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At least 487 records · Page 27Linked to original sources
PubMed1990

The relationship of intercondylar notch size and content to notchplasty requirement in anterior cruciate ligament surgery.

A stenotic intercondylar notch is an indication for a notchplasty at the time of ACL reconstructive surgery. However, the absence of a stenotic notch does not ensure that impingement of the ligament upon the intercondylar notch will not occur. An excessively large ligament, even in the presence of a normal intercondylar notch, will result in abrasion of the ligament on the notch. This can result in the premature failure of the reconstructed ACL. Therefore, both the notch size and notch content are important determinants in assessing whether a notchplasty is required as part of the ACL reconstructive procedure.

Adolescent↗
PubMed2005

Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.

The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21(WAF1/Cip1) gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-Jkappa protein to the p21 promoter. We show here that Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control.

Alopecia↗
PubMed1999

Human ligands of the Notch receptor.

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.

Amino Acid Sequence↗
PubMed2002

Expression of Notch genes and their ligands during gastrulation in the chicken embryo.

Notch signalling is an important evolutionary conserved mechanism known to control cell fate choices through local interactions. Here, the patterns of expression of Notch-1 and -2 genes and their ligands Delta-1, Serrate-1 and -2, were established in the early blastodisc of the chicken embryo from the pre-streak to the first somite stages. Delta-1 was detected as early as the pre-streak stage in the posterior part of the embryo shortly followed in the same region by Notch-1 at the initial streak stage. Thereafter both were strongly expressed in the posterior part of the primitive streak until HH4. Notch-2 was also found at the level of the streak although at low levels. Notch-1 was homogeneously expressed by the epiblast and by mesodermal cells ingressing at the level of the streak whereas Delta-1 expression formed a 'salt and pepper' pattern. The difference between the two was clearly detected by double in situ hybridisation. From the mid-streak to the first somite stages, Notch-1 and Delta-1 expressions appeared in the anterior part of the embryo. Serrate-1 and -2 were not detected at these stages. Taken together, these results constitute a framework for analysing the role(s) for Notch signalling during gastrulation.

Animals↗
PubMed1998

The Notch signalling pathway in hair growth.

The Notch signalling pathway is an important mediator of cell fate selection whose involvement in epidermal appendage formation is now becoming recognised. Hair follicle development and hair formation involve the co-ordinated differentiation of several different cell types in which Notch appears to have a role. We report intricate expression patterns for the Notch-1 receptor and three ligands, Delta-1, Jagged-1 and Jagged-2 in the hair follicle. Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1 is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode. Expression of Jagged-1 or Jagged-2 overlaps Notch-1 expression at all stages. In mature follicles, Jagged-1 and Jagged-2 are expressed in complementary patterns in the follicle bulb and outer root sheath, Jagged-1 in suprabasal cells and Jagged-2 predominantly in basal cells. In the follicle bulb, Jagged-2 is localised to the inner (basal) bulb cells next to the dermal papilla which do not express Notch-1, whereas Jagged-1 expression in the upper follicle bulb overlaps Notch-1 expression and correlates with bulb cell differentiation into hair shaft cortical and cuticle keratinocytes.

Animals↗
PubMed2004

Notch 1 signaling regulates peripheral T cell activation.

Notch signaling has been identified as an important regulator of leukocyte differentiation and thymic maturation. Less is known about the role of Notch signaling in regulating mature T cells. We examined the role of Notch 1 in regulating peripheral T cell activity in vitro and in vivo. Coligation of Notch 1 together with TCR and CD28 resulted in a dramatic inhibition of T cell activation, proliferation, and cytokine production. This effect was dependent on presenilin activity and induced the expression of HES-1, suggestive of Notch 1 signaling. Biochemical analysis demonstrated an inhibition of AKT and GSK3beta phosphorylation following Notch 1 engagement while other biochemical signals such as TCR and ERK phosphorylation remained intact. Similar effects were observed in vivo in an adoptive transfer model. Therefore, Notch 1 signaling may play an important role in regulating naive T cell activation and homeostasis.

