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PubMed2004

Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines.

The NOTCH ligand, JAG2, was found to be overexpressed in malignant plasma cells from multiple myeloma (MM) patients and cell lines but not in nonmalignant plasma cells from tonsils, bone marrow from healthy individuals, or patients with other malignancies. In addition, JAG2 overexpression was detected in 5 of 5 patients with monoclonal gammopathy of undetermined significance (MGUS), an early phase of myeloma disease progression. This overexpression appears to be a consequence of hypomethylation of the JAG2 promoter in malignant plasma cells. An in vitro coculture assay was used to demonstrate that JAG2 induced the secretion of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) in stromal cells. Further, the induction of IL-6 secretion was blocked in vitro by interference with anti-Notch-1 monoclonal antibodies raised against the binding sequence of Notch-1 with JAG2. Taken together, these results indicate that JAG2 overexpression may be an early event in the pathogenesis of multiple myeloma involving IL-6 production.

Cell Communication↗
PubMed2004

Evidence for the notch signaling pathway on the role of estrogen in angiogenesis.

We have investigated the molecular mechanisms involved in 17 beta-estradiol-induced angiogenic pathway. We show here that 17 beta-estradiol promoted a 6-fold increase in Jagged1 expression and an 8-fold increase in Notch1 expression by cDNA arrays in breast cancer MCF7 cells. Interestingly, Jagged1 was abrogated by incubation with the estrogen antagonist, ICI182,780. A similar up-regulation of both Notch1 receptor and Jagged1 ligand was found in endothelial cells. Additionally, imperfect estrogen-responsive elements were found in the 5' untranslated region of Notch1 and Jagged1 genes. Treatment with 17 beta-estradiol also led to an activation of Notch signaling in MCF7 cells expressing Notch1 reporter gene or by promoting Jagged1-induced Notch signaling in coculture assays. Inoculation of MCF7 cells in 17 beta-estradiol-treated nude mice resulted in up-regulation of Notch1 expression as well as increased number of tumor microvessels in comparison to placebo-treated mice. Notch1-expressing endothelial cell cultures formed cord-like structures on Matrigel in contrast to cells expressing a dominant-negative form of Notch1, emphasizing the relevance of Notch1 pathway in vessel assembly. Finally, Notch1-expressing MCF7 cells up-regulated hypoxia-inducible factor 1 alpha gene, a well-known angiogenic factor that clustered with Notch1 gene. This study implicates Notch signaling in the cross talk between 17 beta-estradiol and angiogenesis.

Animals↗
PubMed2006

The Notch-effector HRT1 gene plays a role in glomerular development and patterning of the Xenopus pronephros anlagen.

Notch signaling has been shown to play a role in cell fate decisions in the Xenopus pronephros anlagen. Here, we show that the Xenopus Hairy-related transcription factor (HRT) gene XHRT1, and the Hairy/Enhancer of split (HES) genes Xhairy1, Xhairy2b, esr9 and esr10, have distinct restricted dynamic expression patterns during pronephros development, and that their expression is regulated by Notch. XHRT1, which is the earliest and strongest gene expressed in the pronephric region, is initially transcribed predominantly in the forming glomus, where it is downregulated by antisense morpholino oligonucleotide inhibition of xWT1. Later, it is activated in the most dorsoanterior part of the pronephros anlagen that gives rise to the proximal tubules. In agreement with this dynamic expression profile, we found that early activation of Notch favors glomus, whereas only later activation promotes proximal tubule formation. We show that, among the bHLH-O factors tested, only XHRT1 efficiently inhibits distal tubule and duct formation, and that only its translational inhibition causes a reduction of the expression of proximal tubule and glomus markers. Using domain swap experiments, we found that the XHRT1 C-terminal region is crucial for its activity. Together, our results provide evidence that XHRT1 plays an important role in glomerular development and early proximodistal patterning that is distinct from those of the other pronephric bHLH repressors.

