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At least 685 records · Page 38Linked to original sources
PubMed2005

Notch signaling represses myocardin-induced smooth muscle cell differentiation.

Notch signaling is essential for vascular patterning and response of the vasculature to injury and growth factor stimulation. Despite these findings, the molecular basis of Notch signaling in the vasculature is poorly understood. Here we report that activation of Notch signaling mediated through members of the HRT family of basic helix-loop-helix transcription factors represses smooth muscle cell (SMC) differentiation and expression of genes encoding smooth muscle cell contractile markers. Activation of Notch receptors by Jagged1 or forced expression of the constitutively active Notch1 intracellular domain in C3H10T1/2 fibroblasts inhibited myocardin-dependent transcription of SMC-restricted genes and activity of multiple SMC-restricted transcriptional regulatory elements. Consistent with these findings, forced expression of HRT2 inhibited myocardin-induced expression of SMC-restricted genes and activity of SMC-restricted transcriptional regulatory elements. Moreover, forced expression of HRT2 repressed transcription of multiple SMC-restricted transcriptional regulatory elements in A10 SMCs. The repressive function of HRT2 was not mediated via the capacity of HRT2 to bind SMC CArG elements or by disruption of myocardin-SRF protein complexes. Structure-function analyses of HRT2 indicated that repression required the basic DNA binding domain and additional C-terminal sequence. Taken together, these results demonstrate that Notch signaling represses myocardin-dependent SMC transcription. These data are consistent with a model wherein Notch signaling represses SMC differentiation and maintenance of the contractile SMC phenotype.

Animals↗
PubMed1989

Physical and functional definition of the Drosophila Notch locus by P element transformation.

Notch is a developmentally regulated locus which controls the differentiation of various Drosophila tissues, among them the embryonic nervous system. Molecular analysis has suggested that Notch is defined by an approximately 40-kb transcription unit which is spliced into a 10.2-kb mRNA composed of nine exonic regions and coding for a 2703-amino acid long transmembrane protein that shows homology to the mammalian epidermal growth factor. Here, we define the 5' end of the transcription unit and determine the sequences deleted in a Notch mutation involving the 5' nontranscribed region. Using a Notch cosmid vector we demonstrate by P element-mediated transformation that all sequences necessary for Notch function are confined in an approximately 40-kb long genomic region. cDNA sequences are used to construct a 15-kb "minigene" which lacks most, but not all, introns and its functionality is also tested by P element transformation. We show that, unlike the cosmid vector which is capable of rescuing completely all Notch mutations, only certain phenotypes can be rescued by the "minigene." The functional implications of our findings are discussed.

Animals↗
PubMed1998

Notching of orthodontic bonding resin to facilitate ceramic bracket debond--an ex vivo investigation.

This ex vivo study assessed the potential of introducing a notch in the bond layer, as a means of facilitating the removal of ceramic brackets. Sixty extracted premolar teeth were divided into three groups of 20 teeth and bonded with Intrigue brackets using Concise chemically-cured adhesive. The bonding technique was modified with groups 1 and 2 by introducing a notch in the bond layer. Group 1 was notched from the gingival aspect, group 2 from the occlusal, and group 3 served as a control. The brackets were removed by applying a shear load from the gingival aspect using an Instron universal testing machine. The mean force to debond was calculated for each group. The results showed that introducing a notch significantly reduced the mean and maximal debond forces. This was confirmed with Weibull analysis with the notched specimens having a higher probability of failure at any force. In addition, ceramic bracket fracture was eliminated. Notching the bonding resin may be helpful in facilitating the removal of ceramic brackets.

Ceramics↗
PubMed1994

Frequency-resolution measurements with notched noises for clinical purposes.

Knowledge of the frequency resolving power of the pathological ear can be helpful for good hearing-aid prescription. In particular, the slope of the low-frequency edge of the auditory filter will determine the extent of upward spread of masking. The most precise method for measuring this filter is the "notched-noise" procedure developed in the early 1980s. However, at this moment, the notched-noise protocol is too time consuming for clinical use. In this paper we developed a protocol that is applicable in the clinic. In the first part of the study we investigated the minimum number of threshold measurements necessary for a reliable estimation of the filter parameters. For this purpose we analyzed 99 filters originally obtained with 13 threshold measurements. The influence of reducing the number of notch widths used to obtain filter shapes on the variability of filter parameters was investigated. Subsets of seven and five notch widths gave about the same standard deviations of the differences between the parameters obtained with the subset and the parameters obtained with the full set of 13 thresholds, while subsets of four and three notch widths gave significantly higher variability. However, because small deviations of one threshold determination can give rise to a large change in filter parameters, especially for filters with flatter skirts, it is strongly recommended to reduce the variability by measuring thresholds twice (test and retest). In the second part of the study we investigated a faster method for measuring thresholds. The forced-choice paradigm normally used in notched-noise procedures was replaced by a Békésy paradigm. The Békésy paradigm did not significantly increase intra-individual standard deviations, but did reduce the measuring time by more than 50%. In conclusion, the new procedures reduce the measurement time needed to obtain reliable estimates of auditory-filter parameters by a factor of about 5. The new protocol lasts about 15 min for each filter measurement, which appears to be acceptable for clinical use, at least for difficult-to-fit hearing aid users.

