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In Timeless: Nature’s Formula for Health and Longevity, Cozolino challenges the common thought that the aging brain is destined to decline and provides the evidence to prove the fallacy of this tho...

The timing of behavior under natural light-dark conditions is a function of circadian clocks and photic input pathways. Yet a mechanistic understanding of how these pathways collaborate in animals is lacking. Here we demonstrate in Drosophila that the Phosphatase of Regenerating Liver-1 (PRL-1) sets period length and behavioral phase gated by photic signals. PRL-1 knockdown in PDF clock neurons dramatically lengthens circadian period. PRL-1 mutants exhibit allele-specific interactions with the light- and clock-regulated gene timeless (tim). Moreover, we show that PRL-1 promotes TIM accumulation and dephosphorylation. Interestingly, the PRL-1 mutant period lengthening is suppressed in constant light and PRL-1 mutants display a delayed phase under short, but not long, photoperiod conditions. Thus, our studies reveal that PRL-1 dependent dephosphorylation of TIM is a core mechanism of the clock that sets period length and phase in darkness, enabling the behavioral adjustment to changing day-night cycles.

Mega-projects are projects that require immense resources to create. This includes all different aspects; funding, labour, etc. These projects are meant to create a massive effect on the city or national level through providing job opportunities during construction as well as after completion. Moreover, these projects usually have an intercontinental effect that echoes worldwide and may affect other projects, cities or even countries either positively or negatively. Mega-projects are not restricted to certain project typologies; in fact they range from Olympic cities to water dams and channels. We can even claim that the first mega-project was the great pyramid. Mega-projects can also be linked to mega-events thus achieving more international acknowledgement. This paper discusses the creation of new capital cities as a mega-project typology. It analyzes different examples worldwide where a new capital city was created to act as a mega-project that would create ripples of economic and urban development through a country. The capitals of Brazil, Kazakhstan and Egypt are studied to display the authors view of them as mega-projects that have the same function but span across time, space and cultures.

The sun may seem timeless, but it is constantly evolving and is already halfway through its life, says Chanda Prescod-Weinstein

Ray Bolger was called an amiable fellow with a chinless profile, skittish feet, and a snickering spirit. At five feet, ten and one-half inches, he weighed between 135 and 140 pounds at any given time and was said to be skinnier than even Frank Sinatra. After an evening of dancing on Broadway, he could come off the stage as much as three pounds lighter, his dark brown hair blackened with sweat. “His face and body acquire their unusually eccentric quality only when he’s on a stage,” wrote show business reporter Maurice Zolotow. “Otherwise he’s quite nondescript.” Bolger himself said, “I look like everyone’s second cousin. I don’t look like Ray Bolger.”...

A major consequence of the world industrialized lifestyle is the increasing period of unnatural light in environments during the day and artificial lighting at night. This major change disrupts endogenous homeostasis with external circadian cues, which has been associated to higher risk of diseases affecting human health, mainly cancer among others. Circadian disruption promotes tumor development and accelerate its fast progression. The dysregulation mechanisms of circadian genes is greatly affected by the genetic variability of these genes. To date, several core circadian genes, also called circadian clock genes, have been identified, comprising the following: ARNTL, CLOCK, CRY1, CRY2, CSNK1E, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, RORA, and TIMELESS. The polymorphic variants of these circadian genes might contribute to an individual's risk to cancer. In this short review, we focused on clock circadian clock-related genes, major contributors of the susceptibility to endocrine-dependent cancers through affecting circadian clock, most likely affecting hormonal regulation. We examined polymorphisms affecting breast, prostate and ovarian carcinogenesis, in addition to pancreatic and thyroid cancer. Further study of the genetic composition in circadian clock-controlled tumors will be of great importance by establishing the foundation to discover novel genetic biomarkers for cancer prevention, prognosis and target therapies., SM-S would like to thank the grant awards from SEIOMM (2017) and SEEN (2018). JJ-L was funded by a Ramon y Cajal Research Program from the Spanish Ministry of Economy, Industry and Competitiveness (grant ref. number YC-2014-16536); the grant ref. BFU2016-77243-P; by the CSIC—intramural grant ref. 201540E065; and by the EU Marie Curie Research Program FP7-PEOPLE-2011-IOF, grant ref. PIOF-GA-2011-301550. All authors thank Michela Verbeni for the English language edition performed on the manuscript.