Animals↗
PubMed2000

Delta 1-activated notch inhibits muscle differentiation without affecting Myf5 and Pax3 expression in chick limb myogenesis.

The myogenic basic helix-loop-helix (bHLH) transcription factors, Myf5, MyoD, myogenin and MRF4, are unique in their ability to direct a program of specific gene transcription leading to skeletal muscle phenotype. The observation that Myf5 and MyoD can force myogenic conversion in non-muscle cells in vitro does not imply that they are equivalent. In this paper, we show that Myf5 transcripts are detected before those of MyoD during chick limb development. The Myf5 expression domain resembles that of Pax3 and is larger than that of MyoD. Moreover, Myf5 and Pax3 expression is correlated with myoblast proliferation, while MyoD is detected in post-mitotic myoblasts. These data indicate that Myf5 and MyoD are involved in different steps during chick limb bud myogenesis, Myf5 acting upstream of MyoD. The progression of myoblasts through the differentiation steps must be carefully controlled to ensure myogenesis at the right place and time during wing development. Because Notch signalling is known to prevent differentiation in different systems and species, we sought to determine whether these molecules regulate the steps occurring during chick limb myogenesis. Notch1 transcripts are associated with immature myoblasts, while cells expressing the ligands Delta1 and Serrate2 are more advanced in myogenesis. Misexpression of Delta1 using a replication-competent retrovirus activates the Notch pathway. After activation of this pathway, myoblasts still express Myf5 and Pax3 but have downregulated MyoD, resulting in inhibition of terminal muscle differentiation. We conclude that activation of Notch signalling during chick limb myogenesis prevents Myf5-expressing myoblasts from progressing to the MyoD-expressing stage.

Animals↗
PubMed2000

Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1.

Presenilin 1 (PS1), a polytopic membrane protein, is required for endoproteolytic processing at gamma-secretase site within the transmembrane domain of amyloid precursor proteins (APP). In addition, PS1 and its orthologues facilitate signaling of Notch family members, cell-surface receptors that specify cell fates during development. To clarify the mechanism(s) by which PS facilitates Notch signaling, we examined human Jagged-2-dependent metabolism and activity of a chimeric full-length Notchl-GFP molecule expressed in fibroblasts with heterozygous, or homozygous deletions of PS1. We demonstrate that PS1 is required for facilitating Jagged 2-mediated proteolysis and that translocation and accumulation of NICD in the nucleus correlates with signaling activity. Moreover, in a ligand-independent, Ca2+-depletion paradigm, we demonstrate that PS1 facilitates endoproteolysis of a plasma-membrane-associated, Notch1-GFP derivative. Finally, we report that NICD production is inhibited by L-685,458, a potent and selective inhibitor that blocks solubilized gamma-secretase activity and Abeta production in cultured cells. These findings strongly suggest that intramembranous processing of APP and Notch 1 are mediated by similar, if not identical, proteases that require PS1 for their activation.

Alzheimer Disease↗
PubMed2001

The labiogingival notch: an anatomical variation of clinical importance.

BACKGROUND: The labiogingival notch is a developmental phenomenon affecting the maxillary central incisors. Clinically, it can be easily misdiagnosed and improperly treated. Thus, it is important for dentists to recognize this condition. CASE DESCRIPTIONS: The authors describe two cases of misdiagnosed labiogingival notch on a maxillary central incisor. In one case, the notch was misinterpreted as a carious lesion and placement of a restoration was advised. In the second case, external resorption was suspected and forced eruption of the incisor was requested. In both cases, no treatment was needed. CLINICAL IMPLICATIONS: Misdiagnosis of this developmental phenomenon may lead to unnecessary invasive interventions. Because of this, clinicians need to be aware of this clinical variant.

Adolescent↗
PubMed2005

Oligodendrocyte specification in zebrafish requires notch-regulated cyclin-dependent kinase inhibitor function.

