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Biomedical subjects

J Moll

Publications and source records attributed to J Moll.

At least 37 records · Page 2Linked to original sources
PubMed1999

Genetic evaluation for length of productive life with censored records.

This study was conducted to investigate the impact of censoring on the accuracy of sire evaluation for the length of productive life estimated by means of survival analysis using simulated and real dairy cattle data from the Swiss Braunvieh population. Data were simulated under a Weibull model with two fixed effects and a random sire effect with a sire variance of 0.04. Two different family structures investigated were 1000 sires with 10 daughters each and 200 sires with 50 daughters each. Sires were assumed to be related through their sires. The reference data were generated assuming no censoring. Sire effects were estimated from the reference data with and without considering the relationships among sires and referred to as the estimated transmitting abilities (ETA) of sires. The impact of censoring on accuracy of ETA and ranking of sires was investigated by computing rank correlations among true and estimated sire effects and among estimated sire effects from the reference data and from several different data files with increased proportion of censored records. Estimated transmitting abilities were generally more accurate with a large number of daughters. The rank correlations among the ETA of sires from the data with censored records and the ETA from the reference data decreased with an increased proportion of censored records. Considering relationships among sires resulted in higher rank correlations when the proportion of censored records was large. With 50 daughters per sire, accuracy of 70% can be achieved approximately 2 yr after first calving of the daughters with about 50% censored records. With the real data, a rank correlation with the ETA of sires from the reference data of 0.70 to 0.80 can be achieved with about 65% of records censored and about 2.5 yr after the first calving of the youngest daughters of the sires.

Animals↗
PubMed1999

Prenatal diagnosis of a fetal left atrial diverticulum.

Fetal echocardiography, performed on a 22-year-old woman at 31 weeks' gestation, revealed a diverticulum of the left atrium. The size of the diverticulum was similar to the size of the fetal heart in a four-chamber view. No evidence of congestive heart failure or changes in size of the diverticulum were observed on subsequent ultrasound examinations. The echocardiographic image suggested presence of a thrombus within the diverticulum. Echocardiography of the newborn confirmed the diagnosis, and surgical correction followed five days after the birth. Our approach to this problem is discussed here.

Adult↗
PubMed1998

Two different functions for CD44 proteins in human myelopoiesis.

CD44 is important during myelopoiesis, although the contributions of variant CD44 proteins are unclear. We show here that in human long-term bone marrow culture antibodies recognizing a CD44 NH2-terminal epitope (mab 25-32) or a CD44v6 epitope (mab VFF18) inhibit myelopoiesis. However, mab 25-32 but not mab VFF18 affects myeloid colony formation. These data suggest that an early precursor cell compartment is the target for the 25-32 antibody, whereas the mab VFF18 targets later stages in myelopoiesis. Since the bulk of hemopoietic precursor cells are negative for the v6 epitope and only a minor subset of myeloid cells express the v6 epitope, we have used several human myeloid progenitor cell lines to unravel the function of different CD44 proteins. These cell lines produce variant CD44 proteins, predominantly a new variant CD44v4-v10, when stimulated towards myeloid differentiation. Features that can be acquired by the expression of CD44v4-v10 are an increased hyaluronate (HA) and a de novo chondroitin sulphate A (CS-A) binding. Although, the expression of CD44v4-v10 per se is necessary for HA and CS-A binding, the protein backbone seems to require appropriate glycosylation. HA binding results in CD44-mediated cellular self-aggregation and adhesion to the stromal cell line MS-5. In summary, our data suggest that different CD44 proteins are important for at least two different steps in myelopoiesis.

Antibodies↗
PubMed1998

RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis.