Acoustic Stimulation↗
PubMed2001

Notch sensitivity of titanium alloy, commercially pure titanium, and stainless steel spinal implants.

STUDY DESIGN: This is a biomechanical study comparing the fatigue life of stainless steel (SS), titanium alloy (TI), and commercially pure titanium (CP) rods that were notched using techniques essential to spine surgery. OBJECTIVES: To show the difference in fatigue life of the three rods and the effect on fatigue life of marks caused by techniques unavoidable in spine surgery. SUMMARY OF BACKGROUND DATA: Past studies have shown a decrease in the fatigue life of titanium when there is a defect or notch in the surface. This has been demonstrated with spinal and fracture implants, prosthetic joints, and in the materials science literature. Previous authors have recommended avoidance of techniques that mark the surface of titanium implants. METHODS: Four Texas Scottish Rite Hospital rods of each metal were prepared in four different ways: 1) no notch, 2) a French bender notch, 3) a top-loading connector--left on, 4) a top-loading connector--removed. The rods were fatigued in four point bending up to 1 million cycles. Before fatigue testing, two samples of each preparation were examined with electron microscopy. RESULTS: No SS rods failed. No TI rods without a notch or connector removed failed. One TI rod with the connector left in place failed (106,635 cycles). Three of the TI rods in the French-bender group failed (average, 87,663 cycles). One CP rod without a notch failed (358,957 cycles). No CP rods with the connector left in place failed. All CP rods with the connector removed failed (average, 230,094 cycles). All CP rods in the French bender group failed (average 120,817 cycles). The following differences were significant (P < 0.05): SS-TI and SS-CP in the French bender group; SS-CP and TI-CP in the connector removed group. Electron micrographs performed before fatigue testing showed cracks in the TI and CP rods that were marked with the French bender. CONCLUSION: Caution is recommended when bending TI or CP rods, or placing a connector and removing it when using CP rods in situations in which fatigue failure is a concern.

Alloys↗
PubMed2002

Absence of a diastolic velocity notch does not indicate hyperemia in traumatic brain injured patients without elevated cerebral blood flow velocity.

Elevated blood flow velocity (BFV), measured by transcranial Doppler (TCD), has been associated with hyperemia and cerebral vasospasm. This study examined whether the lack of a diastolic notch within the TCD waveform was associated with relative hyperemia within 5 days after injury in 35 traumatic brain injured (TBI) patients. Hyperemia (avD(O2) of < 4 ml/dL) was present in 16 patients and absent in 19 patients. Two clinicians independently coded TCD waveforms based on the presence of a diastolic notch (88% agreement). There was no significant difference in the presence of a diastolic notch by group; a diastolic notch was present in 57% (11/19) of patients without hyperemia and 81% (13/16) of patients with hyperemia. Sensitivity and specificity of detecting hyperemia using the diastolic notch was 18.7% and 57.9% respectively. The results showed that relative hyperemia was present without an elevation in blood flow velocities, and that the lack of a diastolic notch did not detect the presence of hyperemia in the TBI patient.

APACHE↗
PubMed1994

Adaptive digital notch filter design on the unit circle for the removal of powerline noise from biomedical signals.

This paper investigates adaptive digital notch filters for the elimination of powerline noise from biomedical signals. Since the distribution of the frequency variation of the powerline noise may or may not be centered at 60 Hz, three different adaptive digital notch filters are considered. For the first case, an adaptive FIR second-order digital notch filter is designed to track the center frequency variation. For the second case, the zeroes of an adaptive IIR second-order digital notch filter are fixed on the unit circle and the poles are adapted to find an optimum bandwidth to eliminate the noise to a pre-defined attenuation level. In the third case, both the poles and zeroes of the adaptive IIR second-order filter are adapted to track the center frequency variation within an optimum bandwidth. The adaptive process is considerably simplified by designing the notch filters by pole-zero placement on the unit circle using some suggested rules. A constrained least mean-squared (CLMS) algorithm is used for the adaptive process. To evaluate their performance, the three adaptive notch filters are applied to a powerline noise sample and to a noisy EEG as an illustration of a biomedical signal.

