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At least 973 records · Page 54Linked to original sources
PubMed1999

Clock drawing is sensitive to executive control: a comparison of six methods.

We examined six clock-drawing task (CDT) scoring systems relative to the Executive Interview (EXIT25, a measure of Executive Control Function [ECF]) and the Mini-Mental State Exam (MMSE). Subjects included n = 33 National Institute of Neurological, Communicative Disorders, and Stroke "probable" Alzheimer's disease (AD) cases and n = 52 independent living controls. AD cases and controls differed on the EXIT25, MMSE, and all CDTs. All CDTs were significantly correlated with the EXIT25 (ranging from r = .56 to r = .78). These associations generally persisted after adjusting for Age, Education, and MMSE scores. In backwards stepwise linear multivariate regression models, only CLOX: An Executive Clock-Drawing Task scores contribute significantly to EXIT25 scores (R2 = .68) and MMSE scores (R2 = .72). Clock drawing draws upon both executive and general cognitive resources. CLOX explains incrementally more variance in ECF than other CDTs.

Age Factors↗
PubMed2025

Detecting Introgression in Shallow Phylogenies: How Minor Molecular Clock Deviations Lead to Major Inference Errors.

Recent theoretical and algorithmic advances in introgression detection, coupled with the growing availability of genome-scale data, have highlighted the widespread occurrence of interspecific gene flow across the tree of life. However, current methods largely depend on the molecular clock assumption-a questionable premise given empirical evidence of substitution rate variation across lineages. While such rate heterogeneity is known to compromise gene flow detection among divergent lineages, its impact on closely related taxa at shallow evolutionary timescales remains poorly understood, likely because these taxa are often assumed to adhere to a molecular clock. To address this gap, we combine theoretical analyses and simulations to evaluate the robustness of widely used site pattern methods (D-statistic and HyDe) to rate variation across phylogenetic timescales. Our results demonstrate that both methods exhibit high sensitivity to even minor deviations from the molecular clock at shallow timescales, complementing previous findings at deeper scales. Specifically, in young phylogenies (with an age of 3 × 105 generations) with small population sizes, weak (17% difference) and moderate (33% difference) rate variation can inflate false-positive rates up to 35% and 100%, respectively, using site pattern counts from a 500 Mb genome. Employing a more distant outgroup intensifies these spurious signals. Our study demonstrates that summary tests for introgression are pervasively vulnerable to minor rate variations and underscores the critical need for advanced methodologies to disentangle genuine introgression from false signals generated by rate heterogeneity.

Phylogeny↗
PubMed2005

Accuracy of rate estimation using relaxed-clock models with a critical focus on the early metazoan radiation.

In recent years, a number of phylogenetic methods have been developed for estimating molecular rates and divergence dates under models that relax the molecular clock constraint by allowing rate change throughout the tree. These methods are being used with increasing frequency, but there have been few studies into their accuracy. We tested the accuracy of several relaxed-clock methods (penalized likelihood and Bayesian inference using various models of rate change) using nucleotide sequences simulated on a nine-taxon tree. When the sequences evolved with a constant rate, the methods were able to infer rates accurately, but estimates were more precise when a molecular clock was assumed. When the sequences evolved under a model of auto-correlated rate change, rates were accurately estimated using penalized likelihood and by Bayesian inference using lognormal and exponential models of rate change, while other models did not perform as well. When the sequences evolved under a model of uncorrelated rate change, only Bayesian inference using an exponential rate model performed well. Collectively, the results provide a strong recommendation for using the exponential model of rate change if a conservative approach to divergence time estimation is required. A case study is presented in which we use a simulation-based approach to examine the hypothesis of elevated rates in the Cambrian period, and it is found that these high rate estimates might be an artifact of the rate estimation method. If this bias is present, then the ages of metazoan divergences would be systematically underestimated. The results of this study have implications for studies of molecular rates and divergence dates.

Algorithms↗
PubMed2006

Analysis of the overdispersed clock in the short-term evolution of hepatitis C virus: Using the E1/E2 gene sequences to infer infection dates in a single source outbreak.