Following the approach of the urban diary discussed in chapter 2, and expanded upon in Seeing the Better City, this chapter presents reflective vignettes of varying lengths, based on my collection of photographs and observations of local and international examples. These vignettes demonstrate how urbanism without effort is premised on common human affinities and varied in expression by cultural context, historical circumstance, and other unique factors, such as geography and climate. They demonstrate the challenges of creating livable cities that are universal and timeless, and how solutions require careful observation in the context of local circumstances.

In this last chapter, we consider the timeless solutions to the dilemma of foreknowledge. In particular, in the first part, we present the Timeless Eternalist view, in which a timeless God eternally sees a world as it is described by a B-theory of time. In the second part, we develop an original account, which we call Perspectival Fragmentalism: this view adopts a particular perspectival framework for the interpretation of the propositions, and it assumes a robust, dynamic, conception of time. The background metaphysics is inspired by Kit Fine’s Fragmentalism.

There is considerable variation in sleep duration, timing and quality in human populations, and sleep dysregulation has been implicated as a risk factor for a range of health problems. Human sleep traits are known to be regulated by genetic factors, but also by an array of environmental and social factors. These uncontrolled, non-genetic effects complicate powerful identification of the loci contributing to sleep directly in humans. The model system, Drosophila melanogaster, exhibits a behavior that shows the hallmarks of mammalian sleep, and here we use a multitiered approach, encompassing high-resolution QTL mapping, expression QTL data, and functional validation with RNAi to investigate the genetic basis of sleep under highly controlled environmental conditions. We measured a battery of sleep phenotypes in &gt, 750 genotypes derived from a multiparental mapping panel and identified several, modest-effect QTL contributing to natural variation for sleep. Merging sleep QTL data with a large head transcriptome eQTL mapping dataset from the same population allowed us to refine the list of plausible candidate causative sleep loci. This set includes genes with previously characterized effects on sleep and circadian rhythms, in addition to novel candidates. Finally, we employed adult, nervous system-specific RNAi on the Dopa decarboxylase, dyschronic, and timeless genes, finding significant effects on sleep phenotypes for all three. The genes we resolve are strong candidates to harbor causative, regulatory variation contributing to sleep.

SUMMARYCircadian rhythms are generated by the cyclic transcription, translation and degradation of clock genes, includingtimeless(tim). Currently, little is known about the mechanisms by which the circadian clock senses and adapts to temperature changes. Here we show that temperature dramatically changes the splicing pattern oftim. We found that at 18°C TIM protein levels are diminished due to the induction of two cold-specific splicing isoforms (tim-coldandtim-short&cold). At 29°C, another isoform,tim-Mediumis strongly upregulated. We found that this isoform switching mechanism allows flies to regulate the levels and activity of TIM by setting miRNA-dependent thresholds for expression as well as by expressing isoforms with specific functions. Flies in which the production oftim-short&coldis abrogated display altered patterns of locomotor activity and alteredtimexpression. Interestingly, the introns oftimcarry the information for the temperature sensitivity, suggesting thattimsplicingper seis the temperature sensor.

The Drosophila circadian pacemaker consists of transcriptional feedback loops subjected to both post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. To have a better understanding of the role and mechanisms of circadian post-transcriptional regulation, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 genes we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI downregulation shortens the period of circadian rhythms both in the brain and in peripheral tissues. Interestingly, we found that PSI regulates the thermosensitive alternative splicing of timeless (tim), promoting splicing events favored at warm temperature over those increased at cold temperature. Moreover, the period of circadian behavior was insensitive to PSI downregulation when flies could produce functional TIM proteins only from a transgene that cannot form the thermosensitive splicing isoforms. Therefore, we conclude that PSI regulates the period of Drosophila circadian rhythms through its modulation of the tim splicing pattern.