Algorithms↗
PubMed2005

The crystal structure of a partial mouse Notch-1 ankyrin domain: repeats 4 through 7 preserve an ankyrin fold.

Folding and stability of proteins containing ankyrin repeats (ARs) is of great interest because they mediate numerous protein-protein interactions involved in a wide range of regulatory cellular processes. Notch, an ankyrin domain containing protein, signals by converting a transcriptional repression complex into an activation complex. The Notch ANK domain is essential for Notch function and contains seven ARs. Here, we present the 2.2 A crystal structure of ARs 4-7 from mouse Notch 1 (m1ANK). These C-terminal repeats were resistant to degradation during crystallization, and their secondary and tertiary structures are maintained in the absence of repeats 1-3. The crystallized fragment adopts a typical ankyrin fold including the poorly conserved seventh AR, as seen in the Drosophila Notch ANK domain (dANK). The structural preservation and stability of the C-terminal repeats shed a new light onto the mechanism of hetero-oligomeric assembly during Notch-mediated transcriptional activation.

Amino Acid Sequence↗
PubMed2005

Bilateral notching of uterine arteries at 12--14 weeks of gestation for prediction of hypertensive disorders of pregnancy.

OBJECTIVE: To assess the value of transvaginal uterine artery Doppler ultrasound at 12--14 weeks of gestation in predicting hypertensive disorders of pregnancy in high-risk women. METHODS: One hundred and twenty high-risk women were evaluated prospectively by Doppler ultrasound of uterine and umbilical arteries at 12--14 weeks of gestation. The presence of bilateral notches, resistance and pulsatility index (PI), mean and maximum flow velocities of uterine arteries, and resistance and PI of umbilical arteries were investigated. Those with bilateral notching were randomized to acetylsalicylic acid (n=43) or placebo groups (n=43) and were followed up twice during pregnancy with the same ultrasound measurements. The women without bilateral notches (n=29) served as controls. In this study, we compared 43 women in the placebo group to 29 controls without bilateral notches. The outcome measures were pregnancy-induced hypertension, pre-eclampsia and intrauterine growth restriction. RESULTS: The sensitivity of bilateral notching in predicting hypertensive disorders of pregnancy decreased with advancing pregnancy from 91 to 35%, and the specificity and the positive predictive values increased from 41 to 94% and from 7 to 70%, respectively. The negative predictive values ranged from 86 to 97%. CONCLUSION: Bilateral notching of uterine arteries at 12--14 weeks is a useful tool in predicting the development of hypertensive disorders in high-risk pregnancies. It is also a suitable test for surveillance of high-risk pregnancies.

Adult↗
PubMed1987

A release from masking by continuous, random, notched noise.

Thresholds for 10-ms sinusoids simultaneously masked by bursts of bandpass noise centered on the signal frequency were measured for a wide range of signal frequencies and noise levels. Thresholds were defined as the signal power relative to the masker power at the output of an auditory filter centered on the signal frequency. It was found that the presentation of a continuous random noise, with a spectral notch centered on the signal frequency, produced a reduction in signal thresholds of up to 11 dB. A notched noise spectrum level of 0-5 dB above that of the masker proved most effective in producing a masking release, as measured by a reduction in masked threshold. A release from masking of up to 7 dB could be obtained with a continuous bandpass noise. The most effective spectrum level of this noise was 5 dB below that of the masker. The effect of the continuous notched noise was to reduce signal-to-masker ratios at threshold to about 0 dB, regardless of the threshold in the absence of continuous noise. Thus the greatest release from masking occurred when "unreleased" thresholds were highest. The release from masking is almost complete within 320 ms of notched noise onset, and persists for about 160 ms after notched noise offset, regardless of notched noise level. The phenomenon is similar in many ways to the "overshoot" effect reported by Zwicker [J. Acoust. Soc. Am. 37, 653-663 (1965)]. It is argued that both effects can be largely attributed to peripheral short-term adaptation, a mechanism which is also believed to be involved in forward masking.

Auditory Fatigue↗
PubMed2005

Role of Notch signal transduction in Kaposi's sarcoma-associated herpesvirus gene expression.