RAP46 was first identified by its ability to bind the glucocorticoid receptor. It has since been reported to bind several cellular proteins, including the anti-apoptotic protein Bcl-2, but the biological significance of these interactions is unknown. Here we show that RAP46 binds the hinge region of the glucocorticoid receptor and inhibits DNA binding and transactivation by the receptor. We further show that overexpression of RAP46 in mouse thymoma S49.1 cells inhibits glucocorticoid-induced apoptosis. Conversely, glucocorticoid-induced apoptosis and transactivation were enhanced after treating S49.1 cells with the immunosuppressant rapamycin, which down-regulates cellular levels of BAG-1, the mouse homolog of RAP46. The effect of rapamycin can, however, be overcome by overexpression of RAP46. These results together identify RAP46 as a protein that controls glucocorticoid-induced apoptosis through its negative regulatory action on the transactivation property of the glucocorticoid receptor.

Animals↗
PubMed1998

A minigene of neural agrin encoding the laminin-binding and acetylcholine receptor-aggregating domains is sufficient to induce postsynaptic differentiation in muscle fibres.

The extracellular matrix molecule agrin is both necessary and sufficient for inducing the formation of postsynaptic specializations at the neuromuscular junction (NMJ). At the mature NMJ, agrin is stably incorporated in synaptic basal lamina. The postsynapse-inducing activity of chick agrin, as assayed by its capability of causing aggregation of acetylcholine receptors (AChRs) on cultured muscle cells, maps to a 21 kDa, C-terminal domain. Binding of chick agrin to muscle basal lamina is mediated by the laminins and maps to a 25 kDa, N-terminal fragment of agrin. Here we show that an expression construct encoding a 'mini'-agrin, in which the laminin-binding fragment was fused to the AChR-clustering domain, is sufficient to induce postsynaptic differentiation in vivo when injected into non-synaptic sites of rat soleus muscle. As shown for ectopic postsynaptic differentiation induced by full-length neural agrin, myonuclei underneath the ectopic sites expressed the gene for the AChR epsilon-subunit. Altogether, our data show that a 'mini'-agrin construct encoding only a small fraction of the entire agrin protein is sufficient to induce postsynapse-like structures that are reminiscent of those induced by full-length neural agrin or innervation by motor neurons.

Agrin↗
PubMed1998

Activation-dependent modulation of hyaluronate-receptor expression and of hyaluronate-avidity by human monocytes.

During inflammation, activated monocytes (Mo) migrate into tissues where they interact with extracellular matrix components such as hyaluronate (HA), produced in high amounts at inflammatory sites. We determined whether Mo that had invaded sites of cutaneous inflammation bind HA and express the putative HA receptors CD44 isoforms, ICAM-1, or receptor for hyaluronate-mediated motility (RHAMM). In cutaneous inflammation, activated infiltrating Mo displayed high HA avidity and expressed epitopes encoded by CD44s, CD44 variant exons v3, v4, v5, v6, v7, and v9, and ICAM-1, but not RHAMM. We further investigated how activation affects the avidity of Mo for HA and which receptors were responsible for such binding. Mo freshly purified from human peripheral blood bound little HA and expressed CD44s but no epitopes encoded by CD44v exons, ICAM-1, or RHAMM. During short-term tissue culture, Mo upregulated their HA avidity and expression of ICAM-1, CD44s, and epitopes encoded by CD44v, all of which were further augmented by IFN-gamma or lipopolysaccharide, whereas RHAMM was not detectable. Thus in vitro activated Mo resembled Mo that had migrated to inflammatory sites in vivo. Lipolysaccharide or IFN-gamma-induced HA binding was inhibited by more than 90% with monoclonal antibodies directed against N-terminal HA binding domains of CD44s, but not by monoclonal antibodies against CD44v epitopes or ICAM-1. In conclusion, we show that upon in vitro or in vivo activation, Mo enhance their capacity to bind HA. This is critically dependent upon the expression ofCD44s epitopes. Regulated CD44-HA interactions may be important for the ability of Mo to migrate into and within sites of inflammation and for Mo effector functions.

Humans↗
PubMed1998

Activation of left intraparietal sulcus using a fMRI conceptual praxis paradigm.

