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PubMed2001

A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock.

Tissue-specific overexpression of the glycogen synthase kinase-3 (GSK-3) ortholog shaggy (sgg) shortens the period of the Drosophila circadian locomotor activity cycle. The short period phenotype was attributed to premature nuclear translocation of the PERIOD/TIMELESS heterodimer. Reducing SGG/GSK-3 activity lengthens period, demonstrating an intrinsic role for the kinase in circadian rhythmicity. Lowered sgg activity decreased TIMELESS phosphorylation, and it was found that GSK-3 beta specifically phosphorylates TIMELESS in vitro. Overexpression of sgg in vivo converts hypophosphorylated TIMELESS to a hyperphosphorylated protein whose electrophoretic mobility, and light and phosphatase sensitivity, are indistinguishable from the rhythmically produced hyperphosphorylated TIMELESS of wild-type flies. Our results indicate a role for SGG/GSK-3 in TIMELESS phosphorylation and in the regulated nuclear translocation of the PERIOD/TIMELESS heterodimer.

Active Transport, Cell Nucleus↗

PubMed2004

Mouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signaling.

During vertebrate embryogenesis, the formation of reiterated structures along the body axis is dependent upon the generation of the somite by segmentation of the presomitic mesoderm (PSM). Notch signaling plays a crucial role in both the generation and regulation of the molecular clock that provides the spatial information for PSM cells to form somites. In a screen for novel genes involved in somitogenesis, we identified a gene encoding a Wnt antagonist, Nkd1, which is transcribed in an oscillatory manner, and may represent a new member of the molecular clock constituents. The transcription of nkd1 is extremely downregulated in the PSM of vestigial tail (vt/vt), a hypomorphic mutant of Wnt3a, whereas nkd1 oscillations have a similar phase to lunatic fringe (L-fng) transcription and they are arrested in Hes7 (a negative regulator of Notch signaling) deficient embryos. These results suggest that the transcription of nkd1 requires Wnt3a, and that its oscillation patterns depend upon the function of Hes7. Wnt signaling has been postulated to be upstream of Notch signaling but we demonstrate in this study that a Wnt-signal-related gene may also be regulated by Notch signaling. Collectively, our data suggest that the reciprocal interaction of Notch and Wnt signals, and of their respective negative feedback loops, function to organize the segmentation clock required for somitogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed1981

Clocked cell cycle clocks.

The cell division cycle of both mammalian cells and microorganisms, which apparently has both deterministic and probabilistic features, is a clock of sorts in that the sequence of events that comprise it measures time under a given set of environmental conditions. The cell division cycle may itself be regulated by a programmable clock that, under certain conditions, can generate circadian periodicities by interaction with a circadian pacemaker. These clocks must insert time segments into the cell division cycle in order to generate the observed variability in cellular generation times.

Animals↗

PubMed2004

Control of chemical pattern formation by a clock-and-wavefront type mechanism.

The segmentation of many animals ranging from insects to mammals involves the sequential formation of stationary stripes of gene expression that are perpendicular to the growth axis of the developing embryo. This process has been accounted for by a variety of theoretical "clock-and-wavefront" type models that involve the arrest of an oscillation (the clock) at a moving boundary (the wavefront). Here, we demonstrate experimentally that progressive arrest of a homogeneous oscillation can control the symmetry as well as the wavelength of spatial structures in a chemical system. We show how a spontaneously formed, labyrinthine pattern can be converted into a pattern composed of ordered, parallel stripes and confirm a previously predicted proportionality between the wavelength and the period of the homogeneous oscillation. Our experiments provide the first experimental demonstration of a general mechanism for the control of pattern formation that has been hypothesized to operate in the context of biological morphogenesis.

Animals↗

PubMed1977

Timing control accuracy in normal speakers and stutterers.

