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The program will end in 2023 funded by the World Bank in partnership with the Tongan government.
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Reading comprehension requires the construction of a coherent mental representation of the information in a text. Reading involves three interrelated elements—the reader, the text, and the activity, all situated into a broader sociocultural context. The complexity inherent in reading comprehension has given rise to a multitude of influential models and frameworks that attempt to account for the various processes that give rise to reading comprehension: for example, activation of prior knowledge and integration of incoming information with currently active memory contents. Other models and frameworks attempt to account for the components that constitute reading comprehension, such as decoding, vocabulary, and language comprehension.
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Ozarks Medical Center receives multiple awards at HealthCare Service Excellence conference
CEO Tom Keller takes home top honors
WEST PLAINS, Mo – Ozarks Medical Center (OMC) and members of its staff received multiple awards of excellence in improving the patient experience at the 20th annual HealthCare Service Excellence conference recently held in New Orleans.
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Pictured: Jordan Lang, Critical Care Manager, Ozarks Medical Center, accepting the 2019 Summit Award for the OMC OASIS Team "Emergency Department Throughput" initiative.
Pictured: Richard McGee, Director, OMC Behavioral Healthcare; 2019 "Super Coach" Summit Award Recipient.
Pictured: Tom Keller, CEO and President, Ozarks Medical Center; 2019 "Inspiring Administrator" Pinnacle Award Winner and recipient of the prestigious Founders Award.
Ozarks Medical Center attendees and award recipients at the 20th annual HealthCare Service Excellence conference held in New Orleans. Pictured from left to right, standing; Tonya Rackley Aaron, Jordan Lange, Richard McGee, Tracy Litchfield, Jennifer Wheeler, Karlee Marvin, Chelsea VanWinkle, Louis Mongillo, Gary Brown, Melody Hubbell; Front row: Tom Keller, Elizabeth Cauthen, Missy Duggar, Amber Tooley.


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Allison, Marla – "Stars & Clouds" Original Acrylic, Gold Leaf, Silver Leaf
$ 1,250.00
Marla Allison is a from Laguna Pueblo in New Mexico. She lives and makes art from her home studio where she finds inspiration by connecting with family, tradition, and being close to her community. Marla is a contemporary Native artist whose primary medium is painting.
This new painting incorporates gold and silver leaf along with the acrylic. The piece is entitled, "Stars & Clouds". Marla says of this painting:
"Oh, the ever brightening stars, how I yearn for more to guide my path. With every twinkle to brighten my eyes I wait for the night when everything is calm and restful. If only the clouds would sway clear so my full sight could see the full brilliance that has long been awaited for. Let these stars and clouds become one and shine together in soft moonlight."
All of Marla's paintings have a "gallery wrap" so the painting continues onto the side so that framing is not necessary.
Marla says of her painting:
"I am from Laguna Pueblo so I paint Laguna Pueblo. I paint and create for Laguna history to be great and remembered. I paint because I was passed down a gift from my grandfathers; I paint to continue what they started. I began with simple works of loose brush strokes, slight symbols of pottery design, and shapes taught to me in my youth. I researched the artists that I found powerful and connected what they did with what I do. From study and admiration, I found that I had something all my own. Most of my influence is from pottery design of Laguna Pueblo and Hopi Pueblo. I have also found much influence by the cubism of Pablo Picasso and squares of Paul Klee. I don't stick with one certain style but it is all my own, that's what makes it mine. With the use of pottery design, I have painted landscapes that have design on them symbolizing where the clay that holds these designs comes from. I have painted mosaic paintings that are broken up squares and by taking these paintings apart with the image, the viewer is forced to visually put them back together as a way of putting themselves and their past into it in the process. I paint so I remember where I came from. I paint so others can remember where I come from. I paint to be remembered."
Allison began her expression through art in her youth and gained formal education at the Institute of American Indian Arts (IAIA) in Santa Fe, NM where she obtained an Associates Degree in three-dimensional art. Since graduating from IAIA, Marla has exhibited artwork at the Heard Museum Indian Fair and Market, the Santa Fe Indian Market, and the Smithsonian Native Art Market in New York. Permanent collections with Marla's work are found in, The Heard Museum Permanent Collection (Phoenix, AZ), The Museum of Indian Arts and Culture (Santa Fe, NM), The Red Cloud Indian School Collections (Pine Ridge, SD) and various private collections around the country and also Rome, Italy. She was also the 2010 recipient of the Eric and Barbara Dobkin Native Woman's Fellowship at the School for Advanced Research (SAR) in Santa Fe, NM.