Adoptive Transfer↗
PubMed1997

Detection of dicrotic notch in arterial pressure signals.

OBJECTIVE: A novel algorithm to detect the dicrotic notch in arterial pressure signals is proposed. Its performance is evaluated using both aortic and radial artery pressure signals, and its robustness to variations in design parameters is investigated. METHODS: Most previously published dicrotic notch detection algorithms scan the arterial pressure waveform for the characteristic pressure change that is associated with the dicrotic notch. Aortic valves, however, are closed by the backwards motion of aortic blood volume. We developed an algorithm that uses arterial flow to detect the dicrotic notch in arterial pressure waveforms. Arterial flow is calculated from arterial pressure using simulation results with a three-element windkessel model. Aortic valve closure is detected after the systolic upstroke and at the minimum of the first negative dip in the calculated flow signal. RESULTS: In 7 dogs ejection times were derived from a calculated aortic flow signal and from simultaneously measured aortic flow probe data. A total of 86 beats was analyzed; the difference in ejection times was -0.6 +/- 5.4 ms (means +/- SD). The algorithm was further evaluated using 6 second epochs of radial artery pressure data measured in 50 patients. Model simulations were carried out using both a linear windkessel model and a pressure and age dependent nonlinear windkessel model. Visual inspection by an experienced clinician confirmed that the algorithm correctly identified the dicrotic notch in 98% (49 of 50) of the patients using the linear model, and 96% (48 of 50) of the patients using the nonlinear model. The position of the dicrotic notch appeared to be less sensitive to variations in algorithm's design parameters when a nonlinear windkessel model was used. CONCLUSIONS: The detection of the dicrotic notch in arterial pressure signals is facilitated by first calculating the arterial flow waveform from arterial pressure and a model of arterial afterload. The method is robust and reduces the problem of detecting a dubious point in a decreasing pressure signal to the detection of a well-defined minimum in a derived signal.

Algorithms↗
PubMed1998

Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.

Notch proteins are ligand-activated transmembrane receptors involved in cell-fate selection throughout development. No known enzymatic activity is contained within Notch and the molecular mechanism by which it transduces signals across the cell membrane is poorly understood. In many instances, Notch activation results in transcriptional changes in the nucleus through an association with members of the CSL family of DNA-binding proteins (where CSL stands for CBF1, Su(H), Lag-1). As Notch is located in the plasma membrane and CSL is a nuclear protein, two models have been proposed to explain how they interact. The first suggests that the two interact transiently at the membrane. The second postulates that Notch is cleaved by a protease, enabling the cleaved fragment to enter the nucleus. Here we show that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL. Very small amounts of NICD are active, explaining why it is hard to detect in the nucleus in vivo. We also show that it is ligand binding that induces release of NICD.

3T3 Cells↗
PubMed2005

DNER acts as a neuron-specific Notch ligand during Bergmann glial development.

Differentiation of CNS glia is regulated by Notch signaling through neuron-glia interaction. Here, we identified Delta/Notch-like EGF-related receptor (DNER), a neuron-specific transmembrane protein, as a previously unknown ligand of Notch during cellular morphogenesis of Bergmann glia in the mouse cerebellum. DNER binds to Notch1 at cell-cell contacts and activates Notch signaling in vitro. In the developing cerebellum, DNER is highly expressed in Purkinje cell dendrites, which are tightly associated with radial fibers of Bergmann glia expressing Notch. DNER specifically binds to Bergmann glia in culture and induces process extension by activating gamma-secretase- and Deltex-dependent Notch signaling. Inhibition of Deltex-dependent, but not RBP-J-dependent, Notch signaling in Bergmann glia suppresses formation and maturation of radial fibers in organotypic slice cultures. Additionally, deficiency of DNER retards the formation of radial fibers and results in abnormal arrangement of Bergmann glia. Thus, DNER mediates neuron-glia interaction and promotes morphological differentiation of Bergmann glia through Deltex-dependent Notch signaling.

