen for mutations that dominantly suppress Hedgehog overexpression phenotypes in the Drosophila melanogaster wing. We isolated four mutations that influence Hedgehog signaling. These were analyzed in the amenable wing system using genetic and molecular techniques. One of these four mutations affects the stability of the Hedgehog expression domain boundary, also known as the organizer in the developing wing. Another mutation affects a possible Hedgehog autoregulation mechanism, which stabilizes the same boundary.

Animals↗
PubMed2000

Cellular immune response to human cartilage glycoprotein-39 (HC gp-39)-derived peptides in rheumatoid arthritis and other inflammatory conditions.

OBJECTIVE: To study the specificity of the peripheral blood mononuclear cell (PBMC) response to peptides derived from human cartilage glycoprotein-39 (HC gp-39) in patients with rheumatoid arthritis (RA) and the correlation between this response and disease activity. METHODS: RA patients, patients with systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) or osteoarthritis (OA) and healthy controls were studied. All individuals were typed for HLA-DRB1 and their disease activity score was documented. Proliferation of PBMC was measured following incubation with five different HC gp-39-derived peptides, selected by the use of a DR4 (DRB1*0401) binding motif. RESULTS: A proliferative response to one of the five peptides (peptide 259-271 at 10 microg/ml) was more often observed in RA patients than in healthy controls (P=0.001). RA patients who expressed DRB1*0401 more often showed a response against this peptide than RA patients who did not express this RA-associated haplotype. This response was not RA-specific since patients with IBD or OA also showed a response significantly more frequently than healthy controls (P:=0.02 and P=0.03 respectively). However, the level of the response against peptide 259-271 correlated with disease activity in RA patients but not in patients with IBD or SLE. Increased responses to HC gp-39 263-275 were found in patients with IBD or OA; a trend towards such a response failed to reach significance in RA patients in this study. CONCLUSION: In RA patients as well as in patients with other inflammatory conditions, HC gp-39-derived peptides may be targets of the T-cell-mediated immune response. In the RA patient group the immune response to HC gp-39-derived peptide 259-271 correlated with disease activity.

Adipokines↗
PubMed1999

Differential requirements of the fused kinase for hedgehog signalling in the Drosophila embryo.

The two signalling proteins, Wingless and Hedgehog, play fundamental roles in patterning cells within each metamere of the Drosophila embryo. Within the ventral ectoderm, Hedgehog signals both to the anterior and posterior directions: anterior flanking cells express the wingless and patched Hedgehog target genes whereas posterior flanking cells express only patched. Furthermore, Hedgehog acts as a morphogen to pattern the dorsal cuticle, on the posterior side of cells where it is produced. Thus responsive embryonic cells appear to react according to their position relative to the Hedgehog source. The molecular basis of these differences is still largely unknown. In this paper we show that one component of the Hedgehog pathway, the Fused kinase accumulates preferentially in cells that could respond to Hedgehog but that Fused concentration is not a limiting step in the Hedgehog signalling. We present direct evidence that Fused is required autonomously in anterior cells neighbouring Hedgehog in order to maintain patched and wingless expression while Wingless is in turn maintaining engrailed and hedgehog expression. By expressing different components of the Hedgehog pathway only in anterior, wingless-expressing cells we could show that the Hedgehog signalling components Smoothened and Cubitus interruptus are required in cells posterior to Hedgehog domain to maintain patched expression whereas Fused is not necessary in these cells. This result suggests that Hedgehog responsive ventral cells in embryos can be divided into two distinct types depending on their requirement for Fused activity. In addition, we show that the morphogen Hedgehog can pattern the dorsal cuticle independently of Fused. In order to account for these differences in Fused requirements, we propose the existence of position-specific modulators of the Hedgehog response.

Animals↗
PubMed1999

The Drosophila GMII gene encodes a Golgi alpha-mannosidase II.

In this paper we show the organisation of the Drosophila gene encoding a Golgi alpha-mannosidase II. We demonstrate that it encodes a functional homologue of the mouse Golgi alpha-mannosidase II. The Drosophila and mouse cDNA sequences translate into amino acid sequences which show 41% identity and 61% similarity. Expression of the Drosophila GMII sequence in CHOP cells produces an enzyme which has mannosidase activity and is inhibited by swainsonine and by CuSO(4.) In cultured Drosophila cells and in Drosophila embryos, antibodies raised against a C-terminal peptide localise this product mainly to the Golgi apparatus as identified by cryo-immuno electron microscopy studies and by antibodies raised against known mammalian Golgi proteins. We discuss these results in terms of the possible use of dGMII as a Drosophila Golgi marker.

Adaptor Protein Complex alpha Subunits↗
PubMed1997

Characterization of the cells that migrate from metrial glands of the pregnant mouse uterus during explant culture.

Granulated metrial gland (GMG) cells are estrogen-receptor and Interleukin 2 (IL-2) receptor positive lymphocytes of the Natural Killer cell lineage found in the murine uterus during pregnancy. Functional studies of these cells, which are now more frequently called uterine NK (uNK) cells, have been limited due to technical difficulties. The cells are difficult to isolate and their proliferation and differentiation have not been achieved in culture. In 1988, Mukhtar and Stewart (Cell Tiss. Res., 253, 413-417) reported a method for explant culture of metrial glands isolated from pregnant rodents that yielded an almost pure population of uNK cells. This major technical advance has supported most of the subsequent functional and molecular studies of rodent uNK cells. However, the quality of the cells isolated by the explant culture procedure has not been established. A cytochemical approach was used to identify and quantify the cells migrating from metrial glands. At midpregnancy, almost all (> 90%) migrating nucleated cells were NK cells. Earlier in gestation, a significant proportion (25%) of cells having lymphoid morphology could not be assigned to the lineage. The viability of cells migrating from explants was assessed by DNA isolation and electrophoresis on days 6-16 of gestation. At all times evidence for apoptosis was found, even after culture intervals as brief as 4 h. Parallel analyses of histological sections of the metrial gland, using terminal deoxytransferase labelling to detect nuclear fragmentation, did not support significant levels of uNK cell death in situ prior to day 12 of gestation. Supplementation of the explant culture medium with estrogen, IL-2, various extracellular matrices, decidual cells or combinations of these did not lead to in vitro proliferation of uNK cells and usually did not extend the short term viability of these cells in serum supplemented or serum free media. Thus, the optimal culture conditions for uNK cells remain undefined.