Cyclin-dependent kinase inhibitors (Cdkis) influence both cell-cycle progression and differentiation of neural cells. However, the precise roles of Cdkis in coordinating formation of neurons and glia and the mechanisms that regulate expression of genes that encode Cdkis in the vertebrate CNS remain unknown. Here, we report that, in zebrafish, expression of the Cdki gene cyclin-dependent kinase inhibitor 1c (cdkn1c), a p57 homolog, is negatively regulated by Delta-Notch signaling and that Cdkn1c function is required for neural plate cells to stop dividing and differentiate as neurons on schedule, even in the absence of Notch signaling activity. Furthermore, Cdkn1c function is required for specification of oligodendrocytes from ventral spinal cord precursors. We propose that levels of cdkn1c expression are an important factor in regulating neural development: high levels of Cdkn1c promote cell-cycle exit and neuronal development, whereas, during late embryogenesis, neural cells that have low but functional levels of Cdkn1c, regulated by Notch activity, are specified for oligodendrocyte fate.

Animals↗
PubMed2006

A genetic screen for modifiers of the delta1-dependent notch signaling function in the mouse.

The Notch signaling pathway is an evolutionarily conserved transduction pathway involved in embryonic patterning and regulation of cell fates during development. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, which are also involved in distinct human diseases. Delta1 is one of the known ligands of the Notch receptors. Mice homozygous for a loss-of-function allele of the Delta1 gene Dll1(lacZ/lacZ) die during embryonic development. Here, we present the results of two phenotype-driven modifier screens. Heterozygous Dll1(lacZ) knockout animals were crossed with ENU-mutagenized mice and screened for dysmorphological, clinical chemical, and immunological variants that are dependent on the Delta1 loss-of-function allele. First, we show that mutagenized heterozygous Dll1(lacZ) offspring have reduced body weight and altered specific clinical chemical parameters, including changes in metabolites and electrolytes relevant for kidney function. In our mutagenesis screen we have successfully generated 35 new mutant lines. Of major interest are 7 mutant lines that exhibit a Dll1(lacZ/+)-dependent phenotype. These mutant mouse lines provide excellent in vivo tools for studying the role of Notch signaling in kidney and liver function, cholesterol and iron metabolism, cell-fate decisions, and during maturation of T cells in the immune system.

Alleles↗
PubMed2004

Long-term follow-up of notched T waves in female patients with LQT2 (HERG) mutations.

We studied the long-term follow up of abnormal T wave morphology (notched, low amplitude, and inverted T waves) of five female patients with LQT2 (HERG) mutations. The patients, aged 43, 19, 27, 26, and 56 years, had experienced syncopal attacks and were followed up for 3-17 years (average 9.4 years). Patients were treated with a beta-blocker alone (2) or combined with other drugs (3). The mutation in four patients was missense (A614V, T613, E130K) and its location was the pore region (3) or between the S1 transmembrane region and N-terminal (one). The fifth patient had an intragenic deletion (49 bp deletion) at HERG exon 4 (S1 transmembrane region and N-terminal), which was not identified as having any mutation. The patients manifested a notched T wave in at least one left precordial or limb lead (I, II or aVF). A low T wave amplitude was shown in at least one lead, and deeply inverted or biphasic waves in right precordial leads were also associated with these findings. The abnormal T wave finding in any of the 12 leads in our 5 LQT2 patients was shown to be widespread and was always found during the long-term follow up. The present cases suggest that notched T waves are useful for diagnosing female symptomatic LQT2 patients.

Adult↗
PubMed2006

Notch signaling in stem cell systems.

The Notch signaling pathway is among the most commonly used communication channels in animal cells. Recent studies have demonstrated that this pathway is indispensable for cells in various stages of maturation, including terminal differentiation. One main focus in mammalian studies is the role of Notch in embryonic and postembryonic stem cell systems. In this review, the roles of Notch signaling in various mammalian stem and early progenitor cells are summarized.

Animals↗
PubMed1977

Notching of the ureter and renal pelvis in children.

