Circadian clock mutants of Drosophila melanogaster

Three mutants of Drosophila melanogaster have been isolated in which the free-running period of the circadian eclosion rhythm and the adult locomotor activity rhythm is affected. One mutant is arrhythmic, another has a short period of 19 hours, and the third has a long period of 28 hours. The mutants retain their phenotypes over the temperature range 18° to 25° C. All three mutants map near the tip of the X chromosome (distal to the centromere). By deficiency mapping, the short-period mutation has been localized to the 3B1-2 region. Complementation tests show that all three mutations affect the same functional gene.

Analysis of activity rhythms of individual mosaic flies indicates that the site of action of the short-period mutation is probably located in the head of the fly. A few activity patterns of split-head and mixed-head mosaics appear to possess both mutant and heterozygous components, suggesting that the fly head may contain two complete clocks capable of maintaining their periodicities independently.

The short-period mutation affects both the duration of the light-insensitive part of the oscillation and the degree to which the clock can be reset during the light-sensitive part of the oscillation.

Both the short-period and long-period mutant eclosion rhythms can be entrained to a period of 24 hours by a 12:12 light-dark cycle having a light intensity at least two orders of magnitude greater than that required to entrain the normal rhythm. The arrhythmic mutant does not entrain under these conditions. In the presence of a temperature cycle, however, the arrhythmic mutant does entrain, but its rhythm damps out when the temperature cycle is removed.

Evidence is presented that Pittendrigh's two-oscillator model for the clock in D. pseudoobscura applies to D. melanogaster as well. The three clock mutations primarily affect the light- sensitive driving oscillator. The arrhythmic mutation appears to have eliminated the driving oscillator while leaving the temperature-sensitive driven oscillator relatively intact.

A 4 GHz non-resonant clock driver with inductor-assisted energy return to power grid

Power consumption of a multi-GHz local clock driver is reduced by returning energy stored in the clock-tree load capacitance back to the on-chip power-distribution grid. We call this type of return energy recycling. To achieve a nearly square clock waveform, the energy is transferred in a non-resonant way using an on-chip inductor in a configuration resembling a full-bridge DC-DC converter. A zero-voltage switching technique is implemented in the clock driver to reduce dynamic power loss associated with the high switching frequencies. A prototype implemented in 90 nm CMOS shows a power savings of 35% at 4 GHz. The area needed for the inductor in this new clock driver is about 6% of a local clock region. © 2006 IEEE.

40 Gbits/s all-optical clock recovery for degraded signals using an amplified feedback laser

All-optical clock recovery for the return-to-zero modulation format is demonstrated experimentally at 40 Gbits/s by using an amplified feedback laser. A 40 GHz optical clock with a root-mean-square (rms) timing jitter of 130 fs and a carrier-to-noise ratio of 42 dB is obtained. Also, a 40 GHz optical clock with timing jitter of 137 fs is directly recovered from pseudo-non-return-to-zero signals degraded by polarization-mode dispersion (PMD). No preprocessing stage to enhance the clock tone is used. The rms timing jitter of the recovered clock is investigated for different values of input power and for varying amounts of waveform distortion due to PMD.

The performance and persistence of exchange-traded funds: evidence for iShares MSCI country-specific ETFs

The aim of this paper is to investigate the performance and persistence of 20 iShares MSCI country-specific exchange-traded funds (ETFs) in comparison with S&P 500 index over the period July 2001 to June 2006. There are several studies analysing mutual funds performance in past years, but very little is known about ETFs. In our analysis the Sharpe, Treynor and Sortino ratios are used as risk-adjusted performance measures. To evaluate performance persistence and therefore if there is any relationship among past performance and future performance, we apply to the Spearman Rank Correlation Coefficient and the Winner-loser Contingency Table. The main findings are at two levels. First, ETFs can beat the U.S. market index based on risk-adjusted performance measures. Second, there is evidence of ETFs performance persistence based on annual return.