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CISF creates new Guinness world record in single line bicycle parade: CISF had created history by achieving a Guinness world record feat in "single line bicycle parade" to mark the 50 years of the paramilitary force. The record was created at the Yamuna Expressway in Noida when personnel of the central force rode a total of 1,327 bicycles.
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NIIGATA – A 31-year-old woman in Niigata Prefecture was arrested Wednesday on suspicion of killing her 3-month-old daughter by repeatedly dropping her on the floor, police said.
Noriko Ito, a Nagaoka city official in charge of promoting gender equality, admitted the allegation to police after her daughter, Hikari, was confirmed dead in hospital from a brain contusion.
People close to her said she appeared distressed over child-rearing, according to investigative sources. Married to a fellow Nagaoka city official, Ito also has a son. She went on maternity leave starting in April, according to the city.
She was home alone with the newborn at the time of the incident. The case came to light when the baby's grandmother called an ambulance after finding her bleeding on the floor when she visited their home on Wednesday.
Ito accompanied Hikari when she was taken to hospital and appeared panic-stricken, according to police and medical staff.
Police, who searched the home Thursday, said Hikari had no wounds that would make them suspect Ito had previously abused the child.


text: The Bible of kiltmaking arrived at Christmas and I've nearly read it cover to cover. Now I just have to purchase supplies and I will start on my first practice project : a kilt for the wee one. After that I have three planned for myself. While I wait for supplies to arrive, are there any sewing videos I should watch for stitches I'll be using? I am brand new besides sewing on a new button here and there. Thanks!


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Sedos brings The Musical of Musicals (The Musical!) to the Bridewell Theatre
Preview by Lizzie Guilfoyle
SEDOS is presenting The Musical of Musicals (The Musical!) at the Bridewell Theatre from February 25 to February 29, 2020.
In what is described as an hilarious satire of musical theatre, one story becomes five delightful musicals, each written in the distinctive style of a different master of the form, from Rodgers and Hammerstein to Stephen Sondheim.
The basic plot: June is an ingenue who can't pay the rent and is threatened by her evil landlord. Will the handsome leading man come to the rescue?
The variations are: a Rodgers and Hammerstein version, set in Kansas in August, complete with a dream ballet; a Sondheim version, featuring the landlord as a tortured artistic genius who slashes the throats of his tenants in revenge for not appreciating his work; a Jerry Herman version, as a splashy star vehicle; an Andrew Lloyd Webber version, a rock musical with themes borrowed from Puccini; and a Kander and Ebb version, set in a speakeasy in Chicago.
Maximising the opportunities of the five musicals within a musical, the team on this Sedos production have been joined by three guest choreographers. Danielle Capretti, Mary Bennett and Olivier Namet are working under expert guidance of Deborah Lean to bring the five styles to life as they make their choreography debuts for the company.
Director Emma J Leaver said: "This show is incredibly silly; however the silliness covers up its cleverness. It is a show for both those who love musicals and those who do not. The joy for the cast, crew and audience is in watching the actors switching between genres and characters in a mad-cap but controlled style. A fun night out that will bring a smile to your face."
Presented by special arrangement with Samuel French, Inc., The Musical of Musicals (The Musical!) has music by Eric Rockwell, lyrics by Joanne Bogat and book by Eric Rockwell and Joanne Bogat.
The cast includes Laura Ellis (as June), Penny Rodie (Abby), Joe Dickens (Billy) and Daniel Saunders (Jitter). Ensemble members are Lucy Spreckley and Alex Yelland.
The production has lighting by Martin Walton, sound by Henry Whittaker, costume design by Frederica Byron, set construction by Stuart Massey and photography by Michael Smith and Adrian Hau. Assistant director is Chris Foxwell.
Tickets: £15.50 – £24. To book, visit sedos.co.uk/.
Times: 7.30pm with a Saturday matinee at 2.30pm.