The excretory urograms of 14 children with ureteral notching were reviewed. In 10 of 14 cases the vascular impressions on the ureters were due to either venous obstruction and dilated collaterals or to dilated noncollateral veins. In two cases the notching was associated with arterial collaterals in renal ischemia and in two with dilated lymphatic channels. The implications of notching in children and the differences and similarities of this urographic sign between children and adults are discussed.

Adolescent↗
PubMed1975

Fracture of the scapular notch associated with lesion of the suprascapular nerve.

In a material consisting of 18 patients with scapula fractures, the scapular notch was involved in two cases. In one of these cases injury of the suprascapular nerve function was proved. The value of X-ray examination with projections visualizing the scapular notch is pointed out. EMG examination in selected cases with the combination of reduced supraspinatus muscle function and a fracture of the scapular notch is recommended in order to diagnose injury of the suprascapular nerve.

Female↗
PubMed1996

Meningiomas of the tentorial notch: surgical anatomy and management.

Twenty-five meningiomas located at the tentorial notch were surgically treated between 1978 and 1993 at the Neurosurgical Department of Nordstadt Hospital in Hannover, Germany. Nineteen meningiomas were classified as originating from the lateral tentorial incisura (Group I) and six were from the posteromedial tentorial incisura (Group II). Clinically, the most common symptom was trigeminal neuralgia, followed by headache. Neuroradiologically, 64% of the meningiomas were larger than 30 X 30 mm. Further evaluation revealed signs of brainstem compression in 88% of the patients. Radical surgical removal (Simpson I and II) was achieved in 88% of the cases. There was no mortality. Follow up revealed that 80% of patients were able to return to their premorbid activity. Surgical approaches to the tentorial notch included the suboccipital retrosigmoidal or the combined subtemporal-presigmoidal approach for Group I tentorial notch meningiomas; and the supracerebellar-infratentorial or the suboccipital-transtentorial approaches for Group II meningiomas. Because the best surgical approach to the tentorial incisura is still a matter of debate, the anatomy of the tentorial incisura, the clinical presentation of the patients, diagnostic indications, surgical findings, and follow up are discussed, with reference to the literature.

Adult↗
PubMed2000

The effect of elastic modulus of the backing material on the fatigue notch factor and stress.

In cemented acetabular cup design it is acknowledged that bone resorption and fatigue fracture of cement may cause the most common problems after total hip replacement. Previous studies have optimized the shape of metal backing (MB) shell used in cemented acetabular components in order to minimize the fatigue notch factor (Kf) in cement, whilst at the same time maximizing Kf in bone at the central part of acetabulum to prevent stress shielding and subsequent bone resorption [1]. The optimal shape was found to be thin at the edges and thick at the dome. The present study describes the effect of changing the elastic modulus of the backing material on Kf and stresses as predicted by the initial shape of the backing shell of (3 mm) thick, and the optimized backing shape of non-uniform thickness in order to find the optimal material for the backing shell. It is recommended to use a backing shell material with elastic modulus equals 70 GPa (which can be readily attained using a fiber reinforced polymer composite). It is shown that such a material will decrease the fatigue notch factor and the stresses in cement at cup edges, at the same time it will increase the stresses and the fatigue notch factor in bone at the central part of acetabulum. Thereby, reducing the possibility of fatigue fracture of cement, whilst at the same time decreasing the stress shielding effect and the resulting bone resorption. The effect of lower bone resorption and lower probability of fatigue fracture of the cement will also reduce the incidence of loosening and premature revision operations.

Aged↗
PubMed2001

Open reduction of a lateral femoral notch associated with an acute anterior cruciate ligament tear.