The present paper reports the results of a fMRI subtraction study of the pattern of cortical activation induced by an ideational praxis paradigm in six normal right-handed subjects. The control task consisted of a sequence of complex meaningless hand movements. A complete study was done for each hand in each subject. The left intraparietal sulcus was the only structure activated in all subjects regardless of the hand used in the task. These findings, albeit preliminary, suggest that the organization of actions involving the mediation of tools and utensils are strongly lateralized to the left hemisphere and that damage to the dominant intraparietal sulcus may be critical for the development of the clinical syndrome of conceptual apraxia.

Cerebral Cortex↗
PubMed1997

Variant exons v6 and v7 together expand the repertoire of glycosaminoglycans bound by CD44.

Isoforms of the glycoprotein CD44 are cell surface receptors for the glycosaminoglycan hyaluronate. They have been implicated in many biological processes, but their function in these is poorly understood and cannot be explained solely by hyaluronate binding. In the present work we examine the ligand binding properties of alternatively spliced CD44 variant isoforms which are functionally involved in the immune system, embryonic development, and tumor behavior. We show that these isoforms bind directly to the purified glycosaminoglycans chondroitin sulfate, heparin, and heparin sulfate, in addition to being able to bind to hyaluronate. Binding to this extended repertoire of glycosaminoglycans by CD44 depends on the inclusion of peptide sequences encoded by the alternatively spliced exons v6 and v7, and occurs both when the CD44 is solubilized from the plasma membrane and when it is expressed on intact cells. A single point mutation in the most N-terminal hyaluronate binding motif of CD44 ablates both hyaluronate and chondroitin sulfate binding, suggesting that glycosaminoglycans are bound through a common motif, and that only one of the hyaluronate binding motifs is responsible for the majority of glycosaminoglycan binding by CD44 on the cell surface. Taken together, these observations indicate that alternative splicing regulates the ligand binding specificity of CD44 and suggest that structural changes in the CD44 protein have a profound effect on the range of ligands to which this molecule can bind with potentially wide-ranging functional consequences.

Alternative Splicing↗
PubMed1997

Constitutive expression of a CD44 variant isoform on T cells facilitates regaining of immunocompetence in allogeneic bone marrow transplantation.

Constitutive expression of a rat CD44 variant isoform, rCD44v4-v7, on murine T cells accelerates immune responsiveness. Because prolonged immunodeficiency can be a major drawback in allogeneic bone marrow transplantation, we considered it of special interest to see whether repopulation of lethally irradiated syngeneic and allogeneic mice may be influenced by constitutive expression of the rCD44v4-v7 transgene. When lethally irradiated syngeneic and allogeneic mice were reconstituted with bone marrow cells (BMC) from rCD44v4-v7 transgenic (TG) or nontransgenic (NTG) mice, the former had a clear repopulation advantage: thymocytes expanded earlier after reconstitution and, as a consequence, higher numbers of lymphocytes were recovered from spleen and lymph nodes. Lymphocytes also displayed functional activity in advance to those from mice reconstituted with BMC from NTG mice. Most importantly, after the transfer of BMC from TG mice into an allogeneic host, the frequency of host-reactive T cells decreased rapidly. Apparently, this was due to accelerated induction of tolerance. Because these effects were counterregulated by an rCD44v6-specific antibody, it is likely that they could be attributed to the rCD44v4-v7 TG product. Thus, expression of a CD44 variant isoform at high levels facilitated reconstitution with allogeneic BMC by accelerated establishment of tolerance and the regaining of immunocompetence.

Animals↗
PubMed1997

C-myc overexpression facilitates radiation-induced DHFR gene amplification.

To investigate the role of myc-overexpression on radiation-induced amplification of the dihydrofolate reductase gene (DHFR) we compared diploid Chinese hamster ovary cells (CHO-9) to cells of the same line that had been stably transfected with a dexamethasone-inducible c-myc cDNA. The application of flow-cytofluorometry and fluorescent in situ hybridization (FISH) allowed the evaluation of an increase in DHFR gene copy number following radiation treatment without the use of a preceding selection procedure. We show that DHFR gene amplification may occur independently of p53 status in cells overexpressing c-myc.

