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At least 865 records · Page 48Linked to original sources
PubMed2005

Hematopoietic stem cell fate is established by the Notch-Runx pathway.

Identifying the molecular pathways regulating hematopoietic stem cell (HSC) specification, self-renewal, and expansion remains a fundamental goal of both basic and clinical biology. Here, we analyzed the effects of Notch signaling on HSC number during zebrafish development and adulthood, defining a critical pathway for stem cell specification. The Notch signaling mutant mind bomb displays normal embryonic hematopoiesis but fails to specify adult HSCs. Surprisingly, transient Notch activation during embryogenesis via an inducible transgenic system led to a Runx1-dependent expansion of HSCs in the aorta-gonad-mesonephros (AGM) region. In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow. This increase was followed by the accelerated recovery of all the mature blood cell lineages. These data define the Notch-Runx pathway as critical for the developmental specification of HSC fate and the subsequent homeostasis of HSC number, thus providing a mechanism for amplifying stem cells in vivo.

Animals↗
PubMed2006

The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis.

The MAML (mastermind-like) proteins are a family of three co-transcriptional regulators that are essential for Notch signaling, a pathway critical for cell fate determination. Though the functions of MAML proteins in normal development remain unresolved, their distinct tissue distributions and differential activities in cooperating with various Notch receptors suggest that they have unique roles. Here we show that mice with a targeted disruption of the Maml1 gene have severe muscular dystrophy. In vitro, Maml1-null embryonic fibroblasts failed to undergo MyoD-induced myogenic differentiation, further suggesting that Maml1 is required for muscle development. Interestingly, overexpression of MAML1 in C2C12 cells dramatically enhanced myotube formation and increased the expression of muscle-specific genes, while RNA interference (RNAi)-mediated MAML1 knockdown abrogated differentiation. Moreover, we determined that MAML1 interacts with MEF2C (myocyte enhancer factor 2C), functioning as its potent co-transcriptional regulator. Surprisingly, however, MAML1's promyogenic effects were completely blocked upon activation of Notch signaling, which was associated with recruitment of MAML1 away from MEF2C to the Notch transcriptional complex. Our study thus reveals novel and nonredundant functions for MAML1: It acts as a coactivator for MEF2C transcription and is essential for proper muscle development. Mechanistically, MAML1 appears to mediate cross-talk between Notch and MEF2 to influence myogenic differentiation.

Animals↗
PubMed1995

Elimination of AC interference in electrocardiogram using IIR notch filter with transient suppression.

In this paper, a technique for suppressing the transient states of IIR notch filter is investigated. This technique uses the vector projection to find better initial values for notch filters. When a notch or comb filter is used to eliminate power line (AC) interference in the recording of electrocardiograms (ECG), the performance of the notch filter with transient suppression is better than that of the conventional notch filter with arbitrary initial condition. The improvements with this technique are at the cost of additional computation load at the beginning of filtering.

Artifacts↗
PubMed1996

The effect of notch shape and self-cured acrylic resin repair on the fatigue resistance of an acrylic resin denture base.

This study compares four different notch shapes made on the anterior margin of the palatal plates of heat-cured acrylic resin test specimens as well as the effect of self-cured acrylic resin repair on the fatigue resistance of dentures. The test specimens had the shape of an upper partial denture (n = 25). The fatigue test applied was a constant-force fatigue test at a force of 150 N. The stress concentrations during loading the replicas of the test specimens were determined in the field of a circular polarized light. The results showed that the fatigue resistance of the test specimens decreased dramatically (P = 0.002) when there was a notch at the anterior margin of the palatal plate in the test specimen. A 90 degree notch decreased the fatigue resistance most effectively. The test specimens repaired with self-cured acrylic resin were also weaker than the original unnotched test specimens. Examination of the replicas in the field of polarized light showed that stresses occurred only very close to the notch. The highest stress concentrations were detected in the test specimen with a 90 degree notch, i.e. the test specimens with the lowest fatigue resistance. The results of this study suggest that the shape of the anterior margin of the palatal plate in the acrylic resin-based partial denture plays an important role in the fatigue resistance of the dentures.

