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PubMed2006

Synergy between the pre-T cell receptor and Notch: cementing the alphabeta lineage choice.

Notch1 signaling suppresses B cell development and promotes T lineage commitment in thymus-seeding hematopoietic progenitors. Notch1 is also activated in early T cell progenitors, but the functions of these later Notch signals have not been clearly defined. Recent studies reveal that Notch signaling is not essential for pre-T cell receptor (TCR) expression or gammadelta lineage choice. Rather, pre-TCR signaling enhances progenitor competitiveness for limiting Notch ligands, leading to preferential expansion of TCRbeta-bearing progenitors.

Cell Differentiation↗
PubMed1973

Is the notch locus of Drosophila melanogaster a tandem repeat? Correlation of the genetic map and complementation pattern of selected mutations.

Correlation of the complementation relationships between the Notch locus alleles fa(g), fa(no), Ax(59d) and nd, with their genetic map order, suggests a tandem repetition within the locus of functionally related sites. This observation is discussed in relation to two hypotheses: (1) that the Notch locus contains a tandem repeat of genetic material; and (2) that the tertiary structure of the Notch locus product has a spiral configuration.

Alleles↗
PubMed1991

Repair of UV-induced pyrimidine dimers in the individual genes Gart, Notch and white from Drosophila melanogaster cell lines.

The excision repair of UV-induced pyrimidine dimers was investigated in three genes: Gart, Notch and white in a permanent Drosophila cell line Kc, derived from wild type Drosophila melanogaster embryonic cells. In this cell line Gart and Notch are actively transcribed, whereas white is not expressed. In all three genes UV-induced pyrimidine dimers were removed with the same rate and to the same extent: 60% removal within 16 hours, up to 80-100% in 24 hours after irradiation with 10 or 15 J/m2 UV. These kinetics are similar to the time course of dimer removal measured in the genome overall. No difference in repair of the inactive white locus compared to the active Gart and Notch genes was found. Similar results were obtained using a different wild type cell line, SL2, although repair appeared to be somewhat slower in this cell line. The results are discussed with respect to the data found for gene specific repair in other eukaryotic systems.

Animals↗
PubMed1995

Thresholds for auditory brain stem responses to tones in notched noise from infants and young children with normal hearing or sensorineural hearing loss.

OBJECTIVE: To assess the accuracy of threshold estimates determined using the auditory brain stem responses (ABRs) to brief tones presented in notched noise in a group of infants and young children with normal hearing or sensorineural hearing loss (SNHL). DESIGN: The thresholds for ABRs to brief duration 500, 2000, and 4000 Hz tones presented in notched-noise masking were evaluated in infants and young children with normal hearing (N = 34) or SNHL (N = 54). Tone-evoked ABR thresholds were compared with behavioral thresholds obtained at follow-up audiologic assessments, for a total of 220 comparisons. RESULTS: ABR thresholds for the infants with bilateral normal hearing were 23.6, 12.9, and 12.6 dB nHL for 500, 2000 and 4000 Hz, respectively. Most (92 to 100%) infants with normal hearing showed ABRs to 30 dB nHL tones. Across all subjects (i.e., those with normal hearing and those with impaired hearing), high ( > or = 0.94) correlations were found between the ABR and behavioral thresholds. The mean differences between ABR (dB nHL) and behavioral (dB HL) thresholds across all subjects were 8.6, -0.4, and -4.3 dB for 500, 2000, and 4000 Hz, respectively. Overall, 98% of the ABR thresholds were within 30 dB of the behavioral thresholds, 93% were within 20 dB, and 80% were within 15 dB. CONCLUSIONS: These threshold results for the ABR to brief tones in notched noise obtained for infants and young children are similar to those obtained in similar studies of adults. The technique may be used clinically with reasonable accuracy to estimate pure-tone behavioral thresholds in infants and young children who are referred for diagnostic threshold ABR testing.

Audiometry, Pure-Tone↗
PubMed1998

Notch is expressed in adult brain, is coexpressed with presenilin-1, and is altered in Alzheimer disease.