The Bhagavad Gitā literally means the “Song of the Supreme Being.” This opening chapter introduces the Bhagavad Gitā as a timeless manual for Self-mastery and leadership. After briefly recounting the author’s preparation for this book, it offers pointers on how to approach the teachings of the Gitā. It lays out the setting by providing an overview of the subject matter of the Gitā and its relevance for contemporary leaders and organizations. Additionally, it provides a synoptic overview of all the chapters of this book. Each chapter of the book is presented integrally as an independent whole, and yet the teachings of the Gitā are unfolded in a progressive manner.

Transcription-translation feedback loops that comprise eukaryotic circadian clocks rely upon temporal delays that separate the phase of active transcription of clock genes, such as Drosophila period (per) and timeless (tim), from negative feedback by the two proteins. However, our understanding of the mechanisms involved is incomplete. Through an RNA interference screen, we found that pre-mRNA processing 4 (PRP4) kinase, a component of the U4/U5.U6 triple small nuclear ribonucleoprotein (tri-snRNP) spliceosome, and other tri-snRNP components regulate cycling of the molecular clock as well as rest:activity rhythms. Unbiased RNA-Sequencing uncovered an alternatively spliced intron in tim whose increased retention upon prp4 downregulation leads to decreased TIM levels. We demonstrate that the splicing of tim is rhythmic with a phase that parallels delayed accumulation of the protein in a 24 hr cycle. We propose that alternative splicing constitutes an important clock mechanism for delaying the daily accumulation of clock proteins, and thereby negative feedback by them.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Psychiatric diseases are often accompanied by circadian disruptions, but the molecular underpinnings remain largely unclear. To address this, we screened genes that have been previously reported to be associated with psychiatric diseases and found that TRRAP, a gene associated with schizophrenia, is involved in circadian rhythm regulation. Knocking down Nipped-A, the Drosophila homolog of human TRRAP, leads to lengthened period of locomotor rhythms in flies. Molecular analysis demonstrates that NIPPED-A sets the pace of the clock by increasing the mRNA and protein levels of core clock genes timeless (tim) and Par domain protein 1e (Pdp1e). Furthermore, we found that NIPPED-A promotes the transcription of tim and Pdp1e possibly by facilitating deubiquitination of histone H2B via the deubiquitination module of the transcription co-activator Spt-Ada-Gcn5 acetyltransferase complex. Taken together, these findings reveal a novel role for NIPPED-A in epigenetic regulation of the clock.

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Background: Asthma is a chronic respiratory disease characterized by diurnal oscillations of symptoms severity with the highest intensity at 4 a.m. and improvement at 4 p.m. The underlying cause may be central circadian clock dysregulation that also controls the target tissues such as lungs. We hypothesized that altered circadian regulation in asthma may result from circadian clock genes variants. This study aimed to investigate the possible association of genetic variants of core circadian clock genes and asthma risk in the population of Polish children. Methods: In the study we included 165 asthmatic patients and 138 healthy children. Asthma diagnosis was based on GINA 2006 guidelines. In the control group, asthma and allergic disease were excluded based on clinical examination and lung function testing. Genotyping was performed for 32 polymorphisms in CLOCK, BMAL1, PER3, and TIMELESS genes using real-time PCR with TaqMan genotyping assays. Statistical calculations were performed in Statistica 12 and linkage disequilibrium was analysed using Haploview 4.2. Results: Three SNPs in TIMELESS (rs10876890, rs2291739, rs11171856), were significantly associated with asthma. Moreover, haplotype analysis showed that two TIMELESS haplotypes (TTTT and CTAC) were also associated with asthma risk, although after multiple testing correction only TTTT haplotype showed significant association with childhood asthma. Conclusions: We have shown for the first time that TIMELESS may be a novel candidate gene for childhood asthma and thus indicating that circadian oscillation in symptoms severity may be genetically predisposed.