Acrylic Resins↗
PubMed1998

The reliability of the detection of an early diastolic notch with uterine artery Doppler velocimetry.

This study evaluates the ability of two reviewers to detect independently an early diastolic notch in 1371 uterine artery Doppler velocity waveform recordings. Agreement between the two reviewers for the detection of uterine artery notching was assessed by using the Kappa statistic. The inter-rater reliability for the detection of unilateral notching was 0.75 (95% CI 0.70-0.80), whereas that for the presence or absence of bilateral notching was 0.66 (95% CI 0.60-0.71). The results suggest that there was good reviewer agreement for the presence or absence of a notch on uterine artery Doppler velocimetry.

Arteries↗
PubMed2006

TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones.

p73, like Notch, has been implicated in neurodevelopment and in the maintenance of the mature central nervous system. In this study, by the use of reporter-gene assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene transcription driven by the Notch-1 intracellular domain (N1(ICD)) is potently antagonized by exogenously expressed transactivating (TA) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated that the inhibitory effects of TAp73 are direct and are not mediated via the product of a downstream target gene. We found that endogenous TAp73 stabilized by either c-Abl or cisplatin treatment also potently antagonized N1(ICD)/CBF-1-dependent gene transcription. Furthermore, western blotting revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein induced by exogenous N1(ICD) expression. Evidence of a direct physical interaction between N1(ICD) and TAp73alpha was demonstrated by co-immunoprecipitation. Using Notch deletion constructs, we demonstrate that TAp73alpha binds the N1(ICD) in a region C-terminal of aa 2094. Interestingly, DeltaNp73alpha and TAp73alpha(R292H) also co-purified with N1(ICD), but neither inhibited N1(ICD)/CBF-1-dependent transcription. This suggests that an intact transactivation (TA) domain and the ability to bind DNA are necessary for TAp73 to antagonize Notch signalling. Finally we found that TAp73alpha reversed the N1(ICD)-mediated repression of retinoic acid-induced differentiation of SH-SY5Y neuroblastomas, providing functional evidence for an inhibitory effect of TAp73alpha on notch signalling. Collectively, these findings may have ramifications for neurodevelopment, neurodegeneration and oncogenesis.

Basic Helix-Loop-Helix Proteins↗
PubMed2003

Scattering of the fundamental shear horizontal mode from steps and notches in plates.

The scattering of the SH0 mode from discontinuities in the geometry of a plate has been studied. Both finite element and modal decomposition methods have been used to study the reflection and transmission characteristics from a thickness step in a plate, obtaining very good agreement. The significance of nonpropagating modes in the scattering from steps in plates has been specifically investigated. A method to approximate the reflection from rectangular notches by superimposing the reflection from a step down (start of the notch) and a step up (end of the notch) has been proposed. It is demonstrated that it is possible to use this method to obtain the reflection from a notch of any depth and at any frequency. The effect of frequency on the reflection from notches has been examined. The limits of this method in approximating cracklike defects have also been studied.

Journal Article↗
PubMed2003

Localization of notches with Lamb waves.

A time-frequency representation (TFR) is used to analyze the interaction of a multimode and dispersive Lamb wave with a notch, and then serves as the basis for a correlation technique to locate the notch. The experimental procedure uses a laser source and a dual-probe laser interferometer to generate and detect Lamb waves in a notched plate. The high fidelity, broad-bandwidth, point-like and noncontact nature of laser ultrasonics are critical to the success of this study, making it possible to experimentally measure transient Lamb waves without any frequency biases. A specific TFR, the reassigned spectrogram, is used to resolve the dispersion curves of the individual modes of the plate, and then the slowness-frequency representation (SFR) of the plate is calculated from this reassigned spectrogram. By considering the notch to be an additional (second) source, the reflected and transmitted contributions of each Lamb mode are automatically identified using the SFRs. These results are then used to develop a quantitative understanding of the interaction of an incident Lamb wave with a notch, helping to identify mode conversion. Finally, two complementary, automated localization techniques are developed based on this understanding of scattering of Lamb waves.