The assumption of a molecular clock for dating events from sequence information is often frustrated by the presence of heterogeneity among evolutionary rates due, among other factors, to positively selected sites. In this work, our goal is to explore methods to estimate infection dates from sequence analysis. One such method, based on site stripping for clock detection, was proposed to unravel the clocklike molecular evolution in sequences showing high variability of evolutionary rates and in the presence of positive selection. Other alternatives imply accommodating heterogeneity in evolutionary rates at various levels, without eliminating any information from the data. Here we present the analysis of a data set of hepatitis C virus (HCV) sequences from 24 patients infected by a single individual with known dates of infection. We first used a simple criterion of relative substitution rate for site removal prior to a regression analysis. Time was regressed on maximum likelihood pairwise evolutionary distances between the sequences sampled from the source individual and infected patients. We show that it is indeed the fastest evolving sites that disturb the molecular clock and that these sites correspond to positively selected codons. The high computational efficiency of the regression analysis allowed us to compare the site-stripping scheme with random removal of sites. We demonstrate that removing the fast-evolving sites significantly increases the accuracy of estimation of infection times based on a single substitution rate. However, the time-of-infection estimations improved substantially when a more sophisticated and computationally demanding Bayesian method was used. This method was used with the same data set but keeping all the sequence positions in the analysis. Consequently, despite the distortion introduced by positive selection on evolutionary rates, it is possible to obtain quite accurate estimates of infection dates, a result of especial relevance for molecular epidemiology studies.

Bayes Theorem↗
PubMed2006

A mitogenomic timescale for birds detects variable phylogenetic rates of molecular evolution and refutes the standard molecular clock.

Current understanding of the diversification of birds is hindered by their incomplete fossil record and uncertainty in phylogenetic relationships and phylogenetic rates of molecular evolution. Here we performed the first comprehensive analysis of mitogenomic data of 48 vertebrates, including 35 birds, to derive a Bayesian timescale for avian evolution and to estimate rates of DNA evolution. Our approach used multiple fossil time constraints scattered throughout the phylogenetic tree and accounts for uncertainties in time constraints, branch lengths, and heterogeneity of rates of DNA evolution. We estimated that the major vertebrate lineages originated in the Permian; the 95% credible intervals of our estimated ages of the origin of archosaurs (258 MYA), the amniote-amphibian split (356 MYA), and the archosaur-lizard divergence (278 MYA) bracket estimates from the fossil record. The origin of modern orders of birds was estimated to have occurred throughout the Cretaceous beginning about 139 MYA, arguing against a cataclysmic extinction of lineages at the Cretaceous/Tertiary boundary. We identified fossils that are useful as time constraints within vertebrates. Our timescale reveals that rates of molecular evolution vary across genes and among taxa through time, thereby refuting the widely used mitogenomic or cytochrome b molecular clock in birds. Moreover, the 5-Myr divergence time assumed between 2 genera of geese (Branta and Anser) to originally calibrate the standard mitochondrial clock rate of 0.01 substitutions per site per lineage per Myr (s/s/l/Myr) in birds was shown to be underestimated by about 9.5 Myr. Phylogenetic rates in birds vary between 0.0009 and 0.012 s/s/l/Myr, indicating that many phylogenetic splits among avian taxa also have been underestimated and need to be revised. We found no support for the hypothesis that the molecular clock in birds "ticks" according to a constant rate of substitution per unit of mass-specific metabolic energy rather than per unit of time, as recently suggested. Our analysis advances knowledge of rates of DNA evolution across birds and other vertebrates and will, therefore, aid comparative biology studies that seek to infer the origin and timing of major adaptive shifts in vertebrates.

Animals↗
PubMed2000

Estimation of primate speciation dates using local molecular clocks.

Protein-coding genes of the mitochondrial genomes from 31 mammalian species were analyzed to estimate the speciation dates within primates and also between rats and mice. Three calibration points were used based on paleontological data: one at 20-25 MYA for the hominoid/cercopithecoid divergence, one at 53-57 MYA for the cetacean/artiodactyl divergence, and the third at 110-130 MYA for the metatherian/eutherian divergence. Both the nucleotide and the amino acid sequences were analyzed, producing conflicting results. The global molecular clock was clearly violated for both the nucleotide and the amino acid data. Models of local clocks were implemented using maximum likelihood, allowing different evolutionary rates for some lineages while assuming rate constancy in others. Surprisingly, the highly divergent third codon positions appeared to contain phylogenetic information and produced more sensible estimates of primate divergence dates than did the amino acid sequences. Estimated dates varied considerably depending on the data type, the calibration point, and the substitution model but differed little among the four tree topologies used. We conclude that the calibration derived from the primate fossil record is too recent to be reliable; we also point out a number of problems in date estimation when the molecular clock does not hold. Despite these obstacles, we derived estimates of primate divergence dates that were well supported by the data and were generally consistent with the paleontological record. Estimation of the mouse-rat divergence date, however, was problematic.