In C. elegans, the Notch family member lin-12 has been shown to have a genetic interaction with sel-12, the homologue of the Alzheimer disease-associated presenilin (PS) genes in humans. Mutations in PS genes cause autosomal dominant Alzheimer disease, with age of onset frequently in the 40s. Notch is known as a developmental protein that plays an important role in lateral inhibition and specifying cell fate decisions in proliferating immature cells, and is not known to be present in adult neurons. We reasoned that, if Notch1/PS-1 interaction is relevant in Alzheimer disease, Notch1 would also need to be expressed in neurons in adult brain and colocalized with PS-1. We found that Notch1, Notch2, and a Notch ligand, Jagged1, are expressed in adult brain in mouse and in human, with strongest expression in the hippocampal formation and Purkinje cells of the cerebellum. Double immunofluorescent staining demonstrates neuronal colocalization of Notch1 with PS-1. Moreover, Notch1 expression in sporadic Alzheimer disease hippocampus is elevated more than 2-fold in comparison to that in control human hippocampus by both immunohistochemistry and Western blot analysis (p < 0.007). These results support the hypothesis that Notch1 continues to play a role in terminally differentiated neurons, and that Notch1/PS-1 interactions may occur in adult mammalian brain. The alteration in Notch1 expression in sporadic Alzheimer disease raises the possibility that disruption of Notch1/PS-1 functional interactions may occur in Alzheimer disease.

Aged↗
PubMed2003

Relationship of cervical spinal rootlets and the inferior vertebral notch.

The anatomic features of cervical spinal rootlets from C5 to T1 and their relationships to the inferior vertebral notches were studied. Fifteen fresh cadavers were dissected and the cervical spinal cord and spinal rootlets were exposed by posterior total laminectomy. The dorsal rootlet entry zone of each spinal root was located proximal to the inferior vertebral notch, with an increasing distance from 15 mm at C5 to 28 mm at T1. The angle sustained by the rootlets to the cord decreased from 45 degrees to 89 degrees at C5 and to 23 degrees to 41 degrees at T1. Ventral rootlet exit zones shared similar arrangements and orientations, but they could not be exposed with posterior laminectomy only. Spinal rootlets of a particular cervical spinal segment may be found medial to the pedicles or through the intervertebral foramen one level above. They may be exposed by foraminotomy or partial excision of the pedicles. The inferior vertebral notch, which is the inferior border of the pedicle, is a reliable landmark for location of the rootlets. The information is useful for safe surgical manipulation and instrumentation around the pedicles, and when reimplantation of spinal nerve roots is considered for total brachial palsy.

Adult↗
PubMed2003

Anatomic basis of notch deformity in open rhinoplasty.

Notch deformity at the columella after the stairstep incision is an unsightly sequel that fuels negativism for open rhinoplasty critics. Obvious causes cited include surgical misadventures involving division of the foot of the medial crus and poor healing. The authors offer yet an additional etiology based on the contraction distortion caused by the depressor septi nasi muscle. The purpose of this study is to investigate the anatomic basis for notch deformity after stairstep technique in open rhinoplasty. For this anatomic study, 10 fresh cadavers were used. Dissections were performed, exposing the columellar components. The macroscopic and microscopic photo documentation gathered supports the authors' theory that depressor septi nasi action causes skin-edge deformation that leads to closure malalignment and notch deformity. Pre-incision landmark defining tattoo or sutures will assure proper alignment at closure.

Cadaver↗
PubMed2006

Canonical notch signaling functions as a commitment switch in the epidermal lineage.

Mammalian epidermis consists of a basal layer of proliferative progenitors that gives rise to multiple differentiating layers to provide a waterproof envelope covering the skin surface. To accomplish this, progenitor cells must detach from the basal layer, move upward, and execute a terminal differentiation program consisting of three distinct stages: spinous, granular layer, and stratum corneum. Notch signaling has been implicated in late stages of differentiation, but the commitment switch remains unknown. Here we show with loss and gain-of-function studies that active Notch intracellular domain (NICD) and its obligate canonical signaling partner RBP-J act at the basal/suprabasal juncture to induce spinous and down-regulate basal fate. Spinous layers are absent in RBP-J conditional null epidermis and expanded when Notch1 signaling is elevated transgenically in epidermis. We show that RBP-J is essential for mediating both spinous gene activation and basal gene repression. In contrast, the NICD/RBP-J target gene Hes1 is expressed in spinous layers and mediates spinous gene induction but not basal gene repression. These data uncover an early role for RBP-J and Notch in commitment of epidermal cells to terminally differentiate and reveal that spinous gene induction is mediated by a Hes1-dependent mechanism, while basal gene repression occurs independently of Hes1.