Models, Theoretical↗
PubMed1986

Auditory brain stem responses from human adults and infants: restriction of frequency contribution by notched-noise masking.

The frequency contribution to the click-evoked ABR wave V was examined in adults and 3-month-old infants through the use of notch-filtered broadband noise. Notch center frequencies were set at 1.0, 4.0, and 8.0 kHz. Responses were obtained at 20, 40, and 60 dBnHL during the simultaneous presentation of each notched-noise masker as well as in an unmasked condition. The ABR wave V was analyzed for absolute latency and amplitude, as well as latency and amplitude changes resulting from the introduction of masking. Analyses showed wave V latency and amplitude values to be similar for adults and infants within the 1.0-kHz notch. Differences between adult and infant groups were observed as the notch was shifted to the high frequencies. Further, latency and amplitude shifts resulting from the introduction of masking noise produced differential effects on infant responses when compared to adults.

Adult↗
PubMed1995

Comparison of auditory filter shapes obtained with notched-noise and noise-tone maskers.

The notched-noise method has been widely used to estimate the shape of the auditory filter. Results obtained using this method may be influenced by combination bands produced by the interaction of components within the upper band of noise in the notched-noise masker. To assess the possible effect of such combination bands, results were compared for two types of masker: A notched noise, as used in previous experiments; and a masker in which the upper band of noise was replaced by a sinusoid with a frequency corresponding to the lower edge frequency of that band. This is referred to as the noise-tone masker. The signal frequency was 2 kHz, and measurements were obtained for two different spectrum levels of the noise masker, 30 and 45 dB. Auditory filter shapes derived using the two maskers were similar on their low-frequency sides, as expected. The low-frequency sides were less steep at the higher masker level. The high-frequency sides of the auditory filters derived using the noise-tone masker were sometimes slightly steeper than those obtained using the notched-noise masker, but the effect was generally small. Changes with level on the high-frequency sides were not consistent across subjects. An analysis of the notched-noise data taking into account the effects of the combination bands suggests that the maximal spectrum level of the combination bands, in the region just below the lower spectral edge of the primary noise band, is about 20 to 30 dB below the spectrum level of the primary band.(ABSTRACT TRUNCATED AT 250 WORDS)

Auditory Perception↗
PubMed1998

Variable-duration notched-noise experiments in a broadband noise context.

A variable-duration notched-noise experiment was conducted in a noise context. Broadband noise preceded and followed a tone and notched noise of similar duration. Thresholds were measured at four durations (10, 30, 100, and 300 ms), two center frequencies (0.6, 2.0 kHz), and five relative notch widths (0.0, 0.1, 0.2, 0.4, 0.8). At 0.6 kHz, 10-ms thresholds decrease 6 dB across notch widths, while 300-ms thresholds decrease over 35 dB. These trends are similar but less pronounced at 2 kHz. In a second experiment, the short-duration notched noise was replaced with a flat noise which provided an equivalent amount of simultaneous masking and thresholds dropped by as much as 20 dB. A simple combination of simultaneous and nonsimultaneous masking is unable to predict these results. Instead, it appears that the elevated thresholds at short durations are dependent on the spectral shape of the simultaneous masker.

Adult↗
PubMed2003

Notch-mediated restoration of regenerative potential to aged muscle.

A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.

Aging↗
PubMed2004

Papillomavirus-mediated neoplastic progression is associated with reciprocal changes in JAGGED1 and manic fringe expression linked to notch activation.