Kaposi's sarcoma-associated herpesvirus (KSHV) RTA transcription factor is recruited to its responsive elements through interaction with a Notch-mediated transcription factor, RBP-Jkappa, indicating that RTA mimics cellular Notch signal transduction to activate viral lytic gene expression. To test whether cellular Notch signal transduction and RTA are functionally exchangeable for viral gene expression, human Notch intracellular (hNIC) domain that constitutively activates RBP-Jkappa transcription factor activity was expressed in KSHV-infected primary effusion lymphoma BCBL1 cells (TRExBCBL1-hNIC) in a tetracycline-inducible manner. Gene expression profiling showed that like RTA, hNIC robustly induced expression of a number of viral genes, including viral interleukin 6 (vIL-6), K3, and K5. Unlike RTA, however, hNIC was not capable of evoking the full repertoire of lytic viral gene expression and thereby lytic replication. To further understand the role of Notch signal transduction in KSHV gene expression, vIL-6 growth factor and K5 immune modulator genes were selected for detailed analysis. Despite the presence of multiple RBP-Jkappa binding sites, hNIC targeted the specific RBP-Jkappa binding sites of vIL-6 and K5 promoter regions to regulate their gene expression. These results indicate that cellular Notch signal transduction not only is partially exchangeable with RTA in regard to activation of viral lytic gene expression but also provides a novel expression profile of KSHV growth and immune deregulatory genes that is likely different from that of RTA-independent standard latency program as well as RTA-dependent lytic reproduction program.

Cell Line↗
PubMed1981

Suprasternal notch echocardiography: a two-dimensional technique for evaluating congenital heart disease.

Two-dimensional suprasternal notch echocardiography was performed in 1033 patients, ages 1 day to 18 years. For the long-axis suprasternal notch view, the transducer was positioned in the suprasternal notch and angled to obtain a plane passing between the right nipple and left scapular tip. In this view, the entire aortic arch, vessels to the head and neck, right pulmonary artery and right bronchus were imaged. The long-axis view was useful for evaluating coarctation and interruption of the aorta, hypoplastic left heart, aortic and pulmonic stenosis and cervical aortic arch. For the short-axis suprasternal notch view the transducer was positioned in the suprasternal notch and angled to obtain a coronal body plane. In this view the transverse aorta, right pulmonary artery, left atrium, innominate veins and superior vena cava were imaged. The short-axis view was useful in the evaluation of children with increased or decreased pulmonary blood flow, persistent left superior vena cava, total anomalous pulmonary venous return to the right superior vena cava, and superior vena caval obstruction after Mustard's operation. In the evaluation of children with congenital heart disease, the suprasternal notch views added significant information to the two-dimensional echocardiographic examination.

Adolescent↗
PubMedDate not supplied

The relationship between intercondylar notch width of the femur and the incidence of anterior cruciate ligament tears. A prospective study.

For 714 consecutive patients who underwent autogenous patellar tendon graft anterior cruciate ligament reconstructions we intraoperatively measured intercondylar notch width. We prospectively recorded height, weight, sex, and which patients subsequently tore their contralateral anterior cruciate ligament or the 10-mm autograft. The patients were divided into two groups based on notch width (group 1, < or = 15 mm; group 2, > or = 16mm. The mean notch width was 13.9 +/- 2.2 mm for women and 15.9 +/- 2.5 mm for men. There was no statistically significant difference in notch width between height groups for women or men. Analysis showed that, with height and weight as covariates, women had statistically significantly narrower notches than men. Twenty-three of 388 patients in group 1 and 4 of 326 patients in group 2 tore their contralateral anterior cruciate ligaments. Within groups, no statistically significant differences in contralateral tear rates existed between men and women. Once the men and women had reconstructions with equally sized 10-mm autografts, there was no difference in graft tear rate between groups or between men and women. Our results show that patients with narrower notches have a higher incidence of tearing their contralateral anterior cruciate ligament. After reconstruction with a 10-mm autograft, the incidence of graft rupture is the same for men and women.

Adult↗
PubMed1997

Conservation of the Notch signalling pathway in mammalian neurogenesis.

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

Animals↗
PubMed1998

Delta-Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant.