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The Rotolight Anova Pro Dual V-Lock Charger is designed for use with Rotolight RL-BATT-95, SWIT®, PAG®, Blueshape® and IDX® V Mount batteries. It features space for two batteries, and a convenient top handle for added portability.View more
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The Swit SP-82/302S V-Mount battery kit consists of a SC-302S dual sequential charger and 2x 88Wh V-lock S-8082S batteries. Featuring 2 V-mount plates, the Swit SC-302S 2-ch V-Lock Battery Charger has an output of DC 14-20V, 1.9A and will sequentially charge 2 V-mount batteries. The high-performance Swit S-8082S Li-ion Battery with built-in V-mount is designed...View more
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Designed for use on todays professional rigs/15mm bars, the Hawk-Woods GR-100K Gripper Kit is made up of the Hawk-Woods Gripper GR-100K 14.4v 75Wh Battery and Gripper GR-1C Single Channel Fast Charger. The GR-100 battery is a great all-rounder and a popular choice for weight to power ratio, it features two power-con (D-Taps) outputs and an...View more
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Author(s): Rosie Banks
When mean Queen Malice puts a spell on King Merry, Ellie, Summer and Jasmine must find six magical ingredients to make a cure. They're soon off to Bubble Volcano to find the first ingredient. Can they find the hidden bubblebee hive and get the magic honeycomb they need to save King Merry?
Enter a magical world of friendship and fun!
Rosie Banks is in her late twenties, and grew up in a small village. She spent her childhood dreaming of magical creatures and faraway places, so it was natural that she grew up to write a series of stories where such dreams came true! Rosie has always been close to her two best friends, and their special relationship provided her with inspiration for the magical trio of Jasmine, Ellie and Summer.


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Circadian clocks enhance the efficiency and survival of living things by organizing their behavior and body functions. There has been a long history of research seeking a link between circadian clock and tumorigenesis. Studies of animal models and human tumor samples have revealed that the dysregulation of circadian clocks is an important endogenous factor causing mammalian cancer development. The core circadian clock regulators have been implicated in the control of both the cell cycle and DNA damage responses (DDR). Conversely, several intracellular signaling cascades that play important roles in regulation of the cell cycle and the DDR also contribute to circadian clock regulation. This review describes selected regulatory aspects of circadian clocks, providing evidence of a molecular link of the circadian clocks with cellular DDR.
- circadian clock
- DNA damage response
- DNA repair
- oncogenes
1. Introduction
Circadian (derived from Latin "around the day") clocks constitute ubiquitous processes that regulate various biochemical and physiological events occurring with a 24 h periodicity, even in the absence of external cues [1, 2]. Under natural conditions, clocks are entrained to a 24 h day by environmental time cues, most commonly light. Circadian clocks are established in cell-autonomous oscillators, referred to as cellular clocks, which are controlled by a transcription/translation-based negative feedback loop [3, 4]. In humans, the circadian clock generates circadian rhythms in synthesis and release of hormones and cardiovascular activities such as heart rate, blood pressure, and vascular tone [5, 6]. Moreover, immune responses show temporal changes in antibody levels and total number of lymphocytes, which are related to circadian variations [7]. Therefore, dysfunction of the clock can cause a variety of diseases. In particular, it has been reported that the circadian clocks are associated with tumor suppression in vivo, indicative of the theoretical foundations for cancer chronotherapy [8, 9].
At the molecular level, the circadian clocks can be divided into three conceptual components [10, 11]. The first is the pacemaker, dedicated to generating and sustaining circadian rhythms by receiving and integrating signals from external time cues. The second component is the input which refers to the pathway through which these cues are perceived and act upon the central pacemaker. The third element applies to how the clock affects physiology, which is achieved through the output pathways. In vertebrates, the cellular clocks are comprised of the circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain-containing protein 2 (NPAS2), brain and muscle arnt-like protein-1 (BMAL), period (PER), and cryptochrome (CRY) proteins (Figure 1A) [11]. CLOCK or NPAS2 heterodimerize with BMAL to form an active transcription complex that transactivates clock-controlled genes, including Cry and Per. Once the CRY and PER proteins have been translated, they are translocated to the nucleus, where they inhibit CLOCK(NPAS2):BMAL-mediated transcription through a direct protein-protein interaction. Importantly, when active, the CLOCK (NPAS2):BMAL complex stimulates the transcription of many other clock-controlled genes. These genes in turn influence functions external to the oscillatory mechanism itself and mediate the "output" function of the clock. This accounts in part for the presence of circadian rhythms in a variety of physiological processes.