Deficiency of the sleep-wake cycle can accelerate the progression of Huntington’s disease (HD) and exacerbate symptoms making it a target of investigation to better understand the molecular pathology of the disorder. In this study we analyzed sleep defects in a Drosophila model of HD and investigated whether disturbed sleep coincides with alterations in the molecular mechanism controlling circadian rhythm. To analyze sleep defects we recorded the daily activity of flies in 12:12 hours light:dark entrainment and in regard to the underlying molecular mechanism measured circadian “clock” gene expression. In HD flies we observed reduced amount of sleep, sleep fragmentation and prolonged sleep latency. We found changes in gene expression patterns of both transcriptional feedback loops of circadian regulation. We detected prolonged expression of the core feedback loop components period and timeless, whilst the secondary feedback loop member vrille had lower expression rates in general. Our results show that the Drosophila HD model recapitulates most of the sleep related symptoms reported in patients therefore it can be a potential tool to study the molecular background of sleep defects in HD. Altered expression of circadian “clock” genes suggests that disturbed sleep pattern in HD might be the consequence of disturbed circadian regulation.

The importance of the circadian clock for the regulation of behaviour and physiology, and the molecular control of these rhythms by a set of clock genes are well defined. The circadian clock deteriorates with advancing age but the mechanism underlying is unclear. Here we recorded the expression of two key clock genes in young, middle-aged and old Drosophila using transgenic luciferase lines reporting period and timeless in vivo. We report a novel marker of imminent death in the expression of TIMELESS. In the days immediately preceding death TIMELESS expression increased to at least 150% of previous acrophase values (88.0% of n = 217) and lost circadian rhythmicity, which predicted death equally well in flies of different ages and under light and temperature cycles. We suggest this transient aberrant clock-gene expression is central to the mechanism of the disturbance in circadian behaviour before death (82.7% of n = 342). We also find that PERIOD expression in central-clock neurons remained robust with age, however PERIOD and TIMELESS in peripheral clocks showed a reduction in both expression level and rhythmicity. In conclusion, as flies age the molecular clock gradually declines at the peripheral level but continues to function at the central until days before death.

TIMELESS protein is known to be essential for normal circadian rhythms. Aging is a deleterious process which affects all the physiological functions of complex organisms including the circadian rhythms. The circadian aging may produce disorganization among the circadian rhythms, arrhythmicity and even, disconnection from the environment, resulting in a detrimental situation to the organism. However, the role of circadian genes on the aging process is poorly understood. In present study, we found TIMELESS was down-regulated in cellular senescence, and further research indicated E2F1 bound to the promotor of TIMELESS and regulated its expression in cellular senescence. Knockdown of TIMELESS accelerated cellular senescence induced by ectopic expression of RasV12, and overexpression of TIMELESS delayed this kind onset of senescence. Meanwhile, micrococcal nuclease assays proved depletion of TIMELESS exacerbated genomic instability at the onset of senescence. Together, our data reveal that TIMELESS plays a role in OIS, which is associated with genome stability changing.