This study attempted to assess the abilities of 10 normal speakers, five stutterers in therapy, and five stutterers no longer in therapy, to control the time program of repeated utterances. The speech sample comprised repeated sentences, paragraphs, and nursery rhymes, and a finger-tapping task was included as a control. Temporal accuracy was measured. Results suggest that (1) there is a wide range of timing abilities, even among the normal speakers, with considerable overlap between the different groups of speakers; (2) on most of the experimental tasks, normal speakers are more accurate timers than are stutterers; (3) stutterers released from therapy are more accurate timers than are stutterers still in therapy, whenever these groups differ; and (4) subjects' speech timing scores correlate moderately with their tapping scores. These results are discussed in terms of (1) theoretical timing control processes, such as a neural clock for controlling speech segment durations, and a speech motor output buffer, whose capacity may be limited in stutterers, and (2) known effects of rhythmic constraints and respiratory irregularity on fluency.

Female↗

PubMedDate not supplied

Evaluation of the effect of aging on retinal nerve fiber layer thickness measured by optical coherence tomography.

PURPOSE: To evaluate the relationship between age and retinal nerve fiber layer (RNFL) thickness in normal subjects, as measured by optical coherence tomography (OCT). METHODS: One hundred and forty-four normal subjects (144 eyes), ranging from 16 to 84 years of age, were enrolled in this cross-sectional study. The RNFL thickness was determined using OCT with three circle scans 3.4 mm in diameter. RESULTS: The average RNFL thickness was inversely correlated with age (r = -0.348, p < 0.001). Analyzing the quadrants as a parameter, RNFL thickness in the superior, temporal and inferior quadrants also decreased with age. Using 30-degree segments, there were significant correlations between age and the RNFL thickness of temporal segments (7-11 o'clock). The average RNFL thickness had the highest correlation among all parameters (r = -0.348, p < 0.001). Regarding nasal quadrant thickness, RNFL ratios (average, superior, temporal and inferior RNFL thickness relative to the nasal quadrant thickness) were not significantly correlated with age. The refractive error did not affect RNFL thickness (r = 0.091, p = 0.276). CONCLUSION: Our study revealed that RNFL thickness, in particular in the temporal quadrant, measured by OCT significantly decreased with age. Age has to be taken into consideration when we compare RNFL thickness between normal and glaucomatous eyes.

Adolescent↗

PubMed1990

Serial conditioning as a function of stimulus, response, and temporal dependencies.

Six experiments were used to examine the effects of explicit response, stimulus, and temporal dependencies on responding in an interfood interval. The first two experiments demonstrated that 10-segment 60-s interfood clocks controlled similar distributions of key pecking in pigeons regardless of whether response-reinforcement contiguity was required, allowed, or precluded. The third and fourth experiments found that in the absence of an explicit response-reinforcement dependency, systematic explicit stimuli in an interfood interval were sufficient to establish and maintain the characteristic distribution of key pecking and that an interval without an explicit clock failed to establish or maintain key pecking. The last two experiments demonstrated that the interfood interval need not be of fixed length, and that a simple correlation of stimuli with increments from either a minimum to a maximum imminency or probability of food presentation controlled behavior in a similar manner. Successively higher rates generally occurred to successively later stimuli in the upper half of the range.

Journal Article↗

PubMed2003

New evidence for genome-wide duplications at the origin of vertebrates using an amphioxus gene set and completed animal genomes.

The 2R hypothesis predicting two genome duplications at the origin of vertebrates is highly controversial. Studies published so far include limited sequence data from organisms close to the hypothesized genome duplications. Through the comparison of a gene catalog from amphioxus, the closest living invertebrate relative of vertebrates, to 3453 single-copy genes orthologous between Caenorhabditis elegans (C), Drosophila melanogaster (D), and Saccharomyces cerevisiae (Y), and to Ciona intestinalis ESTs, mouse, and human genes, we show with a large number of genes that the gene duplication activity is significantly higher after the separation of amphioxus and the vertebrate lineages, which we estimate at 650 million years (Myr). The majority of human orthologs of 195 CDY groups that could be dated by the molecular clock appear to be duplicated between 300 and 680 Myr with a mean at 488 million years ago (Mya). We detected 485 duplicated chromosomal segments in the human genome containing CDY orthologs, 331 of which are found duplicated in the mouse genome and within regions syntenic between human and mouse, indicating that these were generated earlier than the human-mouse split. Model based calculations of the codon substitution rate of the human genes included in these segments agree with the molecular clock duplication time-scale prediction. Our results favor at least one large duplication event at the origin of vertebrates, followed by smaller scale duplication closer to the bird-mammalian split.