The phenotypes of mice with targeted disruptions of the genes encoding cellular clock's components have revealed direct links between the circadian clock and non-circadian aspects of animal physiology [6, 9]. In particular, these findings argue in favor of a major role played by the circadian machinery in cellular genotoxic stress responses and reveal intriguing links between the DNA damage responses (DDR) pathways and the circadian clocks. In this review, we summarize the evidence and explore the implications of such a link.
2. The relationship between transcriptional regulation of oncogenes and circadian clocks
The disruption of circadian clocks can have a profound effect on animal health and is linked to abnormal development and cancer [6, 9]. Expression of the circadian clock genes has been reported to be dysregulated in human cancers [12]. The circadian transcriptional machinery, cellular clock, has been reported to control expression of tumor suppressors. Thus, the abnormal control of clock genes' expression in cancer cells activates oncogenic signaling pathways by functional inhibition of tumor suppressors, such as ataxia telangiectasia mutated (ATM), p53, p21, and WEE1 [12].
The Wingless-related integration site (Wnt) signaling pathways collectively play important roles in developmental, proliferative, and cell death processes [13]. Mutations in genes encoding the various components of Wnt pathways have been identified that contribute to various types of cancer including hepatocellular carcinoma, pancreatic tumors, ovarian cancer, and breast cancer. Importantly, there are several lines of evidence that suggest the existence of an interaction between circadian clocks and Wnt signaling pathways. Previous study have performed microarray-based screening for circadian genes in several mouse tissues and have constructed a publicly accessible database, by which users can query for finding circadianly regulated genes or for the study of the temporal expression patterns of their genes of interest [14]. Interestingly, in this database, several Wnt signaling pathway genes, such as Axin2, Frizzled3 (Fzd3), and Disheveled (Dvl1), show a circadian pattern of expression, suggesting the possibility that circadian clocks control transcription of Wnt signaling pathway genes. The future study of the connecting routes that link the circadian transcriptional machinery to Wnt signaling pathway will reveal a molecular link between circadian clock deficiency and tumorigenesis.
3. Possible roles of clock proteins in functional regulation of crucial components of DDR pathways
The activities associated with the physiological processes are organized in daily manner: during the daytime, the animal's physiology is given over to the catabolic processes, whereas at night, it concentrates on the anabolic functions of growth, repair, and consolidation [5, 6]. Disrupt, the time-dependent regulation of physiological functions in animals has profound effects on their health. In particular, many studies have provided evidence that disruption of the circadian clocks results in tumorigenesis [8, 9]. Importantly, mice with mutations in the Bmal1 gene show premature aging phenotype [15]. In addition, human CLOCK has been suggested to be involved in metastasis of colorectal cancer [16]. These findings implicate the core circadian machinery in the regulation of DDR and the cell cycle. Indeed, the circadian regulators have been demonstrated to interact with crucial components of cellular stress response pathways including the ATM, the checkpoint kinase 2 (Chk2) kinase [17], sirtuin1 (SIRT1) deacetylase [18], and nuclear receptors 19, 20], whereas it has been reported that DNA damage can act as a resetting cue for the mammalian circadian clock [21].
Histone acetyltransferases (HATs) such as CBP/p300 are known to acetylate nonhistone targets and have also been recognized as tumor suppressors [22, 23]. Translocation, amplification, overexpression, or mutation of HAT genes are known to occur in several forms of cancer, and several key cell cycle proteins (including p53 and c-MYC) are known targets of HATs. These observations suggest that HATs can also affect cell proliferation and differentiation in multiple ways, in addition to chromatin remodeling. It was previously reported that a core circadian regulator, CLOCK, has intrinsic HAT activity [24] and further that it acetylates a nonhistone target, the heterodimeric CLOCK-binding partner BMAL (Figure 1B) [25]. CLOCK also acetylates the glucocorticoid receptor and the argininosuccinate synthase, negatively regulating the transactivation capacity and the enzymatic activity, respectively [20, 26]. It is conceivable that CLOCK would directly interact with and regulate key DDR regulators, leading to the acetylation of these proteins and thereby modulating their activities (Figure 1B).