Animals↗
PubMed1997

Analysis of productive life in Swiss brown cattle.

An analysis of productive life of Swiss Brown cattle was performed using a mixed survival model based on Cox regression. Data included 52,862 daughters of 297 sires. The length of productive life was observed from May 1, 1985 through August 15, 1995. Records on cows that were still alive in the end of study (32.4%) were treated as censored. The probability of being culled (hazard) was defined as a product of a baseline hazard function and a function of explanatory variables. In addition to sire effects, the model included effects of age at first calving and the time-dependent variables herd by year, lactation number, stage of lactation, and milk production within the herd to account for culling because of low production. Solutions for fixed effects indicated a higher probability of being culled for primiparous cows, for cows in the end stage of lactation, and for cows with low production. The impact of censoring on the accuracy of estimation was investigated by computing the rank correlations between the estimated transmitting abilities (ETA) of sires using a simplified model from uncensored data (reference) and the ETA from several different data files with an increased proportion of censored records. The rank correlations among sire ETA decreased as number of daughters per sire decreased and as the proportion of censored records increased. The maximum number of censored records that is acceptable to obtain accurate results is 30 to 40%. The acceptable proportion of censored records would be higher if the reference ETA were obtained on a larger data file using daughters of old sires.

Animals↗
PubMed1996

Trans-acting factors regulate the expression of CD44 splice variants.

Variant isoforms of the cell surface glycoprotein CD44 (CD44v) are expressed during development, in selected adult tissues and in certain metastatic tumor cells. CD44v differ from the standard isoform (CD44s) by up to ten additional exon sequences included by alternative splicing. By cell fusion experiments, we have obtained evidence for the existence of cell-type specific trans-acting factors recruiting CD44 variant exon sequences. Stable cell hybrids of CD44s and CD44v expressing cells indicated a dominant mechanism for variant-exon inclusion. In transient interspecies heterokaryons of human keratinocytes and rat fibroblasts, the ability of the keratinocytes to include all variant exon sequences in CD44 was conferred completely on the rat fibroblast nucleus. Fusions of cells with complex CD44 splice patterns do not permit interpretation of splice control by the relative abundance of a single trans-acting factor, but rather by (a) positively acting factor(s) recruiting variant exon sequences in the 3' to 5' direction and additional factors selecting individual exons. Since the pancreatic carcinoma cell line BSp73ASML (in contrast to the cervix carcinoma cell lines SiHa and ME180) could not transfer its specific splice pattern in cell fusions, we conclude that in some tumors, splicing is also controlled by mutation of cis-acting recognition sites.

Alternative Splicing↗
PubMed1996

Increasing incidence of CD44v7/8 epitope expression during uterine cervical carcinogenesis.

Splice variants of the cell surface glycoprotein CD44 (CD44v) have been implicated in the progression of various human tumors. In the present study, we have examined the expression pattern of a CD44v epitope encoded by the adjacent variant exons v7 and v8 during human cervical carcinogenesis. While only l/ll normal cervical squamous epithelia was positive for this epitope by immunohistochemistry, 4/21 samples of low-grade squamous intra-epithelial lesions (LSIL), 17/35 samples of high-grade squamous intra-epithelial lesions (HSIL), 11/12 samples of the HSIL subgroup of carcinomas in situ and 17/17 cases of invasive cervical carcinoma showed CD44v7/8 epitope expression. In addition to CD44 variant expression, we have analyzed 67 lesions for the presence of HPV16/18-DNA using PCR. Most of the samples expressing the v7/8 epitope were also HPV16-positive (29/32), whereas only 17/35 of the v7/8-negative samples were HPV16-positive. HPV18 DNA was found in only one invasive carcinoma. Our data suggests that high-risk HPV infection may precede CD44v7/8 expression and that the number of samples expressing the CD44v7/8 epitope increases during carcinogenesis and reaches nearly 100% at the carcinoma in situ stage. This CD44 epitope could, therefore, serve as a diagnostic marker of cervical squamous cell carcinomas and as a possible target for CD44v7/8 epitope-directed therapies.