Animals↗

PubMed2003

Is the somitogenesis clock really cell-autonomous? A coupled-oscillator model of segmentation.

A striking pattern of oscillatory gene expression, related to the segmentation process (somitogenesis), has been identified in chick, mouse, and zebrafish embryos. Somitogenesis displays great autonomy, and it is generally assumed in the literature that somitogenesis-related oscillations are cell-autonomous in chick and mouse. We point out in this article that there would be many biological reasons to expect some mechanism of coupling between cellular oscillators, and we present a model with such coupling, but which also has autonomous properties. Previous experiments can be re-interpreted in light of this model, showing that it is possible to reconcile both autonomous and non-autonomous aspects. We also show that experimental data, previously interpreted as supporting a purely negative-feedback model for the mechanism of the oscillations, is in fact more compatible with this new model, which relies essentially on positive feedback.

Animals↗

PubMed1982

A bent-tipped vitrophage for anterior segment surgery.

A vitrectomy instrument with a bent shaft designed to allow ease of insertion over the brow ridge at the 12-o'clock position, easier access to anterior segment structures, and a simplified approach to the area of the vitreous close to the sclerotomy incision site is described herein.

Humans↗

PubMed2000

Using alu J elements as molecular clocks to trace the evolutionary relationships between duplicated HLA class I genomic segments.

The class I region of the major histocompatibility complex contains two subgenomic blocks (250-350 kb each), known as the alpha and beta blocks. These blocks contain members of multicopy gene families including HLA class I, HERV-16 (previously called P5 sequences), and PERB11 (MIC). We have previously shown that each block consists of imperfect duplicated segments (duplicons) containing linked members of different gene families, retroelements and transposons that have coevolved as part of two separate evolutionary events. Another region provisionally designated here as the kappa block is located between the alpha and the beta blocks and contains HLA-E, -30, and -92, HERV-16 (P5.3), and PERB11.3 (MICC) within about 250 kb of sequence. Using Alu elements to trace the evolutionary relationships between different class I duplicons, we have found that (a) the kappa block contains paralogous (duplicated) Alu J sequences and other retroelement patterns more in common with the beta than the alpha block; (b) the retroelement pattern associated with the HLA-E duplicon is different from all other HLA class I duplicons, indicating a more complex evolution; (c) the HLA-92 duplicon, although substantially shorter, is closely related in sequence to the HLA-B and -C duplicons; (d) two of the six paralogous Alu J elements within the HLA-B and -C duplicons are associated with the HLA-X duplicon, confirming their evolutionary relationships within the beta block; and (e) the paralogous Alu J elements within the alpha block are distinctly different from those identified within the beta and kappa blocks. The sequence conservation and location of duplicated (paralogous) Alu J elements in the MHC class I region show that the beta and kappa blocks have evolved separately from the alpha block beginning at a time before or during the evolution of Alu J elements in primates.

Alu Elements↗

PubMed2006

Background music as a quasi clock in retrospective duration judgments.

The segmentation-change model of time perception proposes that individuals engaged in cognitive tasks during a given interval of time retrospectively estimate duration by recalling events that occurred during the interval and inferring each event's duration. Previous research suggests that individuals can recall the number of songs heard during an interval and infer the length of each song, exactly the conditions that foster estimates of duration based on the segmentation-change model. The results of a laboratory experiment indicated that subjects who solved word-search puzzles for 20 min. estimated the duration of the interval to be longer when 8 short songs (<3 min.) as opposed to 4 long songs (6+ min.) were played in the background, regardless of whether the musical format was Contemporary Dance or New Age. Assuming each song represented a distinct segment in memory, these results are consistent with the segmentation-change model. These results suggest that background music may not always reduce estimates of duration by drawing attention away from the passage of time. Instead, background music may actually expand the subjective length of an interval by creating accessible traces in memory, which are retrospectively used to infer duration.