Amyloid Precursor Protein Secretases↗
PubMed2002

A novel cell line derived from de novo acute myeloblastic leukaemia with trilineage myelodysplasia which proliferates in response to a Notch ligand, Delta-1 protein.

A novel human leukaemia cell line, designated TMD7, was established from blast cells of a patient with de novo acute myeloblastic leukaemia with trilineage myelodysplasia (AML/TLD). As seen in the original blast cells, TMD7 cells expressed CD7, CD13, CD33 and CD34 and showed an abnormal karyotype containing -5, -7, -8, der(16)t(10;16)(q22;q13). The cells proliferated without added growth factors. Growth was stimulated with the addition of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) and interleukin 3. Differentiation was not observed with the addition of various cytokines. As a cell line derived from AML/TLD has not been reported, TMD7 will be a useful tool as a model of AML/TLD cells. Recently, it was reported that the Notch system has crucial roles to regulate the self-renewal and differentiation of haematopoietic stem cells. We found that TMD7 cells expressed Notch-1 and Notch-2 mRNA. The exposure to recombinant Delta-1 protein, which was one of the Notch ligands, significantly stimulated the growth of TMD7 cells. This is the first human cell line which was shown to proliferate in response to Delta-1, without artificially expressed Notch protein. Therefore, TMD7 will also be a useful tool to study the mechanism of the Notch-Notch ligand interaction.

Calcium-Binding Proteins↗
PubMed2003

Could the presence of a Carhart notch predict the presence of glue at myringotomy?

The Carhart notch is a dip in the bone conduction at 2000 Hz without a corresponding dip in the air conduction. The main objective of this study was to establish how reliable is the presence of the Carhart notch in a preoperative audiogram in predicting the presence of glue at myringotomy. A prospective study has been carried out in 50 children presenting with glue ear to find out the association between the Carhart notch and the presence of glue at myringotomy. Children were seen before the operation and an audiogram and tympanogram were carried out. Myringotomy was carried out in 95 ears and the presence or absence of glue was recorded. The significance of the air-bone gap and the type of tympanogram in predicting a middle ear effusion were also examined. The audiograms of 37 ears showed a Carhart notch; of these, 36 ears were noted to have glue ear. The correlation between the presence of a Carhart notch in the preoperative audiogram and the presence of glue at myringotomy was found to be significant (P < 0.001) (chi-square test). Using the decision rule that the presence of a Carhart notch predicts the presence of glue, the following operating characteristics were determined: correct, 83 ears (87.4%); false positive, one ear (1.1%); false negative, 11 ears (11.6%). The presence of a Carhart notch was found to be a strong predictor of the presence of glue at myringotomy.

Acoustic Impedance Tests↗
PubMed1996

Doppler ultrasound of the uterine arteries: the importance of bilateral notching in the prediction of pre-eclampsia, placental abruption or delivery of a small-for-gestational-age baby.

The use of Doppler studies of the uterine arteries in the prediction of pre-eclampsia and intrauterine growth retardation has had mixed success. The introduction of color Doppler imaging and the use of the "notch' to define an abnormal waveform have helped to improve the predictive value of uterine artery Doppler screening. The aim of this study was to evaluate the use of uterine artery Doppler in a group of women of mixed race and parity. This study was a prospective, cross-sectional analysis of 1326 unselected women who were screened with continuous wave uterine Doppler at 19-21 weeks, as part of a fetal anomaly/dating scan. A total of 214 women with abnormal uterine artery waveforms (notching) were referred for assessment at 24 weeks; 191 attended and had color Doppler imaging/pulsed Doppler studies of both uterine arteries. Data from 185 pregnancies were suitable for analysis. There were abnormal uterine Doppler findings (uni- or bilateral notching) in 110 patients at 24 weeks; 48 had bilateral notching. The sensitivity of notching for the prediction of proteinuric pregnancy-induced hypertension (PPIH) was similar in primiparas (76.9%), multiparas (77.7%), African-Caribbean women (82.6%) and Caucasian women (71.4%). The sensitivity of bilateral notching for the prediction of PPIH requiring delivery before 34 weeks was 81.2%, and 57.6% for babies small for gestational age (SGA), with positive predictive values of 27% (PPIH), 31.2% (SGA) and 37.5% (any complication). Patients with persistent bilateral notching are particularly at risk of developing PPIH or delivering an SGA baby before 34 weeks' gestation; they warrant increased surveillance, and may be a group that could benefit from prophylactic therapies.