4. Roles of circadian clocks in regulation of cell cycle
Circadian clock proteins appear to play roles in cell cycle control, acting as tumor suppressors. They control the timing of cell proliferation by transcriptional control of key cell cycle genes such as Wee1, c-Myc, and cyclin-dependent kinase inhibitor 1d (20 kDa protein, p20) [27, 28, 29]. In mammals, PER proteins directly interact with ATM and Chk2 proteins, inducing cell growth inhibition, cell cycle arrest, and apoptosis [17]. In addition, it has been also reported that PER1 and PER2 interact with the androgen receptor (AR) or estrogen receptor (ER), respectively, in that PER1 inhibits AR-dependent transcription and PER2 induces ER degradation [19, 30]. These findings support the idea that clock proteins act as key players in the cell cycle by interacting directly with and regulating the functions of the cell cycle regulators.
In zebrafish, the cell cycle is directly regulated by light [31, 32]. Light determines the timing of mitosis (M phase) and DNA synthesis (S phase), establishing a circadian rhythm for cell cycle progression. At the molecular level, cellular clocks establish the circadian expression of the cell cycle genes, zebrafish Wee1 and p20 [29, 32]. The Wee-l kinase controls the timing of the G2/M transition by directly phosphorylating and inhibiting cell division cycle2 (Cdc2)/cyclin B, leading to the suppression of mitotic cell division. In contrast, p20 regulates the G1/S transition of the cell cycle. Thus, the circadian control of these cell cycle regulators could be a mechanism establishing the circadian rhythm of cell cycle. Both cell cycle and circadian clock are endogenous pacemakers, and these mechanisms coexist in most eukaryotic cells and share several conceptual characteristics. The abovementioned findings point to functional links between the cell cycle and circadian clock in different organisms.
5. Posttranslational modifications contributing to both the circadian clock regulation and the cellular DDR
Posttranslational modifications of proteins regulate various biological processes at molecular levels, including gene expression, chromatin remodeling, and protein stabilization. These molecular events have essential roles in appropriately regulating biological phenomena, including development and circadian clock, by maintaining cellular functions, such as proliferation and molecular clocks, respectively. Posttranslational modifications, such as phosphorylation, sumoylation, and acetylation, control the transcriptional activity, subcellular localization, and stability of circadian clock regulators in multiple ways [4, 33]. In particular, the defects in phosphorylating the circadian clock regulators have been implicated in human sleep disorders [34, 35]. It is also well established that posttranslational modifications are vital for the regulation of the cell cycle and DDR. SIRT1 and casein kinase2 (CK2), already identified as responsible factors for posttranslational modifications of clock proteins [18, 36, 37, 38, 39], have also been implicated in posttranslational modifications of proteins such as p53, forkhead box class O (FoxO), and E-cadherin that are involved in cellular metabolism, the cell cycle, and DDR [40, 41]. These findings support the hypothesis that the circadian clocks may be linked to other cellular processes, such as cell cycle control and DDR, through shared posttranslational modifications.
6. Studies on light-dependent regulation of zebrafish circadian clock have revealed links of circadian clock with DNA repair and cellular DDR
To guarantee that an organism's behavior remains tied to the rhythms of its environment, the circadian clocks must respond to environmental stimuli to be reset [2, 10]. The main cue for animals is light, which is provided by the day-night cycle. The mammalian route for circadian entrainment by light uses the retinohypothalamic tract, which connects directly to the central clock located in the suprachiasmatic nucleus of the brain [42]. This makes it difficult to analyze the light entrainment mechanisms of the circadian clocks, especially at cellular levels. Zebrafish peripheral cellular clocks display a striking feature as they are directly light responsive [43]. Notably, in the zebrafish-cultured cell lines, oscillations of clock gene expression can be entrained to new light-dark cycle, and expression of clock genes, such as zebrafish Cryptochrome1a (zCry1a) and Period2 (zPer2), is transactivated by an acute light pulse [44, 45, 46]. These observations show that zebrafish cultured cells have the clock components required for a light-induced reset of circadian clock, therefore, providing a valuable tool for the study of general light-dependent regulation of cellular clocks.