Adult↗

PubMed2003

Vertebrate somitogenesis: a novel paradigm for animal segmentation?

In vertebrates, the primary segmented tissue of the body axis is the paraxial mesoderm, which lies bilaterally to the axial organs, neural tube and notochord. The segmental pattern of the paraxial mesoderm is established during embryogenesis through the production of the somites which are transient embryonic segments giving rise to the vertebrae, the skeletal muscles and the dorsal dermis. Somitogenesis can be subdivided into three major phases (see Fig. 1). First a growth phase during which new paraxial mesoderm cells are produced by a growth zone (epiblast and blastopore margin or primitive streak and later on tail bud) and become organized as two rods of mesenchymal tissue,forming the presomitic mesoderm. Second a patterning phase occuring in the PSM, during which the segmental pattern is established at the molecular level. Third, the somitic boundaries are formed during the morphological segmentation phase. In all vertebrates, all cells of the paraxial mesoderm, during their maturation in the PSM, go successively through these three phases, which are tightly regulated at the spatio-temporal level. The first phase of paraxial mesoderm production falls out of the scope of this review, as it essentially pertains to the gastrulation process. Here, I essentially discuss the segmental patterning phase in vertebrates. Recent data suggest that establishment of the segmental pattern relies on a clock and wavefront mechanism which has been conserved in vertebrates. Furthermore, conservation of this system could extend to invertebrates, suggesting that the clock and wavefront is an ancestral mechanism.

Animals↗

PubMed1999

[Optimising CPAP accommodation time by feedback-supported training phases in patients with obstructive sleep apnea syndrome].

Mask fitting and accommodation of CPAP-devices are of great importance. Only by accommodation over several hours, problems concerning mask size and fixation of mask are recognised and solved. Many patients overestimate the time they needed for achieving accommodation. We therefore asked whether by visualizing the time required for accommodation the accommodation time can be prolonged. Additionally we compared the subjective estimation on the time with the objectively measured time. We studied 20 patients with sleep apnoea syndrome, 13 men and 7 women, age 53 +/- 4 years, apnoea/hypopnoea index 32 +/- 16, lowest O2 saturation 83 +/- 6%. In a randomized cross-over study, a clock with a large 7 segment-display was either not visible in one setting, so that the patient had no control of the training-time, or the time was visible on the display. Thus the patient could possibly be motivated to increase his time of CPAP-accommodation during the day. The pressure-controlled clock counted only the time during which the pressure was above 4 HPa. In the setting with visible time-counter the accommodation time was 265.8 +/- 114 min, if the counter was not visible, time was only 210.8 +/- 91 min. If the patient cannot observe the time-counter he over-estimates the objectively measured time by half an hour (247.2 +/- 97.5 estimated vs. 210.8 +/- 91.0 actually). Thus the self-control of CPAP-accommodation by a visible clock leads to a significant prolongation of the exercise time. The estimation by the patient is only a limited means to evaluate the time of CPAP accommodation during the day.

Biofeedback, Psychology↗

PubMedDate not supplied

[Pellucid marginal degeneration: diagnosis and treatment].

Pellucid marginal degeneration is characterized by a progressive stromal thinning of the inferior corneal segment, between 4 and 8 o'clock, with a crescentic shape. The area of corneal thinning has a width of about 1 to 2 mm, and it is separated from the corneoscleral limbus by an area of normal corneal tissue. The initial treatment consists of optical correction. However, when the disease progresses to advanced stages, surgical procedures are necessary such as wedge resection, lamellar crescentic resection, penetrating keratoplasty, lamellar keratoplasty, epikeratoplasty and, recently, intracorneal segments.

Astigmatism↗

PubMed2000

The bHLH regulator pMesogenin1 is required for maturation and segmentation of paraxial mesoderm.