Animals↗
PubMed1995

Phylogenetic test of the molecular clock and linearized trees.

To estimate approximate divergence times of species or species groups with molecular data, we have developed a method of constructing a linearized tree under the assumption of a molecular clock. We present two tests of the molecular clock for a given topology: two-cluster test and branch-length test. The two-cluster test examines the hypothesis of the molecular clock for the two lineages created by an interior node of the tree, whereas the branch-length test examines the deviation of the branch length between the tree root and a tip from the average length. Sequences evolving excessively fast or slow at a high significance level may be eliminated. A linearized tree will then be constructed for a given topology for the remaining sequences under the assumption of rate constancy. We have used these methods to analyze hominoid mitochondrial DNA and drosophilid Adh gene sequences.

Alcohol Dehydrogenase↗
PubMed2002

The APRR3 component of the clock-associated APRR1/TOC1 quintet is phosphorylated by a novel protein kinase belonging to the WNK family, the gene for which is also transcribed rhythmically in Arabidopsis thaliana.

In higher plants, clock-controlled circadian rhythms are a longstanding issue in physiology, and a newly emerging paradigm of molecular biology. In the model higher plant Arabidopsis thaliana, several genes have been proposed to encode potential clock-associated components, including a member (APRR1/TOC1) of the pseudo-response regulator family. We previously showed that transcripts of the APRR1/TOC1 family start accumulating after dawn rhythmically and sequentially at approximately 2 h intervals in the order of APRR9-->APRR7-->APRR5-->APRR3-->APRR1/ TOC1. This and other results led us to propose that this APRR1/TOC1 quintet might play coordinate roles in the mechanism underlying circadian rhythms in higher plants. To gain further insight as to such an idea, we here attempt to identify proteins that interact with one of the quintet members, APRR3. The identified component is a novel protein kinase, named WNK1, which is considerably similar to, but clearly distinct from, mitogen-activated protein kinases (MAPKs). It was found that APRR3 is a substrate of this novel protein kinase, the gene for which also shows a rhythmic transcription profile that is well coincident with the APRR3 rhythm. These findings give new insight into the mechanisms underlying the circadian rhythm in A. thaliana, providing a molecular link between the putative clock component, APRR3, and WNK1, a novel protein kinase that might be implicated as a signal transducer.

Amino Acid Sequence↗
PubMed1985

Effects of ovariectomy on clock-timed daily gonadotropin rhythms in prepubertal golden hamsters.

Daily rhythms of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are measurable in the serum of prepubertal female golden hamsters by 17 days after birth. These rhythms, which are characterized by peak levels at 1700 h, persist until they are replaced by a 4-day rhythm as ovulatory cycles begin, approximately 3 wk later. We have tested the proposition that the ovaries are required for the onset and maintenance of clock-timed gonadotropin release by removing the ovaries and measuring the levels of LH and FSH in prepubertal hamsters. Ovariectomy was performed both before and after the onset of the rhythm and the effect of removal was determined by subsequent collection of blood samples during the mid- to late-prepubertal period. Ovariectomy on 7, 10 or 13 days after birth results in tonic levels of LH and FSH in blood samples collected at 1400, 1700 and 2000 h on Days 17 through 29. Sham-operated or intact controls had significantly elevated levels of these hormones at 1700 h. Ovariectomy on Day 21 and killing on Day 25 at the same times of day abolished the rhythm of serum LH measured in sham-ovariectomized controls. Ovariectomy on Day 21 and killing on Days 26, 28 or 30 at hourly intervals resulted in variable but nonrhythmic patterns of circulating LH. Thus, ovariectomy before the initiation of clock-timed gonadotropin release prevented its initiation; ovariectomy after its initiation abolished the rhythm. These results show that the ovary provides an essential "message" to the brain-pituitary axis for the initiation and maintenance of clock-timed gonadotropin release in prepubertal females.