Studies using zebrafish-cultured cells have contributed to identification of cellular signaling cascades involved in the light-dependent regulation of cellular clocks [47]. In several organisms, external stimuli are connected to a cell's nucleus via MAPK signaling pathways, such as p38 and extracellular signal-regulated kinase (ERK) [48]. Light has been reported to activate these signaling cascades in zebrafish cells (Figure 2) [49]. By a pharmacological approach, it has also been reported that the light-induced ERK activation triggers expression of zPer2 and zCry1a genes, whereas the light-induced p38 activation suppresses it, highlighting a MAPK-mediated cross-regulatory mechanism of the expression of circadian clock genes [49, 50]. Importantly, an increased understanding of the light-dependent cellular clock regulation in zebrafish has suggested intriguing associations of the circadian clock with DNA repair and cellular DDR as described below.
7. Shared regulatory pathway for circadian clock and DNA repair in zebrafish
Although solar light has several beneficial uses, including the regulation of circadian clocks, the UV component of solar light is harmful to living cells because it produces cytotoxic and mutagenic lesions in DNA called cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts [(6-4) photoproducts] (Figure 2) [51, 52]. Natural selective pressure has forced the development of a self-defense system mediated by photoreactivation. Photoreactivation is the light-dependent DNA repair mechanism mediated by DNA photolyases (PHRs), which bind to and repair the UV-induced DNA damage using visible light as an energy source [53]. Two classes of PHRs have been identified, one specific for CPDs and the other specific for (6-4) photoproducts. Importantly, both the induction of PHRs in response to light and subsequent light-dependent repair of DNA by PHRs are essential for a successful photoreactivation in zebrafish cells [42, 54, 55]. Notably, the expression of the zebrafish Phr repairing (6-4) photoproduct (z64Phr) is regulated by the same light-induced MAPK cascades as those controlling the expression of the clock genes zCry1a and zPer2 (Figure 2) [49]. The light-induced ERK activation triggers the expression of z64Phr, whereas the light-induced p38 activation inhibits it. Thus, the light-dependent DNA repair and regulation of the circadian clock are governed by shared regulatory pathways. Both CRYs and PHRs belong to the DNA photolyase/cryptochrome protein family and have highly similar amino acid sequences [42, 55, 56]. Evolutionary studies have shown that the animal CRY proteins functionally diverged first from the CPD photolyase and then further to generate 64PHR [57]. These facts, together with the observation that zCry1a and z64Phr share regulatory pathways, strongly indicate an evolutionary link between the circadian clock and DNA repair. Importantly, evolutionary links functionally coupling the circadian clock and DNA repair also have been reported in other organisms. For example, Neurospora PRD-4, an orthologue of mammalian Chk2, transduces stress signals into the core circadian clock machinery, contributing the regulation of circadian clock [58]. Additionally, in the diatom Phaeodactylum tricornutum, Phaeodactylum tricornutum cryptochrome/photolyase family1 (PtCPF1), a novel cryptochrome/photolyase family member, not only repairs UV-induced DNA damage but also acts as a transcriptional repressor of the circadian clock [59].
8. Cellular responses to photooxidative stress are the candidate evolutionary origin of circadian clocks
Cellular reactive oxygen species (ROS) were originally thought to solely act as toxic metabolites because they react with components of DNA, proteins, and lipids and exert oxidative stress. However, ROS are also ideally suited as signaling molecules because they are small and can easily diffuse to short distances within a cell [60]. In addition, mechanisms for ROS production and the rapid removal (such as via catalase) are present in almost all cell types [61]. Much evidence has accumulated indicating significant roles of ROS in circadian clock controls that have resulted in the functional coupling of the circadian clock and DDR. For example, in Drosophila, a genome-wide screen identified several redox molecules as essential for the light entrainment of the circadian clock [62]. Similarly, a study in mammals showed that changes in reduced NADPH and NADH levels altered the affinity of the NPAS2:BMAL1 complex for its target DNA in vitro [63]. Thus, redox state may be an important determinant of circadian oscillations in mammalian cells. Nuclear factor erythroid-derived 2-like 2 (NRF2) is one of the components involved in the major cellular antioxidant defense pathways [64]. It induces a transcriptional program that maintains cellular redox balance and protects cells from oxidative insults. Importantly, it has been reported in mouse that cellular clock generates circadian rhythm in NRF2 level, which is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the lung [65].