Abruptio Placentae↗
PubMed1999

Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis.

Signaling induced by interaction between the receptor Notch and its ligand Delta plays an important role in cell fate determination in vertebrates as well as invertebrates. Vertebrate Notch signaling has been investigated using its constitutively active form, i.e. the truncated intracellular region which is believed to mimic Notch-Delta signaling by interaction with a DNA-binding protein RBP-J. However, the molecular mechanism for Notch signaling triggered by ligand binding, which leads to inhibition of differentiation, is not clear. We have established a myeloma cell line expressing mouse Delta1 on its cell surface which can block muscle differentiation by co-culture with C2C12 muscle progenitor cells. We showed that Delta-induced Notch signaling stimulated transcriptional activation of RBP-J binding motif, containing promoters including the HES1 promoter. Furthermore, ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA. Since cycloheximide treatment did not inhibit induction of HES1 mRNA, the HES1 promoter appears to be a primary target of activated Notch. In addition, a transcriptionally active form of RBP-J, i.e. VP16-RBP-J, inhibited muscle differentiation of C2C12 cells by blocking the expression of MyoD protein. These results suggest that HES1 induction by the Delta1/Notch signaling is mediated by RBP-J and blocks myogenic differentiation of C2C12 cells by subsequent inhibition of MyoD expression.

Animals↗
PubMed2003

The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage.

The evolutionary conserved Notch signaling pathway is involved in cell fate specification and mediated by molecular interactions between the Notch receptors and the Notch ligands, Delta, Serrate, and Jagged. In this report, we demonstrate that like Notch, Delta1 and Jagged2 are subject to presenilin (PS)-dependent, intramembranous "gamma-secretase" processing, resulting in the production of soluble intracellular derivatives. Moreover, and paralleling the observation that expression of familial Alzheimer's disease-linked mutant PS1 compromises production of Notch S3/NICD, we show that the PS-dependent production of Delta1 cytoplasmic derivatives are also reduced in cells expressing mutant PS1. These studies led us to conclude that a similar molecular apparatus is responsible for intramembranous processing of Notch and it's ligands. To assess the potential role of the cytoplasmic derivative on nuclear transcriptional events, we expressed a Delta1-Gal4VP16 chimera and demonstrated marked transcriptional stimulation of a luciferase-based reporter. Our findings offer the proposal that Delta1 and Jagged2 play dual roles as activators of Notch receptor signaling and as receptors that mediate nuclear signaling events via gamma-secretase-generated cytoplasmic domains.

Amino Acid Sequence↗
PubMed2000

Suppression of erythroid but not megakaryocytic differentiation of human K562 erythroleukemic cells by notch-1.

The Notch signal transduction pathway is a highly conserved regulatory system that controls multiple developmental processes. We have established an erythroleukemia cell model to study how Notch regulates cell fate and erythroleukemic cell differentiation. K562 and HEL cells expressed the Notch-1 receptor and the Notch ligand Jagged-1. The stable expression of the constitutively active intracellular domain of Notch-1 (NIC-1) in K562 cells inhibited erythroid without affecting megakaryocytic maturation. Expression of antisense Notch-1 induced spontaneous erythroid maturation. Suppression of erythroid maturation by NIC-1 did not result from down-regulation of GATA-1 and TAL-1, transcription factors necessary for erythroid differentiation. Microarray gene expression analysis identified genes activated during erythroid maturation, and NIC-1 disrupted the maturation-dependent changes in the expression of these genes. These results show that NIC-1 alters the pattern of gene expression in K562 cells leading to a block in erythroid maturation and therefore suggest that Notch signaling may control the developmental potential of normal and malignant erythroid progenitor cells.