The cell cycle is under circadian regulation. Oncogenes can dysregulate circadian-regulated genes to disrupt the cell cycle, promoting tumor cell proliferation. As a regulator of G2/M arrest in response to DNA damage, the circadian gene Timeless Circadian Clock (TIMELESS) coordinates this connection and is a potential locus for oncogenic manipulation. TIMELESS expression was evaluated using RNASeq data from TCGA and by RT-qPCR and western blot analysis in a panel of colon cancer cell lines. TIMELESS expression following ERK inhibition was examined via western blot. Cell metabolic capacity, propidium iodide, and CFSE staining were used to evaluate the effect of TIMELESS depletion on colon cancer cell survival and proliferation. Cell metabolic capacity following TIMELESS depletion in combination with Wee1 or CHK1 inhibition was assessed. TIMELESS is overexpressed in cancer and required for increased cancer cell proliferation. ERK activation promotes TIMELESS expression. TIMELESS depletion increases γH2AX, a marker of DNA damage, and triggers G2/M arrest via increased CHK1 and CDK1 phosphorylation. TIMELESS depletion in combination with Wee1 or CHK1 inhibition causes an additive decrease in cancer cell metabolic capacity with limited effects in non-transformed human colon epithelial cells. The data show that ERK activation contributes to the overexpression of TIMELESS in cancer. Depletion of TIMELESS increases γH2AX and causes G2/M arrest, limiting cell proliferation. These results demonstrate a role for TIMELESS in cancer and encourage further examination of the link between circadian rhythm dysregulation and cancer cell proliferation.

Light is one of the chief environmental cues that reset circadian clocks. In Drosophila, CRYPTOCHROME (CRY) mediates acute photic resetting of circadian clocks by promoting the degradation of TIMELESS in a cell-autonomous manner. Thus, even circadian oscillators in peripheral organs can independently perceive light in Drosophila However, there is substantial evidence for nonautonomous mechanisms of circadian photoreception in the brain. We have previously shown that the morning (M) and evening (E) oscillators are critical light-sensing neurons that cooperate to shift the phase of circadian behavior in response to light input. We show here that light can efficiently phase delay or phase advance circadian locomotor behavior in male Drosophila even when either the M- or the E-oscillators are ablated, suggesting that behavioral phase shifts and their directionality are largely a consequence of the cell-autonomous nature of CRY-dependent photoreception. Our observation that the phase response curves of brain and peripheral oscillators are remarkably similar further supports this idea. Nevertheless, the neural network modulates circadian photoresponses. We show that the M-oscillator neurotransmitter pigment dispersing factor plays a critical role in the coordination between M- and E-oscillators after light exposure, and we uncover a potential role for a subset of dorsal neurons in the control of phase advances. Thus, neural modulation of autonomous light detection might play an important role in the plasticity of circadian behavior.SIGNIFICANCE STATEMENT Input pathways provide circadian rhythms with the flexibility needed to harmonize their phase with environmental cycles. Light is the chief environmental cue that synchronizes circadian clocks. In Drosophila, the photoreceptor CRYPTOCHROME resets circadian clocks cell-autonomously. However, recent studies indicate that, in the brain, interactions between clock neurons are critical to reset circadian locomotor behavior. We present evidence supporting the idea that the ability of flies to advance or delay their rhythmic behavior in response to light input essentially results from cell-autonomous photoreception. However, because of their networked organization, we find that circadian neurons have to cooperate to reset the phase of circadian behavior in response to photic cues. Our work thus helps to reconcile cell-autonomous and non-cell-autonomous models of circadian entrainment.

Transcription-translation feedback loops that comprise eukaryotic circadian clocks rely upon temporal delays that separate the phase of active transcription of clock genes, such as Drosophila period (per) and timeless (tim), from negative feedback by the two proteins. However, our understanding of the mechanisms involved is incomplete. Through an RNA interference screen, we found that pre-mRNA processing 4 (PRP4) kinase, a component of the U4/U5.U6 triple small nuclear ribonucleoprotein (tri-snRNP) spliceosome, and other tri-snRNP components regulate cycling of the molecular clock as well as rest:activity rhythms. Unbiased RNA-Sequencing uncovered an alternatively spliced intron in tim whose increased retention upon prp4 downregulation leads to decreased TIM levels. We demonstrate that the splicing of tim is rhythmic with a phase that parallels delayed accumulation of the protein in a 24 hr cycle. We propose that alternative splicing constitutes an important clock mechanism for delaying the daily accumulation of clock proteins, and thereby negative feedback by them. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

