Clock Tick Research Articles

NAMPT-Mediated NAD Biosynthesis as the Internal Timing Mechanism: In NAD+ World, Time Is Running in Its Own Way.

The biological age of organisms differs from the chronological age and is determined by internal aging clock(s). How cells estimate time on a scale of 24 hours is relatively well studied; however, how biological time is measured by cells, tissues, organs, or organisms in longer time periods (years and decades) is largely unknown. What is clear and widely agreed upon is that the link to age and age-related diseases is not chronological, as it does not depend on a fixed passage of time. Rather, this link depends on the biological age of an individual cell, tissue, organ, or organism and not on time in a strictly chronological sense. Biological evolution does not invent new methods as often as improving upon already existing ones. It should be easier to evolve and remodel the existing (circadian) time clock mechanism to use it for measurement or regulation of longer time periods than to invent a new time mechanism/clock. Specifically, it will be demonstrated that the circadian clock can also be used to regulate circannual or even longer time periods. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) levels, being regulated by the circadian clock, might be the missing link between aging, cell cycle control, DNA damage repair, cellular metabolism and the aging clock, which is responsible for the biological age of an organism. The hypothesis that NAMPT/NAD+/SIRT1 might represent the time regulator that determines the organismal biological age will be presented. The biological age of tissues and organs might be regulated and synchronized through eNAMPT blood secretion. The "NAD World 2.0" concept will be upgraded with detailed insights into mechanisms that regulate NAD+-mediated aging clock ticking, the duration and amplitude of which are responsible for the aging rate of humans.

Circadian rhythms: Replication keeps the clock ticking.

DNA replication regulates nucleosome dynamics at the promoter of a negative element of the circadian clock, thereby providing regulatory feedback into circadian rhythms.

Making the clock tick: the transcriptional landscape of the plant circadian clock

Circadian clocks are molecular timekeepers that synchronise internal physiological processes with the external environment by integrating light and temperature stimuli. As in other eukaryotic organisms, circadian rhythms in plants are largely generated by an array of nuclear transcriptional regulators and associated co-regulators that are arranged into a series of interconnected molecular loops. These transcriptional regulators recruit chromatin-modifying enzymes that adjust the structure of the nucleosome to promote or inhibit DNA accessibility and thus guide transcription rates. In this review, we discuss the recent advances made in understanding the architecture of the Arabidopsis oscillator and the chromatin dynamics that regulate the generation of rhythmic patterns of gene expression within the circadian clock.

Rapamycin keeps the reproductive clock ticking.

Two weeks of rapamycin administration in young and old female mice leads to long-term improvements in ovarian function and reproductive longevity.

Clock ticking again on four-hour target.

Emergency departments (EDs) in England have been told they need to start hitting the four-hour target again by March 2018. Health secretary Jeremy Hunt has set the deadline following the announcement of extra money in the Budget.

Tricks for ticks

Optical-lattice clocks have pushed the limits of frequency measurement — to such an extent that a tiny difference in altitude affects the clock's tick rate, as Hidetoshi Katori elucidates.

Scalable and Passive Wireless Network Clock Synchronization in LOS Environments

Clock synchronization is ubiquitous in wireless systems for communication, sensing and control. In this paper we design a scalable system in which an indefinite number of passively receiving wireless units can synchronize to a single master clock at the level of discrete clock ticks. Accurate synchronization requires an estimate of the node positions. If such information is available the framework developed here takes position uncertainties into account. In the absence of such information we propose a mechanism which enables simultaneous synchronization and positioning. Furthermore we derive the Cramer-Rao bounds for the system which show that it enables synchronization accuracy at sub-nanosecond levels. Finally, we develop and evaluate an online estimation method which is statistically efficient.

Broadcast Gossip Ratio Consensus: Asynchronous Distributed Averaging in Strongly Connected Networks

This study proposes a gossip-based algorithm to find the exact average of initial states in strongly connected topologies such as sensor networks. Network members are assumed to have different clock rates where the arrival of a clock tick is a Poisson process with a rate ${{\mathbf{\lambda }}_{{i}}}$ . The algorithm reaches a consensus value faster and with fewer packet transmissions by tolerating omissions of low-rate members’ states. Theoretical analysis is provided to demonstrate that the final consensus value converges to the exact average of initial measurements regardless of the rates of transmission. Additionally, it is shown that the proposed algorithm asymptotically reaches a consensus value even if some algorithm parameters are not precisely measured. Simulation results in a realistic environment confirm that the proposed framework needs considerably fewer packet transmissions than existing methods. The algorithm maintains its excellence in terms of transmission count, convergence speed, and accuracy for different network sizes and transmission rates.

Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL

Objectives: The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation of ARNTL may differ between bipolar disorder (BD) and controls.Methods: The methylation status of one CpG island covering the first exon of ARNTL (PS2) and one site in the 5′ region of ARNTL (cg05733463) were analysed in patients with BD (n = 151) versus controls (n = 66). Methylation analysis was performed by bisulphite-conversion of DNA from fasting blood with the EpiTect Bisulfite Kit, PCR and pyrosequencing. Analysis of covariances considering the covariates age, body mass index, sex, smoking, lithium and anticonvulsant intake were performed to test methylation differences between BD and controls.Results: Methylation at cg05733463 of ARNTL was significantly higher in BD than in controls (F(1,209) = 44.500, P < .001). In contrast, methylation was significantly lower in BD at PS2_POS1 compared to controls (F(1,128) = 5.787, P = .018) and by trend at PS2_POS2 (F(1,128) = 3.033, P = .084) and POS7 (F(1,34) = 3.425, P = .073).Conclusions: Methylation of ARNTL differed significantly between BD and controls. Thus, our study suggests that altered epigenetic regulation of ARNTL might provide a mechanistic basis for better understanding circadian rhythms and mood swings in BD.

The Second Girl

The Second Girl

The Second Girl

The Second Girl

Interfering with time

Quantum Mechanics The interference pattern arising from light or particles passing through a double slit is a simple experiment that belies the subtleties of interpretation when attempting to describe and understand the effect. For example, determining “which path” the light or particles travel can result in the interference pattern disappearing. Margalit et al. present a new take on interferometry using time (see the Perspective by Arndt and Brand). A clock—i.e., the internal state of a cold atom condensate—was coherently split and brought back together to interfere. Making one-half of the clock tick at a different rate resulted in a change in the interference pattern, possibly as a consequence of the time being a “which path” witness. Science , this issue p. [1205][1]; see also p. [1168][2] [1]: /lookup/doi/10.1126/science.aac6498 [2]: /lookup/doi/10.1126/science.aad0683

Out of Sync

Digital devices and 24/7 lifestyles are messing with our body's natural rhythms, threatening our health. What does it take to keep our inner clock ticking?

Ground-based optical atomic clocks as a tool to monitor vertical surface motion

Abstract According to general relativity, a clock experiencing a shift in the gravitational potential ΔU will measure a frequency change given by Δf/f ≈ ΔU/c2. The best clocks are optical clocks. After about 7 hr of integration they reach stabilities of Δf/f ∼ 10−18 and can be used to detect changes in the gravitational potential that correspond to vertical displacements of the centimetre level. At this level of performance, ground-based atomic clock networks emerge as a tool that is complementary to existing technology for monitoring a wide range of geophysical processes by directly measuring changes in the gravitational potential. Vertical changes of the clock's position due to magmatic, post-seismic or tidal deformations can result in measurable variations in the clock tick rate. We illustrate the geopotential change arising due to an inflating magma chamber using the Mogi model and apply it to the Etna volcano. Its effect on an observer on the Earth's surface can be divided into two different terms: one purely due to uplift (free-air gradient) and one due to the redistribution of matter. Thus, with the centimetre-level precision of current clocks it is already possible to monitor volcanoes. The matter redistribution term is estimated to be 3 orders of magnitude smaller than the uplift term. Additionally, clocks can be compared over distances of thousands of kilometres over short periods of time, which improves our ability to monitor periodic effects with long wavelength like the solid Earth tide.

Teaching and learning in an era of time-based access targets: Impact of a new model of care on junior medical officers.

Teaching and learning in an era of time-based access targets: Impact of a new model of care on junior medical officers.

Tread softly and carry a clock's tick.