Animals↗
PubMed2005

Mandibular antegonial and ramus notch depths and condylar bone change.

The present study sought to clarify the relationship between antegonial and ramus notch depths and condylar bone change, and analyse the effects of such change on craniofacial structure. The study sample was of 28 pre-orthodontic patients with signs and symptoms of temporomandibular joint (TMJ) disorders, who underwent helical computed tomography to diagnose their TMJ pathology. Craniofacial structures were compared between 14 subjects with bilateral condylar bone change (BBC group: two male and 12 female) and 14 subjects with no bone change (NBC group: two male and 12 female). Sella-nasion-point B (SNB) and point A-nasion-point B (ANB) angles were significantly smaller in BBC than in NBC, with ramus height and mandibular body lengths significantly shorter in BBC than in NBC. The BBC lower facial height and SN-Go-Ar angle, as well as antegonial and ramus notch depths, were significantly greater than in NBC, and the mandible was significantly more retruded in BBC than in NBC. These results showed that condylar bone change might be related not only to mandibular size (e.g. retrusion) but also to mandibular outline (including antegonial and ramus notch depth).

Adolescent↗
PubMed2006

Notch and NGF/p75NTR control dendrite morphology and the balance of excitatory/inhibitory synaptic input to hippocampal neurones through Neurogenin 3.

We have previously shown that dendrite morphology of cultured hippocampal neurones is controlled by Notch receptor activation or binding of nerve growth factor (NGF) to its low affinity receptor p75NTR, i.e. processes that up-regulate the expression of the Homologue of enhancer of split 1 and 5. Thus, the increased expression of these genes decreases the number of dendrites, whereas abrogation of Homologue of enhancer of split 1/5 activity stimulates the outgrowth of new dendrites. Here, we show that Neurogenin 3 is a proneural gene that is negatively regulated by Homologue of enhancer of split 1/5. It also influences dendrite morphology. Hence, a deficit of Notch or NGF/p75NTR activation can lead to the production of high levels of Neurogenin 3, which stimulates the outgrowth of new dendrites. Conversely, activation of either Notch or p75NTR depressed Neurogenin 3 expression, which not only decreased the number of dendrites but also favoured inhibitory (GABAergic) synaptogenesis, thereby diminishing the ratios of excitatory/inhibitory inputs. NGF also augmented the levels of mRNA encoding the vesicular inhibitory amino acid transporter, but it did not affect the fraction of GAD65/67-positive neurones. Conversely, overexpression of Neurogenin 3 largely reduced the number of inhibitory synaptic contacts and, consequently, produced a strong increase in the ratios of excitatory/inhibitory synaptic terminals. Our results reveal a hitherto unknown contribution of NGF/p75NTR to dendritic and synaptic plasticity through Neurogenin 3 signalling.

Animals↗
PubMed1989

Gene dosage studies of a temperature sensitive Abruptex mutation of the Notch locus of Drosophila melanogaster.

Gene dosage studies of a temperature sensitive Abruptex mutation of the Notch locus of Drosophila melanogaster revealed, firstly, that hemizygous females were lethal at all temperatures studied, while hemizygous males were subvital at 18 degrees C, semilethal at 25 degrees C, and lethal at 29 degrees C. This is due to dosage compensation of the Notch locus. Secondly, it was observed that in general an increasing dose of the wild allele decreased the expression of Abruptex at all temperatures. An exception was the Axtsl/Axtsl/ + genotype, which was more expressed than Axtsl/Axtsl at low temperatures. This suggests antimorphism as the most likely mode of action of the temperature sensitive Abruptex mutation. Thirdly, it was observed that the expression of Abruptex phenotype increased from 18 degrees C to 25 degrees C but decreased from 25 degrees C to 29 degrees C if the wild type allele was involved in the genotype. This suggests that the gene product of the temperature sensitive Abruptex allele loses its function at high temperatures. The putative antimorphic mode of action of the temperature sensitive Abruptex mutation suggests that the Notch gene product interacts with products of other neurogenic loci or with itself.