While much is known about the genes and proteins that make up the circadian clocks in vertebrates and several arthropod species, much less is known about the clock genes in many other invertebrates, including nudibranchs. The goal of this project was to identify the RNA and protein products of putative clock genes in the central nervous system of three nudibranchs, Hermissenda crassicornis, Melibe leonina, and Tritonia diomedea. Using previously published transcriptomes (Hermissenda and Tritonia) and a new transcriptome (Melibe), we identified nudibranch orthologs for the products of five canonical clock genes: brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1, circadian locomotor output cycles kaput, non-photoreceptive cryptochrome, period, and timeless. Additionally, orthologous sequences for the products of five related genes-aryl hydrocarbon receptor nuclear translocator like, photoreceptive cryptochrome, cryptochrome DASH, 6-4 photolyase, and timeout-were determined. Phylogenetic analyses confirmed that the nudibranch proteins were most closely related to known orthologs in related invertebrates, such as oysters and annelids. In general, the nudibranch clock proteins shared greater sequence similarity with Mus musculus orthologs than Drosophila melanogaster orthologs, which is consistent with the closer phylogenetic relationships recovered between lophotrochozoan and vertebrate orthologs. The suite of clock-related genes in nudibranchs includes both photoreceptive and non-photoreceptive cryptochromes, as well as timeout and possibly timeless. Therefore, the nudibranch clock may resemble the one exhibited in mammals, or possibly even in non-drosopholid insects and oysters. The latter would be evidence supporting this as the ancestral clock for bilaterians.

A title like this is a controversial starting point. It alludes to the belief that ethics are not timeless, that they do not exist independently of the particular circumstances of place and time, and, furthermore, that ethics are not innate in human beings, not part of their inalienable being, but rather that they emerge from external, and particularly, social pressures. In other words, the implication is that ethics do not emerge from the individual, but rather from the external environment.

This chapter takes a source-centered approach to introduce the spirit world from the Neolithic period to Han times. Recognizing the nearly universal attributes of spirits as being immaterial, intangible, and invisible, as well as the practical demand of materializing the unseen, three analytical lenses – presencing, practicing, and discoursing – are devised and employed in the analysis of the modes of action that human actors take to interact and communicate with the agentive spirits. As a result, different types and layers of references to spirits – due to different levels of social complexity, the appearance and spread of writing as a transforming technology, and different ways of source preservation (received and excavated) – amalgamated in the sources are unfolded. However, sources of different genesis and nature are not mutually exclusive but necessarily inform one another in the realm of ideas and constitute one another in practice. Therefore, while the spirit world may have been a timeless and stable aspect of early China, the concerns and techniques of those who acted upon and wrote about spirits shifted along with changes in the culture and institutions in early China.

Endogenous molecular circadian clocks drive daily rhythmic changes at the cellular, physiological, and behavioral level for adaptation to and anticipation of environmental signals. The core molecular system consists of autoregulatory feedback loops, where clock proteins inhibit their own transcription. A complex and not fully understood interplay of regulatory proteins influences activity, localization and stability of clock proteins to set the pace of the clock. This study focuses on the molecular function of Ribosomal S6 Kinase (RSK) in the Drosophila melanogaster circadian clock. Mutations in the human rsk2 gene cause Coffin-Lowry Syndrome, which is associated with severe mental disabilities. Knock-out studies with Drosophila orthologue rsk uncovered functions in synaptic processes, axonal transport and adult behavior including associative learning and circadian activity. However, the molecular targets of RSK remain elusive. Our experiments provide evidence that RSK acts in the key pace maker neurons as a negative regulator of Shaggy (SGG) kinase activity, which in turn determines timely nuclear entry of the clock proteins Period and Timeless to close the negative feedback loop. Phosphorylation of serine 9 in SGG is mediated by the C-terminal kinase domain of RSK, which is in agreement with previous genetic studies of RSK in the circadian clock but argues against the prevailing view that only the N-terminal kinase domain of RSK proteins carries the effector function. Our data provide a mechanistic explanation how RSK influences the molecular clock and imply SGG S9 phosphorylation by RSK and other kinases as a convergence point for diverse cellular and external stimuli.