Alternative Splicing↗
PubMed1996

Accelerated immune response in transgenic mice expressing rat CD44v4-v7 on T cells.

Splice variants of the glycoprotein CD44 (CD44v) that confer metastatic behavior to noninvasively growing rat tumor cells are transiently expressed on lymphocytes during activation. A mAb directed against an epitope encoded by CD44 exon v6 blocks both metastasis formations and lymphocyte activation, implicating CD44v in normal immune function. To explore the nature of this function of CD44v, transgenic mice were generated that constitutively express rat CD44v4-v7 on thymocytes and peripheral T cells. The number of lymphocytes as well as the distribution of lymphocyte subpopulations were similar in nontransgenic and rat CD44v4-v7 transgenic mice. T cells of the transgenic mice, however, responded faster to activating stimuli, particularly during primary stimulations with T cell mitogens and T-dependent Ags in vivo and in vitro. This accelerated response depended on the expression of the transgene product, since a rat CD44v6-specific Ab reverted the response profiles of the transgenic mice to those of nontransgenic mice. Since the transgene gained in vivo and in vitro functional activity only upon antigenic stimulation, it is likely that CD44 variant isoforms are involved in the process of signal transduction during lymphocyte activation.

Animals↗
PubMed1996

The pattern of prothymosin alpha gene expression coincides with that of myc proto-oncogenes during mouse embryogenesis.

The nuclear protein prothymosin alpha is thought to play a critical role in cellular proliferation. Transcription of the gene encoding prothymosin alpha has been shown to be activated by the proto-oncogene c-myc. Also, prothymosin alpha mRNA expression correlates with that of c-myc in human colon cancer. We compared the previously reported embryonic expression pattern of the proto-oncogene c-myc and the pattern of the prothymosin alpha gene by in situ hybridization. Prothymosin alpha is transcribed in all tissues expressing c-myc, including brown adipose tissue, salivary gland, thymus and liver. In addition, we show that the prothymosin alpha gene is active in tissues expressing specifically N-myc such as the neuronal anlage and hair follicles in skin. Therefore, during mouse foetal development the temporal, spatial and tissue-specific expression patterns of both myc proto-oncogenes coincide with the pattern of prothymosin alpha.

Adipose Tissue, Brown↗
PubMed1996

Regulated clustering of variant CD44 proteins increases their hyaluronate binding capacity.

Cell contact with the extracellular matrix component hyaluronic acid (HA) plays an important role in many developmental, physiological, and pathological processes, although the regulation of this contact is poorly understood. CD44 proteins carry an amino acid motif that mediates affinity to HA. Artificial clustering of the smallest 85-kD isoform of CD44 (CD44s) has previously been shown to promote binding of the protein to soluble HA (Lesley, J., R. Hyman, and P.W. Kincade. 1993. Adv. Immunol. 54:271-335; Persche, A., J. Lesley, N. English, I. Trowbridge, and R. Hyman. 1995. Eur. J. Immunol. 25:495-501). Here we show that in rat pancreatic carcinoma cells, splice variants of CD44 (CD44v), but not CD44s, form molecular aggregates in the plasma membrane. We demonstrate that reduction-sensitive dimerization of CD44v occurs, and also that larger aggregations of the protein can be stabilized by chemical cross-linking. Different CD44v proteins present on the same cell exclusively form homoaggregates. Molecular clustering does not require an intact cytoplasmic domain of the protein. The ability of cells to bind to soluble HA is upregulated more than one magnitude by the ectopic expression of CD44v4-v7, but only when the CD44v4-v7 protein forms intermolecular aggregates. Tunicamycin treatment inhibits HA binding by CD44v and at the same time destroys oligomerization. We propose that the regulation of clustering of CD44, mediated by factors including the presence of variant exons and glycosylation, allows cells in turn to regulate their HA binding properties.

Alternative Splicing↗