Paraxial mesoderm in vertebrates gives rise to all trunk and limb skeletal muscles, the trunk skeleton, and portions of the trunk dermis and vasculature. We show here that germline deletion of mouse pMesogenin1, a bHLH class gene specifically expressed in developmentally immature unsegmented paraxial mesoderm, causes complete failure of somite formation and segmentation of the body trunk and tail. At the molecular level, the phenotype features dramatic loss of expression within the presomitic mesoderm of Notch/Delta pathway components and oscillating somitic clock genes that are thought to control segmentation and somitogenesis. Subsequent patterning and specification steps for paraxial mesoderm also fail, leading to a complete absence of all trunk paraxial mesoderm derivatives, which include skeletal muscle, vertebrae, and ribs. We infer that pMesogenin1 is an essential upstream regulator of trunk paraxial mesoderm development and segmentation.

Abnormalities, Multiple↗

PubMed1992

A new model for diurnal blood pressure profiling. Square wave fit compared with conventional methods.

For the characterization of diurnal blood pressure variation, we developed a simple mathematical model that nevertheless does justice to the specific form characteristics of individual blood pressure registrations. Analysis was based on 24-hour continuous intra-arterial measurement of blood pressure obtained in 23 hospitalized patients with mild-to-moderate untreated essential hypertension (mean +/- SD, 112 +/- 13 mm Hg). The day-night difference for mean arterial pressure varied markedly (mean, 18.6 mm Hg; range, 6.8-36.0). Inspection of profiles suggested a model of blood pressure as two contiguous, complementary periods of constant pressure, a so-called square wave. Determination of the times of transience between both periods (segmentation) was performed individually using a least-square error criterion. Results were compared with those obtained by conventional methods, including analysis by Fourier modeling. The square wave fit accounted for a larger fraction (66%) of circadian variance of mean arterial pressure than modeling based on segmentation by visual inspection (59%, considerable observer bias) or by clock time (50%). Application of the Minnesota Cosinor Method resulted in the poorest description (47%). Segmentation based on harmonic modeling (61%) appeared to be cumbersome (10 harmonics needed), and the significance of additional information offered over the square wave fit is dubious. Observer bias makes segmentation by visual inspection unsuitable for assessment of the circadian variance of blood pressure. Even when daily activities are strictly regulated (hospital environment), circadian variance is not well modeled by clock time. As compared with harmonic analysis, square wave fitting is simple, and it appears to best model the circadian variance. The method can also be applied to data obtained from noninvasive ambulatory blood pressure monitoring.

Blood Pressure Determination↗

PubMed2000

Endoureterotomy for congenital primary obstructive megaureter: preliminary report.

BACKGROUND AND PURPOSE: Congenital obstructive megaureter (COMU) may be unilateral or bilateral and may present in later years of life. If the obstruction is not relieved in good time, deleterious effects on the proximal ureter and kidney are well known. Stones may complicate the situation further. So far, the only treatment that has been available is to disconnect the ureter proximal to the site of obstruction, remove any stone, and reimplant the ureter into the bladder after any necessary tailoring. After noticing the encouraging results of endopyelotomy for congenital ureteropelvic junction obstruction, we decided to use the same principle for the management of COMU, as similar functional pathology is present in both situations. PATIENTS AND METHODS: Our technique was applied in six ureters in five adult patients. After cystoscopic evaluation of the bladder and ureteral orifice, a guidewire was advanced up the ureter, and the lower ureter was dilated. A ureteroscope or other suitable endoscopic instrument was passed, and the obstructed segment of the ureter was incised at the 6 o'clock position with pure cutting current. All of the layers of the ureter were incised in the long axis through the entire obstructive segment, so as to expose the periureteral areolar tissue. If necessary, a similar cut was made at the 12 o'clock position. Utmost care was taken not to incise the bladder mucosa. A double-J stent was inserted for 3 weeks. RESULTS: Follow-up for 1 to 4 years showed free drainage of urine into the bladder, with marked reduction in proximal stasis and freedom from recurrent infection and pain. CONCLUSION: Although our series is small and follow- up is relatively short, it appears that endoureterotomy is a safe and effective treatment for COMU.

Adult↗