In zebrafish, the transcriptional induction of zCry1a and zPer2 genes has been proposed to be required for the light entrainment of cellular clocks [45, 66, 67]. The light-dependent transcription of zCry1a and zPer2 is controlled through the production and removal of cellular ROS [66, 68]. The light-induced ROS stimulate the intracellular ERK signaling pathway and transduce photic signals to the transactivation of zCry1a and zPer2 (Figure 2). Importantly, light increases the intracellular catalase activity by increasing the expression of catalase, an event that occurs after the maximum expression of the zCry1a and zPer2 genes has been reached. This increased catalase activity diminishes the light-induced cellular ROS levels, resulting in decreased expression levels of zCry1a and zPer2 genes. These findings provide evidence that ROS induced by light are the second messenger coupling photoreception to the entrainment of the circadian clock in zebrafish and further indicate that cellular responses to photooxidative stress would be the evolutionary origin of circadian clocks.
9. The light entrainment of the circadian clock in zebrafish would reflect a cellular response to photooxidative stress
It is conceivable that the development of circadian clocks is one way to segregate daytime from nighttime processes with light-dark cycles acting as selective forces [69, 70]. In this scenario, increasing levels of oxygen-free radicals during the daytime may be a decisive factor in relegating the anabolic processes of mitosis, growth, and consolidation to the dark hours. Thus, it is reasonable that cellular signaling cascade mediated by ROS is utilized in the regulation of the circadian clocks and that common regulatory pathways mediate both cellular responses to photooxidative stress and the light-dependent regulation of the circadian clocks (Figure 2).
In addition to the photooxidative stress derived from sunlight, the UV component of it is major source of harm to organisms [51, 52]. In zebrafish, the light induces expression of PHRs which repair UV-damaged DNA in a light-dependent manner (Figure 2) [49, 71]. Importantly, this light induction of DNA Phr expression appears to be mediated by photooxidative stress [68, 72]. These observations are consistent with the idea that photooxidative stress may be utilized as a signal to activate DNA repair enzymes that can protect the organism's DNA from UV-induced damage. The fact that ROS, a well-known inducer of oxidative stress, can activate zCry1a transcription in zebrafish cells [66], together with the finding that zCry1a and DNA Phr are governed by shared light-induced signaling pathways [49], strongly suggests that, at least in zebrafish, the light entrainment of the circadian clock reflects a long-standing cellular response to photooxidative stress (Figure 2). The zCRY1a protein interacts directly with the CLOCK (NPAS2):BMAL complexes and regulates its transcriptional capacity [67, 73]. The complexes regulate a variety of key genes involved in cellular stress responses, DNA repair, and cell cycle regulation [14, 74]. Thus, the circadian clock protein zCRY1a may be the key integrator of oxidative stress that controls the core circadian machinery to regulate the transcription of genes responsible for DDR and cell cycle adjustments.
10. Conclusion
Many studies have identified a link between the circadian clock and tumorigenesis [8, 12]. The core of the circadian clock mechanism is the cell-autonomous and self-sustained transcriptional machinery called the cellular clock. Importantly, the cellular clocks have been reported to regulate transcription of tumor suppressors and cell cycle regulators [6, 12]. In addition, circadian proteins appear to play roles in cell cycle control, acting as tumor suppressors [9]. For example, it has been hypothesized that a core circadian regulator, CLOCK, directly interacts with key checkpoint proteins, leading to the acetylation of these proteins and thereby modulating their activities. In support of this idea, Clock mutant mice have been reported to be tumor-prone [9].
Cancer chronotherapy relies on the asynchrony that exists in cell proliferation and drug sensitivities between normal and malignant cells [8, 12]. The administration of cancer therapy based on circadian timing has had encouraging results, but still lacks a strong mechanistic foundation. Thus, identification of detailed molecular links between the circadian clocks and tumorigenesis will provide the functional basis of cancer chronotherapy.
This work was supported in part by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research [16K08521 and 18KT0068 (J.H.)]. This work was also supported by grant from Komatsu University (J.I. and J.H.).


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Based in San Diego, GuidedChoice Asset Management, Inc. says it strives toward personalization by utilizing diversified allocation, retirement spending, risk/reward balance and scenario analysis. The firm serves various individual and institutional clients, with approximately $12 billion in assets under management (AUM). The fee-only financial advisor's client base totals more than 170,000.
GuideChoice says on its firm brochure that it provides investment advisory services for institutional clients. If you're an individual looking for investment guidance and you're not in a qualified retirement plan, you may want to consider other firms. Our free financial advisor matching service can help.