Animals↗
PubMed2003

Measurement of surface wave transmission coefficient across surface-breaking cracks and notches in concrete.

In this paper, a technique for measuring a surface wave transmission coefficient across surface-breaking cracks and notches in a heterogeneous but globally isotropic material (concrete) is presented. Once the transmission coefficient across a surface discontinuity is known, its depth may be estimated. There are many difficulties in measuring the transmission coefficient experimentally owing to effects of wave path dependence, unknown characteristics of the receiver and the wave source, and the variation of impact event or receiver coupling. To eliminate the undesired effects, a self-calibrating measurement scheme is applied to obtain the surface wave transmission coefficient across notches and surface-breaking cracks in concrete. The obtained signal transmission coefficient is not affected by the experimental setup or the heterogeneous nature of the material. The testing scheme is described and experimental results obtained from concrete specimens with notches and surface-breaking cracks are presented. Repeatable and reliable measurements of surface wave transmission coefficient are obtained, which demonstrate a strong relation to normalized discontinuity depth. A numerical study using the boundary element method is presented, which verifies the experimental findings.

Journal Article↗
PubMed2005

Extracting the frequencies of the pinna spectral notches in measured head related impulse responses.

The head related impulse response (HRIR) characterizes the auditory cues created by scattering of sound off a person's anatomy. The experimentally measured HRIR depends on several factors such as reflections from body parts (torso, shoulder, and knees), head diffraction, and reflection/ diffraction effects due to the pinna. Structural models (Algazi et al., 2002; Brown and Duda, 1998) seek to establish direct relationships between the features in the HRIR and the anatomy. While there is evidence that particular features in the HRIR can be explained by anthropometry, the creation of such models from experimental data is hampered by the fact that the extraction of the features in the HRIR is not automatic. One of the prominent features observed in the HRIR, and one that has been shown to be important for elevation perception, are the deep spectral notches attributed to the pinna. In this paper we propose a method to robustly extract the frequencies of the pinna spectral notches from the measured HRIR, distinguishing them from other confounding features. The method also extracts the resonances described by Shaw (1997). The techniques are applied to the publicly available CIPIC HRIR database (Algazi et al., 2001c). The extracted notch frequencies are related to the physical dimensions and shape of the pinna.

Acoustics↗
PubMed1995

A computational model for signal processing by the dorsal cochlear nucleus. II. Responses to broadband and notch noise.

In a previous paper a computational model was developed which was shown to account for most of the essential features of the variety of experimentally observed response maps of type-IV cells in the dorsal cochlear nucleus to pure tones. In the present study, the responses of the same model DCN to broadband noise and notch noise are investigated. It is shown that the previous model qualitatively accounts for the observed responses to these more complex sounds. Predictions of the model for inverted notches and for the behavior of type-IV cell output as notch center is varied for different amplitudes are presented. It is shown that the model is suitable for feature detection of auditory signals and an expansion is given as to how this ability arises from the properties of the stellate, type-II, and type-IV cells and the variations in the connectional patterns that were previously shown to account for the response patterns of type-IV cells to pure tones.

Auditory Perception↗
PubMed1999

Different auditory filter bandwidth estimates based on profile analysis, notched noise, and hybrid tasks.

Auditory filter bandwidths were estimated in three experiments. The first experiment was a profile-analysis experiment. The stimuli were composed of sinusoidal components ranging in frequency from 200 to 5000 Hz. The standard stimulus was the sum of equal-amplitude tones, and the signal stimulus had a power spectrum that varied up-down ... up-down. The number of components ranged from four to 60. Interval-by-interval level randomization prevented the change in level of a single component from reliably indicating the change from standard to signal. The second experiment was a notched-noise experiment in which the 1000-Hz tone to be detected was added to a noise with a notch arithmetically centered at 1000 Hz. Detection thresholds were estimated both in the presence of and in the absence of level randomization. In the third, hybrid, experiment a 1000-Hz tone was to be detected, and the masker was composed of equal-amplitude sinusoidal components ranging in frequency from 200 to 5000 Hz. For this experiment, thresholds were estimated both in the presence and absence of level variation. For both the notched-noise and hybrid experiments, only modest effects of level randomization were obtained. A variant of Durlach et al.'s channel model ["Towards a model for discrimination of broadband signals," J. Acoust. Soc. Am. 80, 63-72 (1986)] was used to estimate auditory filter bandwidths for all three experiments. When a two-parameter roex(p,r) filter weighting function was used to fit the data, bandwidth estimates were approximately two to three times as large for the two detection tasks than for the profile-analysis task.