In the Drosophila circadian clock, Period (PER) and Timeless (TIM) proteins inhibit Clock-mediated transcription of per and tim genes until PER is degraded by Doubletime/CK1 (DBT)-mediated phosphorylation, establishing a negative feedback loop. Multiple regulatory delays within this feedback loop ensure ~24 hr periodicity. Of these delays, the mechanisms that regulate delayed PER degradation (and Clock reactivation) remain unclear. Here we show that phosphorylation of certain DBT target sites within a central region of PER affect PER inhibition of Clock and the stability of the PER/TIM complex. Our results indicate that phosphorylation of PER residue S589 stabilizes and activates PER inhibitory function in the presence of TIM, but promotes PER degradation in its absence. The role of DBT in regulating PER activity, stabilization and degradation ensures that these events are chronologically and biochemically linked, and contributes to the timing of an essential delay that influences the period of the circadian clock., eLife digest Many behaviors, such as when we fall asleep or wake up, follow the rhythm of day and night. This is regulated in part by our ‘circadian clock’, which controls biological processes through the timed activation of hundreds of genes over the 24-hour day. In fruit flies, the proteins that form the core of the circadian clock activate and repress each other in such a way that their expression oscillates over a 24-hour cycle. During the late afternoon and early evening, the Clock protein initiates the production of proteins Period and Timeless: these two molecules then accumulate in the cell, and after binding to each other, they are transported into the nucleus. During the late night and early morning, this Period/Timeless complex inhibits the activity of Clock. After a delay, Period and Timeless are degraded. This allows Clock to be reactivated, restarting the cycle for the next day. Period is critical to help maintain the 24-hour oscillation shown by these proteins. A protein called Doubletime is responsible for making a number of chemical modifications on Period. It is unclear how these changes interact with each other, and how they influence the stability and function of Period when it is associated with Timeless. Here, Top et al. generate mutations in the fruit fly gene period to study these processes, and develop a new biomolecular technique to monitor the stability and activity of Period protein in insect cells grown in the laboratory. The experiments reveal new roles for the chemical changes made by Doubletime to Period. First, after Period associates with Timeless, Doubletime triggers certain modifications that lead to Period being able to inactivate Clock. Second, Doubletime makes another change in a nearby region of Period that results in the Period/Timeless complex being stabilized. Both sets of modifications help the complex to stay active and keep inhibiting Clock for long enough such that a 24-hour rhythm can be maintained. Finally, when Timeless is degraded, Period is released from the complex. At this time, the modifications made by Doubletime promote the degradation of Period, resetting the clock. Fruit flies with mutations that block this mechanism perceive the day as shorter. This shows that the smallest change to clock genes can disorganize behavior. Indeed in humans, health problems such as sleep or mental health disorders are associated with irregular circadian clocks. Understanding the biochemical mechanisms that keep the body clocks ticking could help to find new therapeutic targets for these conditions.

To function properly, organisms must adjust their physiology, behavior and metabolism in response to a suite of varying environmental conditions. One of the central regulators of these changes is organisms' internal circadian clock, and recent evidence has suggested that the clock genes are also important in the regulation of seasonal adjustments. In particular, thermosensitive splicing of the core clock gene timeless in a cosmopolitan fly, Drosophila melanogaster , has implicated this gene to be involved in thermal adaptation. To further investigate this link we examined the splicing of timeless in a northern malt fly species, Drosophila montana , which can withstand much colder climatic conditions than its southern relative. We studied northern and southern populations from two different continents (North America and Europe) to find out whether and how the splicing of this gene varies in response to different temperatures and day lengths. Interestingly, we found that the expression of timeless splice variants was sensitive to differences in light conditions, and while the flies of all study populations showed a change in the usage of splice variants in constant light compared to LD 22:2, the direction of the shift varied between populations. Overall, our findings suggest that the splicing of timeless in northern Drosophila montana flies is photosensitive, rather than thermosensitive and highlights the value of studying multiple species and populations in order to gain perspective on the generality of gene function changes in different kinds of environmental conditions.