Tracking clock-shifted homing pigeons from familiar release sites

Clock-shifted homing pigeons were tracked from familiar sites 17.1km and 23.5 km from the home loft in Pisa, Italy, using an on-board route recorder. At the first release site, north of home, the majority of clock-shifted birds had relatively straight tracks comparable with those of control birds, At the second release site, south of home, the clock-shifted birds deflected in the direction predicted for the degree of clock shift, with many birds travelling some distance in the wrong direction before correcting their course. The possible role of large-scale terrain features in homing pigeon navigation is discussed.

Variance-Constrained Capacity of the Molecular Timing Channel with Synchronization Error

Molecular communication is set to play an important role in the design of complex biological and chemical systems. An important class of molecular communication systems is based on the timing channel, where information is encoded in the delay of the transmitted molecule - a synchronous approach. At present, a widely used modeling assumption is the perfect synchronization between the transmitter and the receiver. Unfortunately, this assumption is unlikely to hold in most practical molecular systems. To remedy this, we introduce a clock into the model - leading to the molecular timing channel with synchronization error. To quantify the behavior of this new system, we derive upper and lower bounds on the variance-constrained capacity, which we view as the step between the mean-delay and the peak-delay constrained capacity. By numerically evaluating our bounds, we obtain a key practical insight: the drift velocity of the clock links does not need to be significantly larger than the drift velocity of the information link, in order to achieve the variance-constrained capacity with perfect synchronization.

Exploiting dynamic timing margins in microprocessors for frequency-over-scaling with instruction-based clock adjustment

Static timing analysis provides the basis for setting the clock period of a microprocessor core, based on its worst-case critical path. However, depending on the design, this critical path is not always excited and therefore dynamic timing margins exist that can theoretically be exploited for the benefit of better speed or lower power consumption (through voltage scaling). This paper introduces predictive instruction-based dynamic clock adjustment as a technique to trim dynamic timing margins in pipelined microprocessors. To this end, we exploit the different timing requirements for individual instructions during the dynamically varying program execution flow without the need for complex circuit-level measures to detect and correct timing violations. We provide a design flow to extract the dynamic timing information for the design using post-layout dynamic timing analysis and we integrate the results into a custom cycle-accurate simulator. This simulator allows annotation of individual instructions with their impact on timing (in each pipeline stage) and rapidly derives the overall code execution time for complex benchmarks. The design methodology is illustrated at the microarchitecture level, demonstrating the performance and power gains possible on a 6-stage OpenRISC in-order general purpose processor core in a 28nm CMOS technology. We show that employing instruction-dependent dynamic clock adjustment leads on average to an increase in operating speed by 38% or to a reduction in power consumption by 24%, compared to traditional synchronous clocking, which at all times has to respect the worst-case timing identified through static timing analysis.

CLOCK-controlled polyphonic regulation of circadian rhythms through canonical and noncanonical E-boxes.

In mammalian circadian clockwork, the CLOCK-BMAL1 complex binds to DNA enhancers of target genes and drives circadian oscillation of transcription. Here we identified 7,978 CLOCK-binding sites in mouse liver by chromatin immunoprecipitation-sequencing (ChIP-Seq), and a newly developed bioinformatics method, motif centrality analysis of ChIP-Seq (MOCCS), revealed a genome-wide distribution of previously unappreciated noncanonical E-boxes targeted by CLOCK. In vitro promoter assays showed that CACGNG, CACGTT, and CATG(T/C)G are functional CLOCK-binding motifs. Furthermore, we extensively revealed rhythmically expressed genes by poly(A)-tailed RNA-Seq and identified 1,629 CLOCK target genes within 11,926 genes expressed in the liver. Our analysis also revealed rhythmically expressed genes that have no apparent CLOCK-binding site, indicating the importance of indirect transcriptional and posttranscriptional regulations. Indirect transcriptional regulation is represented by rhythmic expression of CLOCK-regulated transcription factors, such as Krüppel-like factors (KLFs). Indirect posttranscriptional regulation involves rhythmic microRNAs that were identified by small-RNA-Seq. Collectively, CLOCK-dependent direct transactivation through multiple E-boxes and indirect regulations polyphonically orchestrate dynamic circadian outputs.