The lateral notch is a radiographic sign that describes a depression in the lateral femoral condyle near the terminal sulcus. The sign was first described in association with chronic instability in an anterior cruciate ligament-deficient knee. Recently, the senior author, after a prospective study, reported that these lateral notches might occur acutely at the time of anterior cruciate ligament injury. We report such a case in which the lateral femoral condylar depression fracture resulted in symptoms of lateral compartment incongruity. Open reduction and internal fixation were required. Anterior cruciate ligament reconstruction was performed as a staged procedure 2 months after fracture reduction. The postoperative result has been excellent for over 5 years. This case is an example that lateral femoral notches may be acute and a source of symptoms. In some cases, reduction and fixation of significant depressions in association with ligament reconstruction can alleviate these symptoms and may improve the patient's long-term result.

Adult↗
PubMed2004

Suppression of power-line interference by analog notch filtering in the ECG signal for heart rate variability analysis: to do or not to do?

BACKGROUND: Heart rate variability analysis has developed recently to a promising field of cardiology. Measures of heart rate variability can be corrupted by environmental noise or technical artifacts arising from analog and digital signal processing. MATERIAL/METHODS: The present investigation addressed the analysis of the effects of AC interference and its filtering on the precision and accuracy of heart rate detection. Artificial ECG recordings with predefined parameters were simulated by a computer and a data acquisition card, consecutively filtered by an analog notch filter (Q=2, 5 and 10) and digitized at 1 kHz by the same card ahead of and subsequent to the filter circuit. These latter signals were analyzed: the relative time points corresponding to the uncorrupted series at 7 points of the ventricular complexes were obtained and their means, standard deviations and maxima were computed separately. RESULTS: The filtering of uncorrupted ECG signals does not result in heart rate period deviations < or=1 ms. Power-line interference contamination proportionally alters the accuracy of representative point detection (maximal shift: 5% - 2 ms, 10% - 4 ms, 25% - 8 ms, 50% - 14 ms), which is consistently restored by notch filtering with a slight error (L1 ms on the ascending slope and at the peak). The descending slope is more distorted at filter Q=2 and at lower ventricular complex width; however this is constant, which also results in reliable RR-interval detection. CONCLUSIONS: AC notch filtering of ECG signals for heart rate variability analysis is considered important, and further investigation of this area is encouraged.

Analysis of Variance↗
PubMedDate not supplied

[A case of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy) with Notch 3 (Arg169Cys) mutation and typical granular osmiophilic materials in peripheral small arteries].

We report a 64-year-old Japanese woman with recurrent ischemic strokes and progressive dementia without any cardiovascular risk factors. Her first stroke was at 45 years old, and she has a family history of ischemic strokes compatible with an autosomal dominant trait. Marked leukoaraiosis and multiple lacunar infarcts were shown on brain MR images, and no atherosclerotic changes were observed in her extra- and intra-cranial arteries by cervical arterial echography and intracranial MR angiography. Excluded other inherited or metabolic diseases causing leukodystrophy by examination of her blood samples, her disease was diagnosed as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy). We demonstrated granular osmiophilic materials (GOM) on the wall of small arteries from a biopsied peripheral nerve tissue specimen and detected a mutation Arg169Cys of Notch 3 gene. Many CADASIL patients have been reported and over 28 kinds of mutations of the Notch 3 were identified in western countries, while few CADASIL patients have been reported in Japanese people. Among them, eleven CADASIL families have been reported and only five mutations (Arg133Cys, Cys174Phe, Arg213Lys, Arg90Cys and Arg141Cys) have been determined so far. The mutation of Notch 3 in our patient was determined as Arg169Cys, and this is the first report on a Japanese patient with CADASIL due to this mutation.

Arteries↗
PubMed1992

Regulation of hordein synthesis in barley high lysine mutant Notch-2.

Genomic DNA isolated from barley cv. NP 113 and its high lysine mutant Notch-2, and restricted with different restriction enzymes was hybridized with B1 and C-hordein DNA probes. Similar Southern hybridization patterns were observed between NP 113 and Notch-2. Dot blot hybridization analysis of RNA isolated at different developmental stages and from different tissues of seed showed temporal as well as tissue specific expression. The results obtained indicate that regulation at the level of transcription/post transcription may be responsible for lower accumulation of hordein in mutant Notch-2.

Glutens↗