Auditory Perception↗
PubMed2005

Meningioma transcript profiles reveal deregulated Notch signaling pathway.

Meningiomas constitute the second most common central nervous system tumor, and yet relatively little is known about the molecular events that are important for the pathogenesis and malignant progression of these tumors. We have used serial analysis of gene expression to compare the transcriptomes of nonneoplastic meninges and meningiomas of all malignancy grades. A novel finding from this screen is the induction of three components of the Notch signaling pathway: the transcription factor, hairy and enhancer of Split1 (HES1) and two members of the Groucho/transducin-like enhancer of Split family of corepressors, TLE2 and TLE3. TLE corepressors interact and modulate the activity of a wide range of transcriptional regulatory systems, one of which is HES1. We have shown that the transcript and protein levels of HES1, the Notch2 and Notch1 receptors and the Jagged1 ligand are induced in meningiomas of all grades, whereas induction of TLE2 and TLE3 occurs specifically in higher-grade meningiomas. Meningioma cell lines express components of the Notch signaling pathway and an inhibitor of this pathway suppresses meningioma cell survival. These results suggest that deregulated expression of the Notch pathway is a critical event in meningioma pathogenesis and that modulation of this and potentially other signaling pathways by TLE corepressors leads to a more malignant phenotype.

Basic Helix-Loop-Helix Proteins↗
PubMedDate not supplied

Bilaterality in anterior cruciate ligament injuries: associated intercondylar notch stenosis.

Nonsimultaneous, bilateral ACL injuries are not uncommon. We studied a group of patients with these injuries to determine possible predisposing factors that could aid in early detection and prevention of contralateral ACL injury. Retrospective analysis of 1,120 patients with ACL ruptures who were treated between 1983 and 1987 revealed 45 patients with bilateral ruptures. Complete follow-up data were available for 41 of these patients. We examined age at initial injury, sex, interval between initial and contralateral ACL injury, mechanism of injury, activity at injury, medical and family histories, treatment of initial injury, and radiographic measurement of intercondylar notch width. The overall incidence of bilaterality was 4.01% in the 28 male and 13 female patients. Their average age was 19 years and 10 months. The average interval between initial and contralateral injury was 47 months. A noncontact cutting maneuver was the most common mechanism of injury. We devised a method to measure and compare intercondylar notch widths on plain radiographs. We compared the mean notch width index (NWI) of the bilateral group to the mean NWI of a group of 50 consecutive patients with "normal" knees and to the mean NWI of 50 consecutive patients with acute ACL ruptures. The mean NWI for the normal group was .2338, for the acute ACL group, .2248, and for the bilateral group, .1961. We noted a statistically significant difference when we compared the bilateral group to the normal and acute groups (P less than 0.0001, respectively). There was no statistically significant difference between the NWI of the normal and acute ACL groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

CADASIL: what component of the vessel wall is really a target for Notch 3 gene mutations?

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline, dementia and recurrent strokes. The underlying angiopathy of the small vessels is characterized by basophilic degeneration of the media, Notch 3 protein accumulation in vessel wall and a unique type of ultrastructural deposits located nearby the basal lamina. In some cases of CADASIL, morphological changes similar to those observed in panarteritis nodosa (PAN) were found. PAN-like changes manifested as fibrinoid necrosis of the tunica media and perivascular inflammatory infiltrates were found in arteries not only in the central nervous system but also in internal organs. Presence of PAN-like changes indicates that some autoimmunological mechanisms can participate in the CADASIL process. Although vascular smooth muscle cells seem to be a primary target of the pathogenic process triggered by mutations in Notch 3 gene they are probably not the only target. This article gives a brief overview on the morphologic spectrum of the vascular pathological changes in CADASIL and discusses some of the relevant mechanisms that lead from Notch 3 mutations to ischemic infarcts.

Arterioles↗