Regulation of gene expression in the dinoflagellate Lingulodinium polyedrum

Les dinoflagellés sont des eucaryotes unicellulaires que l’on retrouve autant en eau douce qu’en milieu marin. Ils sont particulièrement connus pour causer des fleurs d’algues toxiques nommées ‘marée-rouge’, ainsi que pour leur symbiose avec les coraux et pour leur importante contribution à la fixation du carbone dans les océans. Au point de vue moléculaire, ils sont aussi connus pour leur caractéristiques nucléaires uniques, car on retrouve généralement une quantité immense d’ADN dans leurs chromosomes et ceux-ci sont empaquetés et condensés sous une forme cristalline liquide au lieu de nucléosomes. Les gènes encodés par le noyau sont souvent présents en multiples copies et arrangés en tandem et aucun élément de régulation transcriptionnelle, y compris la boite TATA, n’a encore été observé. L’organisation unique de la chromatine des dinoflagellés suggère que différentes stratégies sont nécessaires pour contrôler l’expression des gènes de ces organismes. Dans cette étude, j’ai abordé ce problème en utilisant le dinoflagellé photosynthétique Lingulodinium polyedrum comme modèle. L. polyedrum est d’un intérêt particulier, car il a plusieurs rythmes circadiens (journalier). À ce jour, toutes les études sur l’expression des gènes lors des changements circadiens ont démontrées une régulation à un niveau traductionnel. Pour mes recherches, j’ai utilisé les approches transcriptomique, protéomique et phosphoprotéomique ainsi que des études biochimiques pour donner un aperçu de la mécanique de la régulation des gènes des dinoflagellés, ceci en mettant l’accent sur l’importance de la phosphorylation du système circadien de L. polyedrum. L’absence des protéines histones et des nucléosomes est une particularité des dinoflagellés. En utilisant la technologie RNA-Seq, j’ai trouvé des séquences complètes encodant des histones et des enzymes modifiant les histones. L polyedrum exprime donc des séquences conservées codantes pour les histones, mais le niveau d’expression protéique est plus faible que les limites de détection par immunodétection de type Western. Les données de séquençage RNA-Seq ont également été utilisées pour générer un transcriptome, qui est une liste des gènes exprimés par L. polyedrum. Une recherche par homologie de séquences a d’abord été effectuée pour classifier les transcrits en diverses catégories (Gene Ontology; GO). Cette analyse a révélé une faible abondance des facteurs de transcription et une surprenante prédominance, parmi ceux-ci, des séquences à domaine Cold Shock. Chez L. polyedrum, plusieurs gènes sont répétés en tandem. Un alignement des séquences obtenues par RNA-Seq avec les copies génomiques de gènes organisés en tandem a été réalisé pour examiner la présence de transcrits polycistroniques, une hypothèse formulée pour expliquer le manque d’élément promoteur dans la région intergénique de la séquence de ces gènes. Cette analyse a également démontré une très haute conservation des séquences codantes des gènes organisés en tandem. Le transcriptome a également été utilisé pour aider à l’identification de protéines après leur séquençage par spectrométrie de masse, et une fraction enrichie en phosphoprotéines a été déterminée comme particulièrement bien adapté aux approches d’analyse à haut débit. La comparaison des phosphoprotéomes provenant de deux périodes différentes de la journée a révélée qu’une grande partie des protéines pour lesquelles l’état de phosphorylation varie avec le temps est reliées aux catégories de liaison à l’ARN et de la traduction. Le transcriptome a aussi été utilisé pour définir le spectre des kinases présentes chez L. polyedrum, qui a ensuite été utilisé pour classifier les différents peptides phosphorylés qui sont potentiellement les cibles de ces kinases. Plusieurs peptides identifiés comme étant phosphorylés par la Casein Kinase 2 (CK2), une kinase connue pour être impliquée dans l’horloge circadienne des eucaryotes, proviennent de diverses protéines de liaison à l’ARN. Pour évaluer la possibilité que quelques-unes des multiples protéines à domaine Cold Shock identifiées dans le transcriptome puissent moduler l’expression des gènes de L. polyedrum, tel qu’observé chez plusieurs autres systèmes procaryotiques et eucaryotiques, la réponse des cellules à des températures froides a été examinée. Les températures froides ont permis d’induire rapidement un enkystement, condition dans laquelle ces cellules deviennent métaboliquement inactives afin de résister aux conditions environnementales défavorables. Les changements dans le profil des phosphoprotéines seraient le facteur majeur causant la formation de kystes. Les phosphosites prédits pour être phosphorylés par la CK2 sont la classe la plus fortement réduite dans les kystes, une découverte intéressante, car le rythme de la bioluminescence confirme que l’horloge a été arrêtée dans le kyste.