Basic Helix-Loop-Helix Proteins↗
PubMed2006

Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling.

Notch proteins are transmembrane receptors that control cell-fate decisions. Upon ligand binding, Notch receptors undergo proteolytic cleavage leading to the release of their intracellular domain (NICD). Overexpression of NICD impairs osteoblastogenesis, but the mechanisms are not understood. We examined consequences of the constitutive activation of Notch 1 in ST-2 cells. Notch opposed the effects of bone morphogenetic protein (BMP)-2 and Wnt 3a on alkaline phosphatase activity (APA). BMP-2 induced the phosphorylation of Smad 1/5/8 and the transactivation of a BMP/Smad-responsive construct (12xSBE-Oc-pGL3), but the effect was not modified by Notch. BMP-2 had minimal effects on the phosphorylation of the mitogen-activated protein kinases ERK, p38, and JNK, in the absence or presence of NICD. Notch overexpression decreased the transactivating effect of Wnt 3a, cytoplasmic beta-catenin levels, and Wnt-dependent gene expression. Transfection of a mutant beta-catenin expression construct, or the use of a glycogen synthase kinase 3beta inhibitor to stabilize beta-catenin, partially blocked the inhibitory effect of NICD on Wnt signaling and on APA. HES-1 or Groucho1/TLE1 RNA interference enhanced basal and induced Wnt/beta-catenin signaling opposing NICD effects, but only HES-1 silencing enhanced Wnt 3a effects on APA. In conclusion, NICD overexpression prevents BMP-2 and Wnt biological effects by suppressing Wnt but not BMP signaling. HES-1 appears to mediate effects of Notch on osteoblastogenesis.

Animals↗
PubMed2001

Characteristics of the audiometric notch as a clinical sign of noise exposure.

This study investigated variability in audiometric notch recognition by asking three clinicians to identify notches in the audiograms of 634 noise-exposed employees. Agreement between the raters was assessed, and three notch characteristics, frequency, depth and shape (a wide or narrow notch), were investigated as recognition factors. The proportions of positive tests reported by each rater were 0.26, 0.49 and 0.68, respectively. The 'all rater' index of agreement was 0.45, and the range for pairwise comparisons was 0.14 to 0.52. With recognition factors, rater 1 was most strongly influenced by depth, rater 2 by shape and rater 3 by a possible combination of criteria. To reduce variability we suggest that narrow notches should be at least 15 dB in depth, and that broad notches should have a depth of 20 dB, with a recovery of at least 10 dB at the high end. Care should also be taken to elicit a sufficient history of noise exposure, and ensure that there are no other explanations for the notch.

Audiometry↗
PubMed2001

Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus.

We have recently reported that Notch 1, a member of the Notch multigene family, is essential for the development of murine T cells. Using a mouse model in which Notch 1 is inactivated in bone marrow (BM) precursors we have shown that B cells instead of T cells are found in the thymus of BM chimeras. However, it is not clear whether these B cells develop by default from a common lymphoid precursor due to the absence of Notch 1 signaling, or whether they arise as a result of perturbed migration of BM-derived B cells and/or altered homeostasis of normal resident thymic B cells. In this report we show that Notch 1-deficient thymic B cells resemble BM B cells in phenotype and turnover kinetics and are located predominantly in the medulla and corticomedullary junction. Peripheral blood lymphocyte analysis shows no evidence of recirculating Notch1(-/)- BM B cells. Furthermore, lack of T cell development is not due to a failure of Notch1(-/)- precursors to home to the thymus, as even after intrathymic reconstitution with BM cells, B cells instead of T cells develop from Notch 1-deficient precursors. Taken together, these results provide evidence for de novo ectopic B cell development in the thymus, and support the hypothesis that in the absence of Notch 1 common lymphoid precursors adopt the default cell fate and develop into B cells instead.

Animals↗