Skilled behavior is thought to rely on the dorsal striatum. A study now reports that skills depend on striatal encoding of movement kinematics, linking learned sequences of movements with temporally distributed striatal activity.

Gravitational and relativistic deflection of X-ray superradiance

A theoretical proposal for time-dependent deflection of X-rays by gravitational and relativistic effects may lead to a table-top technique for probing gravity and relativity. Einstein predicted that clocks at different altitudes tick at various rates under the influence of gravity. This effect has been observed using 57Fe Mössbauer spectroscopy over an elevation of 22.5 m (ref. 1) or by comparing accurate optical clocks at different heights on a submetre scale2. However, challenges remain in finding novel methods for the detection of gravitational and relativistic effects on more compact scales. Here, we investigate a scheme that potentially allows for millimetre- to submillimetre-scale studies of the gravitational redshift by probing a nuclear crystal with X-rays. Also, a rotating crystal can force interacting X-rays to experience inhomogeneous clock tick rates within it. We find that an association of gravitational redshift and special-relativistic time dilation with quantum interference is manifested by a time-dependent deflection of X-rays. The scheme suggests a table-top solution for probing gravitational and special-relativistic effects, which should be within the reach of current experimental technology3,4,5.

T-types make your clock tick.

Voltage gated T-type calcium channels are important regulators of rhythmic activity in the mammalian nervous system. T-type channels are ideally suited towards regulating neuronal excitability for several reasons. First, their voltage dependent gating properties generate a ‘window current’ that allows them to become active near typical neuronal resting membrane potentials. Second, their hyperpolarization induced recovery from inactivation kinetics supports rebound burst activity in many types of neurons (Huguenard & Prince, 1994). Finally, these channels associate with, and regulate, the functions of both calcium activated and voltage gated potassium channels, which in turn shape neuronal firing properties (Turner & Zamponi, 2014). Besides regulating neuronal activity, T-type channels also contribute to low threshold exocytosis through physical coupling to the vesicle release machinery (Weiss et al. 2012). All of these aspects of T-type channel function are of direct relevance to an interesting new study by Yu and colleagues (Yu et al. 2015), reported in this issue of The Journal of Physiology, on the role of T-type channels in the pineal gland.

Transmathematical Basis of Infinitely Scalable Pipeline Machines

Abstract We describe infinitely scalable pipeline machines with perfect parallelism, in the sense that every instruction of an inline program is executed, on successive data, on every clock tick. Programs with shared data effectively execute in less than a clock tick. We show that pipeline machines are faster than single or multi-core, von Neumann machines for sufficiently many program runs of a sufficiently time consuming program. Our pipeline machines exploit the totality of transreal arithmetic and the known waiting time of statically compiled programs to deliver the interesting property that they need no hardware or software exception handling.

Persistent and Nonviolent Steps and the Design of GALS Systems

A concurrent system is persistent if throughout its operation no activity which became enabled can subsequently be prevented from being executed by any other activity. This is often a highly desirable or even necessary property; in particular, if the system is to be implemented in hardware. Over the past 40 years, persistence has been investigated and applied in practical implementations assuming that each activity is a single atomic action which can be represented, for example, by a single transition of a Petri net. In this paper we investigate the behaviour of GALS Globally Asynchronous Locally Synchronous systems in the context of VLSI circuits. The specification of a system is given in the form of a Petri net. Our aim is to re-design the system to optimise signal management, by grouping together concurrent events. Looking at the concurrent reachability graph of the given Petri net, we are interested in discovering events that appear in 'bundles', so that they all can be executed in a single clock tick. The best candidates for bundles are sets of events that appear and re-appear over and over again in the same configurations, forming 'persistent' sets of events. Persistence was considered so far only in the context of sequential semantics. In this paper, we move to the realm of step based execution and consider not only steps which are persistent and cannot be disabled by other steps, but also steps which are nonviolent and cannot disable other steps. We then introduce a formal definition of a bundle and propose an algorithm to prune the behaviour of a system, so that only bundled steps remain. The pruned reachability graph represents the behaviour of a re-engineered system, which in turn can be implemented in a new Petri net using the standard techniques of net synthesis. The proposed algorithm prunes reachability graphs of persistent and safe nets leaving bundles that represent maximally concurrent steps.