The first real-time worldwide ionospheric predictions network: an advance in support of spaceborne experimentation, on-line model validation, and space weather

We report on the first realtime ionospheric predictions network and its capabilities to ingest a global database and forecast F-layer characteristics and "in situ" electron densities along the track of an orbiting spacecraft. A global network of ionosonde stations reported around-the-clock observations of F-region heights and densities, and an on-line library of models provided forecasting capabilities. Each model was tested against the incoming data; relative accuracies were intercompared to determine the best overall fit to the prevailing conditions; and the best-fit model was used to predict ionospheric conditions on an orbit-to-orbit basis for the 12-hour period following a twice-daily model test and validation procedure. It was found that the best-fit model often provided averaged (i.e., climatologically-based) accuracies better than 5% in predicting the heights and critical frequencies of the F-region peaks in the latitudinal domain of the TSS-1R flight path. There was a sharp contrast however, in model-measurement comparisons involving predictions of actual, unaveraged, along-track densities at the 295 km orbital altitude of TSS-1R In this case, extrema in the first-principle models varied by as much as an order of magnitude in density predictions, and the best-fit models were found to disagree with the "in situ" observations of Ne by as much as 140%. The discrepancies are interpreted as a manifestation of difficulties in accurately and self-consistently modeling the external controls of solar and magnetospheric inputs and the spatial and temporal variabilities in electric fields, thermospheric winds, plasmaspheric fluxes, and chemistry.

Clock Genes, Melanopsins, Melatonin, and Dopamine Key Enzymes and Their Modulation by Light and Glutamate in Chicken Embryonic Retinal Cells

The avian circadian system is composed of the retina, the mammalian homolog region of the suprachiasmatic nucleus (SNC), and the pineal gland. The retina, itself, displays many rhythmic physiological events, such as movements of photoreceptor cells, opsin expression, retinal reisomerization, and melatonin and dopamine production and secretion. Altogether, these rhythmic events are coordinated to predict environmental changes in light conditions during the day, optimizing retina function. The authors investigated the expression pattern of the melanopsin genes Opn4x and Opn4m, the clock genes Clock and Per2, and the genes for the key enzymes N-Acetyltransferase and Tyrosine Hidroxylase in chicken embryo dispersed retinal cells. Primary cultures of chicken retina from 8-day-old embryos were kept in constant dark (DD), in 12-h light/12-h dark (12L:12D), in 12L:12D followed by DD, or in DD in the absence or presence of 100 mu M glutamate for 12 h. Total RNA was extracted throughout a 24-h span, every 3 h starting at zeitgeber time 0 (ZT0) of the 6th day, and submitted to reverse transcriptase-polymerase chain reaction (RT-PCR) followed by quantitative PCR (qPCR) for mRNA quantification. The data showed no rhythmic pattern of transcription for any gene in cells kept in DD. However under a light-dark cycle, Clock, Per2, Opn4m, N-Acetyltransferase, and Tyrosine Hydroxylase exhibited rhythmic patterns of transcription. In DD, 100 mu M glutamate was able to induce rhythmic expression of Clock, strongly inhibited the expression of Tyrosine Hydroxylase, and, only at some ZTs, of Opn4x and Opn4m. The neurotransmitter had no effect on Per2 and N-Acetyltransferase transcription. The authors confirmed the expression of the protein OPN4x by immunocytochemistry. These results suggest that chicken embryonic retinal cells contain a functional circadian clock, whose synchronization requires light-dark cycle or glutamate stimuli. (Author correspondence: amdlcast@ib.usp.br).