Animals↗
PubMed1996

Neuropeptide Y phase shifts the circadian clock in vitro via a Y2 receptor.

The suprachiasmatic nuclei (SCN) contain a circadian clock whose activity can be recorded in vitro for several days. This clock can be reset by the application of neuropeptide Y. In this study, we focused on determination of the receptor responsible for neuropeptide Y phase shifts of the hamster circadian clock in vitro. Coronal hypothalamic slices containing the SCN were prepared from Syrian hamsters housed under a 14 h:10 h light:dark cycle. Tissue was bathed in artificial cerebrospinal fluid (ACSF), and the firing rates of individual cells were sampled throughout a 12 h period. Control slices received either no application or application of 200 nl ACSF to the SCN at zeitgeber time 6 (ZT6; ZT12 was defined as the time of lights off). Application of 200 ng/200 nl of neuropeptide Y at ZT6 resulted in a phase advance of 3.4 h. Application of the Y2 receptor agonist, neuropeptide Y (3-36), induced a similar phase advance in the rhythm, while the Y1 receptor agonist, [Leu31, Pro34]-neuropeptide Y had no effect. Pancreatic polypeptide (rat or avian) also had no measurable phase-shifting effect. Neuropeptide Y applied at ZT20 or 22 had no detectable phase-shifting effect. These results suggest that the phase-shifting effects of neuropeptide Y are mediated through a Y2 receptor, similar to results found in vivo.

Animals↗
PubMed2003

Corneal desiccation in rigid contact lens wear: 3- and 9-o'clock staining.

The current knowledge of treatment options together with signs and symptoms, classification, prevalence, and etiology of 3- and 9-o'clock staining in rigid contact lens wear are described in this review article. In total, 11 treatment options for the management of 3- and 9-o'clock staining were found in the literature. Five of these treatment options are related to lens parameters, namely edge lift, edge thickness and shape, back surface geometry, total diameter, and back optic zone radius. Three other options are related to lens performance: movement, centration, and surface wettability. Three more variables can be identified: blinking habits, tear supplements, and, finally, switching to a hydrogel material. There is controversy on how to adjust the most important individual variables for management of 3- and 9-o'clock staining. The advocated treatment options are often related to the fitting techniques used: lid attachment or interpalpebral fit. Implications for practice and for further research are discussed.

Contact Lenses↗
PubMedDate not supplied

Performance of three clock scoring systems across different ranges of dementia severity.

The ability of three different Clock Drawing Test (CDT) scoring systems to detect Dementia of the Alzheimer Type (DAT) was investigated. As part of a neuropsychological battery, fifty DAT Type patients and fifty matched controls drew a clock. Each drawing was scored by three independent raters according to three different scoring systems: the 3-Factor system, the Template system, and the Abbreviated system. The CDT scoring systems were able to detect Dementia of the Alzheimer Type when the disease was moderate to severe, but lacked sensitivity in milder dementia. Animal Fluency was a better single predictor of dementia. Clinicians are advised to interpret the results of the Clock Drawing Test cautiously in an outpatient setting, where milder forms of dementia and low base rates are likely.

Aged↗
PubMed2004

Distinct roles for PP1 and PP2A in the Neurospora circadian clock.

Phosphorylation of the Neurospora circadian clock protein FREQUENCY by several kinases promotes its degradation and is important for the function of the circadian feedback loop. Here, we show that FRQ is less stable in a ppp-1 (catalytic subunit of PP1) mutant, resulting in its advanced phase and short period. In contrast, FRQ stability is not altered in a rgb-1 (a regulatory subunit of PP2A) mutant, but levels of frq protein and mRNA are low, resulting in a low-amplitude and long-period oscillation of the clock. Furthermore, PP1 and PP2A expressed in Neurospora can dephosphorylate the endogenous FRQ in vitro, suggesting that these two phosphatases may differentially regulate FRQ and, consequently, the behavior of the circadian clock.

Catalytic Domain↗
PubMed2005

The COP9 signalosome regulates the Neurospora circadian clock by controlling the stability of the SCFFWD-1 complex.