Infection by high-risk human papillomaviruses (HPV) and persistent expression of viral oncogenes E6 and E7 are causally linked to the development of cervical cancer. These oncogenes are necessary but insufficient for complete transformation of human epithelial cells in vivo. Intracellular Notch1 protein is detected in invasive cervical carcinomas (ICC), and truncated Notch1 alleles complement the function of E6/E7 in the transformation of human epithelial cells. Here we investigate potential mechanisms of Notch activation in a human cervical neoplasia. We have analyzed human cervical lesions and serial passages of an HPV type 16-positive human cervical low-grade lesion-derived cell line, W12, that shows abnormalities resembling those seen in cervical neoplastic progression in vivo. Late-passage, but not early-passage, W12 and progression of the majority of human high-grade cervical lesions to ICC showed upregulation of Notch ligand and Jagged1 and downregulation of Manic Fringe, a negative regulator of Jagged1-Notch1 signaling. Concomitantly, an increase in Notch/CSL (CBF1, Suppressor of Hairless, Lag1)-driven reporter activity and a decrease in Manic Fringe upstream regulatory region (MFng-URR)-driven reporter activity was observed in late-passage versus early passage W12. Analysis of the MFng-URR revealed that Notch signaling represses this gene through Hairy Enhancer of Split 1, a transcriptional target of the Notch pathway. Expression of Manic Fringe by a recombinant adenovirus, dominant-negative Jagged1, or small interfering RNA against Jagged1 inhibits the tumorigenicity of CaSki, an ICC-derived cell line that was previously shown to be susceptible to growth inhibition induced by antisense Notch1. We suggest that activation of Notch in cervical neoplasia is Jagged1 dependent and that its susceptibility to the influence of Manic Fringe is of therapeutic value.

3T3 Cells↗
PubMed2002

Notch signaling induces rapid degradation of achaete-scute homolog 1.

In neural development, Notch signaling plays a key role in restricting neuronal differentiation, promoting the maintenance of progenitor cells. Classically, Notch signaling causes transactivation of Hairy-enhancer of Split (HES) genes which leads to transcriptional repression of neural determination and differentiation genes. We now report that in addition to its known transcriptional mechanism, Notch signaling also leads to rapid degradation of the basic helix-loop-helix (bHLH) transcription factor human achaete-scute homolog 1 (hASH1). Using recombinant adenoviruses expressing active Notch1 in small-cell lung cancer cells, we showed that the initial appearance of Notch1 coincided with the loss of hASH1 protein, preceding the full decay of hASH1 mRNA. Overexpression of HES1 alone was capable of down-regulating hASH1 mRNA but could not replicate the acute reduction of hASH1 protein induced by Notch1. When adenoviral hASH1 was coinfected with Notch1, we still observed a dramatic and abrupt loss of the exogenous hASH1 protein, despite high levels of ongoing hASH1 RNA expression. Notch1 treatment decreased the apparent half-life of the adenoviral hASH1 protein and increased the fraction of hASH1 which was polyubiquitinylated. The proteasome inhibitor MG132 reversed the Notch1-induced degradation. The Notch RAM domain was dispensable but a lack of the OPA and PEST domains inactivated this Notch1 action. Overexpression of the hASH1-dimerizing partner E12 could protect hASH1 from degradation. This novel function of activated Notch to rapidly degrade a class II bHLH protein may prove to be important in many contexts in development and in cancer.

Animals↗
PubMed2000

Directionality derived from pinna-cue spectral notches in cat dorsal cochlear nucleus.

We tested two hypotheses to determine whether dorsal cochlear nucleus (DCN) neurons are specialized to derive directionality from spectral notches: DCN neurons exhibit greater spectral-dependent directionality than ventral cochlear nucleus (VCN) neurons, and spectral-dependent directionality depends on response minima (nulls) produced by coincidence of best frequency (BF) and spectral-notch center frequency. Single-unit responses to 50-ms noise and tone bursts were recorded in barbiturate-anesthetized cats (BFs: 4-37 kHz). Units were classified using BF tone poststimulus time histograms. Pauser, onset-G (type II interneurons), and some chopper units were recorded from the DCN. Primary-like, onset-CIL (onset other than onset-G), and most choppers in the sample were recorded from the VCN. Many pauser and onset-G units were highly directional to noise. Chopper, onset-CIL, and primary-like units (collectively referred to as C-O-P units) were not. The difference in directionality depends on a monaural mechanism as pausers were more directional to monaural noise than C-O-P units. Contralateral inhibition produced a small increase in pauser directionality to noise simulation but had no effect on directionality of C-O-P units. Pauser and C-O-P units exhibited similar low directionality to BF tone, showing that the difference in noise directionality between groups depends on spectral cues. These results show that spectral-dependent directionality is a DCN specialization. Azimuth functions of highly directional units exhibited response nulls, and there was a linear relationship between BFs in the range of 8-13 kHz and azimuthal locations of nulls. This relationship parallels the known spatial distribution of spectral-notch center frequencies on the horizontal plane. Furthermore spatial receptive fields of pausers show response nulls that follow the expected diagonal trajectory of the spectral notch in this frequency range. These results show that DCN spectral-dependent directionality depends on response nulls produced by coincidence of unit BF and spectral-notch center-frequency.