Criticisms of auditors and earnings management during the Asian economic crisis

Auditors were criticised during and after the Asian economic crisis for supplying variable quality across global audit markets. This study examines
the level of earnings management as measured by discretionary accruals in the pre-crisis compared to the post-crisis periods as they impacted Malaysia. Both the Jones (1991) and earnings per share frequency distribution methods are used to examine earnings management behaviour. As hypothesised, the pre-crisis period is associated with significantly higher levels of absolute discretionary accruals and increased propensity to meet or beat the prior year earnings per share, whereas the post-crisis period is not. This finding is consistent with auditors responding to the criticisms that were made. However, the propensity to avoid losses is found to be higher in the post-crisis period, indicating that earnings management is not fully constrained.

Self-adaptive clock synchronization for computational grid

This paper presents an innovative method to synchronize physical clocks for a computational grid, in particular for a computational grid linked through the asynchronous Intranet or Internet environments. The method discussed is an asynchronous self-adaptive clock synchronization mechanism. Two strategies for clock synchronisation are introduced. (1) Use continuous time intervals to calculate the precision of clocks, which can reduce the effect of network delay efficiently. (2) Every node synchronizes its clock with its leader actively. In addition, a node self-adaptive model is presented, and the relationship between the clock precision and synchronization time is induced, hence a node can predict when it should begin the synchronization process. Detailed simulation and extension of this issue are provided at the end of the paper. The presented model is both practical and feasible.

Self-adaptive clock synchronisation based on clock precision difference

This paper presents an innovative strategy to synchronize all virtual clocks in asynchronous Internet environments. Our model is based on the architecture of one reference clock and many slave clocks communicating with each other over the Internet. The paper makes three major contributions to this research area. Firstly, one-way information transmission is applied to reduce traffic overhead on the Internet for the purpose of clock synchronization. Secondly, the slave nodes use local virtual time and the arrival timestamp, from the reference node, to create linear mathematical trend models and to retrieve the clock precision differences between reference clock and slave clocks. Finally, a fault-tolerant and self-adaptive model executed by each slave node based on the above linear trend model is created in order to ensure that the virtual clock is running normally, even when the link between the reference node and this slave node has crashed. We also present detailed simulations of this strategy and mathematical analysis on real Internet environments.

Self-adaptive clock synchronization for computational grid

Abstract This paper presents an innovative method to synchronize physical clocks for a computational grid, in particular for a computational grid linked through the asynchronous Intranet or Internet environments. The method discussed is an asynchronous self-adaptive clock synchronization mechanism. Two strategies for clock synchronization are introduced. (1), Use continuous time intervals to calculate the precision of clocks, which can reduce the effect of network delay efficiently. (2) Every node synchronizes its clock, with its leader actively. In addition, a node self-adaptive model is presented, and the relationship between the clock precision and synchronization time is induced, hence a node can predict when it should begin the synchronization process. Detailed simulation and extension of this issue are provided at the end of the paper. The presented model is both practical and feasible