The COP9 signalosome (CSN) promotes the function of SCF-type cullin-based ubiquitin ligase complexes in vivo. Paradoxically, removal of the Nedd8 modification of cullins by CSN inhibits the ubiquitin ligase activity of SCF complexes in vitro. Ubiquitination-mediated degradation of the Neurospora circadian clock protein FREQUENCY (FRQ) is critical for clock function. Ubiquitination of FRQ requires FWD-1, the substrate-recruiting subunit of an SCF complex. Here we show that disruption of a subunit of CSN (csn-2) impairs the degradation of FRQ and compromises its normal circadian expression. A FRQ-independent oscillator drives conidiation in the csn-2 mutant, resulting in a 2-d conidiation rhythm that persists in constant darkness (DD), constant light (LL), light-to-dark (LD) transitions, and temperature cycles. Strikingly, the levels of FWD-1 are drastically reduced in csn-2 mutant, explaining the impaired degradation of FRQ. Reduction of FWD-1 levels in the mutant requires its F-box, suggesting that its degradation is due to autoubiquitination. In addition, SKP-1 and CUL-1 of the SCF(FWD-1) complex are also unstable in the mutant. Therefore, our results establish an important role of CSN in the circadian clock of Neurospora. Our findings also reconcile the CSN paradox and suggest that a major function of CSN is to maintain the stability of SCF ubiquitin ligases in vivo.

Animals↗
PubMed2001

Roughness exponent in two-dimensional percolation, Potts model, and clock model.

We present a numerical study of the self-affine profiles obtained from configurations of the q-state Potts (with q=2,3, and 7) and p=10 clock models as well as from the occupation states for site percolation on the square lattice. The first and second order static phase transitions of the Potts model are located by a sharp change in the value of the roughness exponent alpha characterizing those profiles. The low temperature phase of the Potts model corresponds to flat (alpha approximately 1) profiles, whereas its high temperature phase is associated with rough (alpha approximately 0.5) ones. For the p=10 clock model, in addition to the flat (ferromagnetic) and rough (paramagnetic) profiles, an intermediate rough (0.5<alpha<1) phase-associated with a soft spin-wave one-is observed. Our results for the transition temperatures in the Potts and clock models are in agreement with the static values, showing that this approach is able to detect the phase transitions in these models directly from the spin configurations, without any reference to thermodynamical potentials, order parameters, or response functions. Finally, we show that the roughness exponent alpha is insensitive to geometric critical phenomena.

Journal Article↗
PubMed2001

Collisional frequency shifts in 133Cs fountain clocks.

We present a theoretical analysis of the density dependent frequency shift in Cs fountain clocks using the highly constrained binary collision model described by Leo et al. [Phys. Rev. Lett. 85, 2721 (2000)]. We predict a reversal in the clock shift at temperatures near 0.08 microK. Our results show that s waves dominate the collision process. However, as a consequence of the large scattering lengths in Cs the clock shift is strongly temperature dependent and does not reach a constant Wigner-law value until temperatures are less than 0.1 nK.

Journal Article↗
PubMed2002

Optical clock with ultracold neutral atoms.

We demonstrate how to realize an optical clock with neutral atoms that is competitive to the currently best single ion optical clocks in accuracy and superior in stability. Using ultracold atoms in a Ca optical frequency standard, we show how to reduce the relative uncertainty to below 10(-15). We observed atom interferences for stabilization of the laser to the clock transition with a visibility of 0.36, which is 70% of the ultimate limit achievable with atoms at rest. A novel scheme was applied to detect these atom interferences with the prospect to reach the quantum projection noise limit at an exceptional low instability of 4 x 10(-17) in 1 s.

Journal Article↗
PubMed2003

Ultrastable optical clock with neutral atoms in an engineered light shift trap.

An ultrastable optical clock based on neutral atoms trapped in an optical lattice is proposed. Complete control over the light shift is achieved by employing the 5s(2) 1S0-->5s5p 3P0 transition of 87Sr atoms as a "clock transition." Calculations of ac multipole polarizabilities and dipole hyperpolarizabilities for the clock transition indicate that the contribution of the higher-order light shifts can be reduced to less than 1 mHz, allowing for a projected accuracy of better than 10(-17).

Journal Article↗