Animals↗
PubMed1997

Uterine natural killer cells do not require interleukin-2 for their differentiation or maturation.

PROBLEM: Natural Killer lymphocytes (NK cells) from the pregnant uterus and from other tissues in pregnant and nonpregnant mammals can be stimulated by interleukin-2 (IL-2) during culture to become Lymphokine Activated Killer (LAK) cells. The susceptibility of cultured trophoblast cells to lysis by LAK cells raises the enigma of why uterine (u) NK cells that are characterized by morphology and by surface phenotyping as "activated," and thus potentially damaging to the placenta, become localized to implantation sites during normal rodent gestation. METHOD: uNK cells migrating from explant cultures of the metrial gland were assessed for expression (mRNA and protein) of each chain of the IL-2 receptor (IL-2R). Implantation sites from transgenic mice lacking a functional IL-2 gene were examined histologically for the differentiation of mature, granulated uNK cells. RESULTS AND CONCLUSION: Early post-implantation, mRNA from migrating uNK cells contains transcripts for all three chains of the IL-2R. Only IL-2Rgamma was expressed at day 12 of gestation; expression of this gene was also lost by day 16. Loss of IL-2R transcription did not result in loss of protein expression; however, it did coincide with loss of uNK cell viability in vivo. Apparently normal differentiation of uNK cells occurred in IL-2(-/-) mice and in doubly mutant IL-2(-/-).beta2m(-/-) mice. Thus, despite uNK cell expression of the full IL-2R at day 8 of gestation, IL-2 is not required for the maturation of uNK cells to their fully granulated form or for normal placental development.

Animals↗
PubMed1996

smoothened encodes a receptor-like serpentine protein required for hedgehog signalling.

Members of the Hedgehog family of secreted proteins control a number of important inductive interactions in the development of both vertebrates and Drosophila, but little is known about the ways in which their signalling activities are transduced. In Drosophila, hedgehog is one of the segment-polarity genes, mutations of which disrupt the pattern and polarity of individual embryonic segments and their adult derivatives; several of these genes have been implicated in transduction of the hedgehog signal. Here we show that the segment-polarity gene smoothened is required for the response of cells to hedgehog signalling during the development of both the embryonic segments and imaginal discs. Sequence analysis of the smoothened transcription unit reveals a single open reading frame encoding a protein with seven putative transmembrane domains. This structure is typical of G-protein-coupled receptors, suggesting that the Smoothened protein may act as a receptor for the Hedgehog ligand.

Alleles↗
PubMed1996

An analysis of the uterine lymphocyte-derived hybridoma cell line GWM 1-2 for expression of receptors for estrogen, progesterone and interleukin 2.

Characterisation of murine hybridoma cell lines derived from the fusion of lymphocytes migrating from explant cultures of early, pregnancy-associated metrial glands (days 6-8 of gestation) to SP 2/0 cells, has been extended (van den Heuvel et al., J. Reprod. Immunol., 27 (1994) 13-36). These hybridomas have been grown in culture for over 2 years and are thought to represent the only immortalized lines of murine pregnancy-associated, uterine natural killer (uNK) cells. Previous studies had shown that these hybridomas, known as GWM cells, lack uNK cell surface markers, but share with uNK cells the expression of the lytic protein perforin and the ability to lyse YAC cells, a natural killer cell target (van den Heuvel et al., J. Reprod. Immunol., 27 (1994) 13-36). We report here, the evaluation of the transcription and expression of genes encoding the estrogen receptor (ER), the progesterone receptor (PR) and the interleukin 2 receptor complex (IL 2R alpha, beta and gamma) by uNK cells at day 8 of gestation and by GWM 1-2 cells and SP 2/0 cells. Our investigations indicate that expression of these genes divides day 8 uNK cells into subsets, with the predominant population being ER+, PR-, IL 2R alpha +, IL 2R beta + and IL 2R gamma +. Like day 8 uNK cells, most GWM 1-2 cells expressed all three chains of the IL 2R complex. In addition, GWM 1-2 cells expressed the ER but the PR was not detected on this cell line. Only the IL 2R alpha was detected on the SP 2/0 myeloma cell line. These studies further validate the use of GWM hybridomas as models for pregnancy-associated uNK cells.

Animals↗
PubMed1996

'Smoothening' the path for hedgehogs.

Studies of the HEDGEHOG signalling pathway in Drosophila have revealed a functional link between two genes, cubitus interruptus and patched, whose human homologues are, respectively, a proto-oncogene and a tumour suppressor. While the former has been implicated as a transcription factor, controversy has surrounded the function of the transmembrane protein encoded by the latter. Somewhere in the signal-transduction pathway between these two lies protein kinase A (PKA), and now SMOOTHENED, whose similarity to G-protein-coupled receptors suggests a link with PKA, has also been implicated in the pathway. This article summarizes the current understanding of the pathway and the interactions between these proteins.

Journal Article↗