Mechanosensory hair cells in the sensory patches of the vertebrate ear are interspersed among supporting cells, forming a fine-grained pattern of alternating cell types. Analogies with Drosophila mechanosensory bristle development suggest that this pattern could be generated through lateral inhibition mediated by Notch signalling. In the zebrafish ear rudiment, homologues of Notch are widely expressed, while the Delta homologues deltaA, deltaB and deltaD, coding for Notch ligands, are expressed in small numbers of cells in regions where hair cells are soon to differentiate. This suggests that the delta-expressing cells are nascent hair cells, in agreement with findings for Delta1 in the chick. According to the lateral inhibition hypothesis, the nascent hair cells, by expressing Delta protein, would inhibit their neighbours from becoming hair cells, forcing them to be supporting cells instead. The zebrafish mind bomb mutant has abnormalities in the central nervous system, somites, and elsewhere, diagnostic of a failure of Delta-Notch signalling: in the CNS, it shows a neurogenic phenotype accompanied by misregulated delta gene expression. Similar misregulation of delta ; genes is seen in the ear, along with misregulation of a Serrate homologue, serrateB, coding for an alternative Notch ligand. Most dramatically, the sensory patches in the mind bomb ear consist solely of hair cells, which are produced in great excess and prematurely; at 36 hours post fertilization, there are more than ten times as many as normal, while supporting cells are absent. A twofold increase is seen in the number of otic neurons also. The findings are strong evidence that lateral inhibition mediated by Delta-Notch signalling controls the pattern of sensory cell differentiation in the ear.

Animals↗
PubMed2001

Notch signaling is required for arterial-venous differentiation during embryonic vascular development.

Recent evidence indicates that acquisition of artery or vein identity during vascular development is governed, in part, by genetic mechanisms. The artery-specific expression of a number of Notch signaling genes in mouse and zebrafish suggests that this pathway may play a role in arterial-venous cell fate determination during vascular development. We show that loss of Notch signaling in zebrafish embryos leads to molecular defects in arterial-venous differentiation, including loss of artery-specific markers and ectopic expression of venous markers within the dorsal aorta. Conversely, we find that ectopic activation of Notch signaling leads to repression of venous cell fate. Finally, embryos lacking Notch function exhibit defects in blood vessel formation similar to those associated with improper arterial-venous specification. Our results suggest that Notch signaling is required for the proper development of arterial and venous blood vessels, and that a major role of Notch signaling in blood vessels is to repress venous differentiation within developing arteries. Movies available on-line

Animals↗
PubMed1986

Supraorbital and supratrochlear notches and foramina: anatomical variations and surgical relevance.

The anatomy of the supraorbital and supratrochlear notches and foramina has been studied in 111 human skulls. Of 108 skulls, 49.07% had bilateral supraorbital notches, 25.93% had bilateral supraorbital foramina, and 25% had a notch on one side and a foramen on the other side. Of 101 skulls, 97.03% had bilateral supratrochlear notches, 0.99% had bilateral foramina, and 1.98% had a notch on one side and a foramen on the other side. The methods of study and clinical relevance are discussed, along with the varying nomenclature used in the literature for defining the supraorbital and supratrochlear structures. Knowledge of the anatomy of the region is important for those doing forehead and brow lift surgery in order to avoid injuring the neurovascular bundles passing through these notches and foramina.

Cephalometry↗
PubMed2002

Stimulation of osteoblastic cell differentiation by Notch.

Notch is a transmembrane protein that plays a critical role in the determination of cellular differentiation pathways. Although its importance in the development of mesenchymal tissues has been suggested, its role in skeletal tissues has not been well investigated. Northern blot experiments showed the expression of Notch1 in MC3T3-E1 osteoblastic cells at early differentiation stages. When a Notch1 cytoplasmic domain (Notch-IC [NIC]) delivered by an adenovirus vector was expressed in osteoblastic MC3T3-E1 cells, a significant increase in calcified nodule formation was observed in long-term cultures. Activation of endogenous Notch in MC3T3-E1 by coculturing them with Delta-like-1 (Dll1)-expressing myeloma cells also resulted in a stimulation of calcified nodule formation. Not only affecting nodule formation, Notch activation also had effects on osteoblastic differentiation of multipotent mesenchymal cells. Osteoblastic differentiation of C3H10T1/2 cells induced by bone morphogenetic protein 2 (BMP-2) was significantly stimulated, whereas adipogenic differentiation was suppressed strongly, resulting in a dominant differentiation of osteoblastic cells. NIC expression in primary human bone marrow mesenchymal stem cells (hMSCs) also induced both spontaneous and stimulated osteoblastic cell differentiation. These observations suggest that osteoblastic cell differentiation is regulated positively by Notch and that Notch could be a unique and interesting target molecule for the treatment of osteoporosis.

Animals↗