Acoustic Stimulation↗
PubMed2004

Expression of notch receptors and ligands in the adult gut.

The Notch signaling pathway has become recognized as a vitally important pathway in regulating proliferative/differentiative decisions and cell fate. To explore the involvement of the Notch pathway in adult gut, we investigated the expression of Notch receptors and their ligands by Northern blotting and in situ hybridization. Notch receptors and ligands were expressed in both proliferative and post-mitotic cells throughout adult rat gut, variously in epithelial, immune, and endothelial cells. Expression of Notch1, Jagged1, and Jagged2 frequently overlapped, whereas Notch2 expression was restricted to specific crypt cells, the lamina propria of the large intestine, and Peyer's patch lymphocytes. We propose that the expression of multiple Notch receptors and ligands in a range of different intestinal cell types indicates that this signaling pathway underpins many of the processes involved in the maintenance and function of the adult gut.

Animals↗
PubMed2006

Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands.

Notch is a major factor mediating interaction between hematopoietic progenitor cells (HPCs) and bone marrow stroma (BMS). However its contribution to dendritic cell (DC) differentiation is controversial. We found that main Notch ligands Delta-1 and Jagged-1 had the opposite effect on DC differentiation. Delta-1 promoted generation of fully differentiated DCs, whereas Jagged-1 stimulated accumulation of DC precursors but prevented their transition to terminally differentiated DCs. BMS expressed a substantially higher level of Jagged-1 than Delta-1. Just the opposite expression pattern was observed in spleen stroma (SS). The BMS effect on DC differentiation was similar to that of Jagged-1, whereas the effect of SS was similar to the effect of Delta-1. Down-regulation of Jagged-1 in BMS substantially increased DC differentiation. Experiments in vivo with adoptive transfer of DC precursors further supported the different roles of BMS and SS in DC development. Jagged-1 and Delta-1 equally activated CBF-1/RBPJkappa transcription factor, which is a major Notch target. However, they produced a different pattern of activation of Notch target gene Hes1. Overexpression of Hes1 resulted in increased DC differentiation from HPCs. Thus, this study not only revealed the different role of Notch ligands in DC differentiation but also may provide a new insight into regulation of DC differentiation by BMS.

Animals↗
PubMed2005

The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear.

The mammalian auditory sensory epithelium, the organ of Corti, contains sensory hair cells and nonsensory supporting cells arranged in a highly patterned mosaic. Notch-mediated lateral inhibition is the proposed mechanism for creating this sensory mosaic. Previous work has shown that mice lacking the Notch ligand JAG2 differentiate supernumerary hair cells in the cochlea, consistent with the lateral inhibitory model. However, it was not clear why only relatively modest increases in hair cell production were observed in Jag2 mutant mice. Here, we show that another Notch ligand, DLL1, functions synergistically with JAG2 in regulating hair cell differentiation in the cochlea. We also show by conditional inactivation that these ligands probably signal through the NOTCH1 receptor. Supernumerary hair cells in Dll1/Jag2 double mutants arise primarily through a switch in cell fate, rather than through excess proliferation. Although these results demonstrate an important role for Notch-mediated lateral inhibition during cochlear hair cell patterning, we also detected abnormally prolonged cellular proliferation that preferentially affected supporting cells in the organ of Corti. Our results demonstrate that the Notch pathway plays a dual role in regulating cellular differentiation and patterning in the cochlea, acting both through lateral inhibition and the control of cellular proliferation.

Animals↗