GuidedChoice also ranks on our San Diego and California top financial advisors lists.
GuidedChoice Asset Management Background
GuidedChoice, which was founded in 1999, is a subsidiary of GuidedChoice.com, Inc. The financial services provider is an independent firm that specializes in retirement plan advisory service. Sherrie E. Grabot is the firm's founder and chief executive officer (CEO), and Louis van Zijl is the firm's chief operating officer (COO).
GuidedChoice Asset Management Client Types and Minimum Account Sizes
The firm primarily offers retirement planning advice for individuals in qualified retirement plans, but it also serves clients like financial institutions, service providers and qualified plans.
The firm doesn't impose a minimum account balance for its advisory services.
Services Offered by GuidedChoice Asset Management
GuidedChoice offers the following advisory services:
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- Pension consulting
GuidedChoice Asset Management Investment Philosophy
GuideChoice says on its website that its mission is to bring financial freedom to everyone. The firm also says it strives to provide investment allocations that allow individuals to reach retirement income goals with appropriate levels of risk. To create personalized plans, the firm uses a software model to combine client needs with actuarial data, probability analysis and mean-variance optimization.
The firm also offers individuals within qualified plans a range of investment options, including open-ended mutual funds, exchange-traded funds (ETFs), money market funds, money market deposit accounts, exchange-listed securities, stable value funds, separate and commingled trusts, real estate investment trusts, guaranteed investment contracts and variable and fixed annuities.
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Clients using the firm's retirement income planning digital service, GuidedSpending, will pay up to $299 annually. The firm charges individuals up to 0.45% for managed account advisory services. Additionally, GuidedChoice may also impose other charges, such as licensing or platform fees, implementation fees and development fees.
|*Estimated investment management fees do not include brokerage, custodial, third-party manager or other fees, which can vary in amount. Estimated fees assume maximum 0.45% advisory fee.
|Estimated Investment Management Fees at GuidedChoice Asset Management*
|Your Assets
|GuidedChoice Asset Management Fee Amount
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|Up to $4,500
|Up to $22,500
|Up to $45,000
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All information was accurate as of the writing of this article.


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Software Deployment Consultant
Location: Edinburgh, Scotland
Salary: £50000 - £55000 per annum + Benefits
Job Type: Permanent
Job Ref. Number: SoftImpCons
Software Deployment Consultant
Job Type: Permanent
Location: Edinburgh, regular worldwide travel
Salary: Circa £50,000 to £55,000
Start Date: ASAP
Post Code EH1 1BB
Benefits: Top class benefits package
Reference: SoftImpConsEdin
The company is looking to recruit a Scientific Software Deployment Consultant. The role focuses on the deployment of the solution, designed to use live data and physical models in calculations to guide the management of oil and gas fields. The post holder will ideally have previous experience of providing deployment services to either multinational oil and gas majors or to National Oil Companies.
Activities include: deployment preparation and product deployment on client sites worldwide; provision of technical advice and support to clients; training client personnel worldwide.
Master's or Bachelor's degree with equivalent level of experience in Engineering, Physical Science or Computer Science
Practical experience in the oil and gas sector including:
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* Software deployment in major international oil and gas companies
* Working with multiple database environments
Technical skills
* Microsoft SQL server 2012 onwards - intermediate/advanced
* Windows 2012 onwards - intermediate/advanced
Some experience using any of the following would be beneficial:
* GIS System (ESRI) preferred
* Oracle
* OsiSoft Pi
The role will suit individuals currently working as a Software Implementation Consultant, Deployment Engineer, Software Project Manager, Delivery Manager, Software Developer, Programmer and living within a commutable distance of Edinburgh, Glasgow, Scotland, UK or willing to relocate.
With over 20 years of experience System Recruitment offers excellence in Permanent and Contract recruitment in a wide range of industry sectors. Though we are a generalist agency, a particular strength of ours lies in Information Technology including Technical, Sales and Managerial positions. We are able to tailor our approach to your needs in order to work effectively with you and provide real value.
If this job is not exactly what you are looking for, register here and we will contact you with opportunities that suit your skill set>> System Recruitment recruits permanent personnel across Europe and the UK. This vacancy is advertised by System Recruitment. The services advertised by System Recruitment are those of an Employment Agency.


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