This paper is an attempt to answer the question, 'could there be causation in a timeless world?' My conclusion: tentatively, yes. The paper and argument have three parts. Part one introduces salient issues and spells out the importance of this (initially somewhat baroque seeming) line of investigation. Section two of the paper reviews recent arguments due to Baron and Miller (2015a), who argue in favor of the possibility of causation in a timeless world, and looks to reject their arguments developed there. Section three is a response to a response. In their (2015a), Baron and Miller also argue that an argument in favor of the possibility of causation at timeless worlds, that I put forward (Tallant, 2008), is an argument that fails. In section three, my response to Baron and Miller is that their argument against me succeeds, but that there is a nearby argument that we can appeal to in order to demonstrate the possibility of causation at timeless worlds.

Once upon a time, there were seemingly no interesting questions to ask about the contextual history of the rise of analysis. The pursuit of timeless truths through logical analysis rendered the his...

Dynastic Egypt, the Assyrians, Rome and the Romans’ Byzantine successors created and developed institutions and ideologies for managing large populations. Together, for that reason, they comprise m...

Can a timeless God act in the world? The purpose of this paper is to address this question by exploring the nature of timeless God’s omniscience. In the first part I argue—having explored what it means to say that God is timeless—that we should think of a timeless God’s omniscience factually rather than propositionally i.e. that a timeless God doesn’t know all propositions, but does know all facts. One consequence of this view is that though everything (what we call past, present and future) is equally present in the mind of a timeless God, being timeless he doesn’t know which events are past, which are present and which are future. For example, he doesn’t know that what is presently happening in the world is presently happening. The central issue I then consider in the second part is whether his knowledge could really be of the right kind for him to act in the temporal world. I argue that though God has knowledge of all the events in the temporal world and even knows (perhaps) their temporal orderings, he is unable to intervene because to do so he would need to have the knowledge he lacks; namely, he would need to know which events in the temporal world are past, which are present and which are future.

Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. We report here that the core circadian clock genes, timeless (tim) and period (per), are required for the metabolic and lifespan responses to DR in Drosophila. Consistent with the involvement of a circadian mechanism, DR enhances the amplitude of cycling of most circadian clock genes, including tim, in peripheral tissues. Mass-spectrometry-based lipidomic analysis suggests a role of tim in cycling of specific medium chain triglycerides under DR. Furthermore, overexpression of tim in peripheral tissues improves its oscillatory amplitude and extends lifespan under ad libitum conditions. Importantly, effects of tim on lifespan appear to be mediated through enhanced fat turnover. These findings identify a critical role for specific clock genes in modulating the effects of nutrient manipulation on fat metabolism and aging.

How does art transcend time? What special power enables it to overcome temporal distance and speak to us not just as evidence of times gone by but as a living presence? The Renaissance concluded that great art is impervious to time – “timeless”, “immortal”, “eternal” – a belief endorsed by Enlightenment aesthetics. Later thinkers such as Hegel, Marx and Taine stressed the historical embeddedness of art, a view also espoused by certain modern theorists such as Sartre, Benjamin and Adorno. The conflict between these two positions has left us without a persuasive account of art’s capacity to transcend time. Andre Malraux offers an entirely new account of this unique power of art. For Malraux, art is neither exempt from history (timeless) nor wholly immersed in it. Art transcends time through metamorphosis, a process of continual transformation in significance in which history plays an essential, but not exclusive, part.