text:
Format: Print Length
Language: English
Format: PDF / Kindle / ePub
Size: 8.13 MB
Downloadable formats: PDF
Pages: 54
Publisher: HardPress (October 28, 2015)
Find extension printables and activities here on our sister site ref.: http://portraitofacreative.com/books/pipilet-basic-kuku-dialect-kuku-english-with-expressions. A long-standing example is that of "...a cat popping on its draws..." (instead of 'dropping on its paws'). The effect is named after Reverend William Archibald Spooner (1844-1930), a warden of New College, Oxford, who has long been said prone to the error. A spoonerism is apparently also known (very rarely) as a marrowsky, supposedly after a Polish count, reputed to be similarly afflicted ref.: read online. Alphabet Organizer features our worksaver so that students can save a draft of their unfinished work or share their final work via e-mail read epub. More technically a verb is the 'predicate' (this describes what is happening to the subject) in a phrase or sentence , source: http://shop.goldmooreassociates.co.uk/books/opposites. Time4Learning provides students with phonetically organized chapters that focus on one sound/spelling skill so that students can explore one sound or blend at a time for mastery , e.g. http://portraitofacreative.com/books/basic-goals-in-spelling. Capitalize a formal title when it is used as a direct address. The more formal the title, the more likely it is to be capitalized. We're sorry to report, Captain, that we're headed for choppy waters. Capitalize relatives' family names (kinship names) when they immediately precede a personal name, or when they are used alone in place of a personal name ref.: http://portraitofacreative.com/books/my-first-1000-words. So do you think you are ready to begin your adventure in Learning Hindi? Remember that although learning a language fluently may take years, it is only ever one small step at a time. The Indian flag - Hindi is mainly spoken in the northern areas of India epub. The Korean language may be written using a mixture of Chinese ideograms (hancha) and a native Korean alphabet known as hangul, or in hangul alone, much as in a more limited way Indo-European languages sometimes write numbers using Arabic symbols and at other times spell numbers out in their own alphabets or in some combination of the two forms pdf.
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This property has been removed by the agent. It may be sold or temporarily removed from the market
3 bedroom semi-detached house for saleDanbury Palace Drive, Danbury, Danbury, Essex, CM3
Property Description
Key features
- Walnut finished internal doors with polished chrome lever handles
- Amtico Spacia flooring.
- Fully fitted Hacker designed kitchen
- Neff Oven, Combination microwave oven, gas hob and extractor
- Double Bowl Sink & Drainer
- Quartz worktop and upstand
- LED lighting under wall cupboards
- White sanitary ware to bathrooms and en suites with chrome fittings
- Low profile walk in showers trays with glazed screens
- Laid To Lawn Garden With Boundary Fencing
Full description
Set within an exclusive private gated development is this three bedroom, semi-detached house offering a contemporary finish which is evident in the fixtures and fittings. Aesthetically designed to complement the historic surroundings, the property offers a fully fitted Hacker designed kitchen, Quartz worktops and upstand with built in Neff oven, hob and extractor, Amtico Spacia flooring and carpets are fitted throughout. The first floor offers three bedrooms, with en suite facilities to the master bedroom and family bathroom, fully fitted with white sanitary ware and a chrome heated towel rail.
Danbury offers a Village setting with the added benefit of being just 5.0 miles from the ever growing City of Chelmsford. The popular Danbury Country Park is a short walk away and is a popular setting with dog walkers. EPC B.
Living/Dining: 5.36m (17'7) x 5.79m (19')
Kitchen: 3.68m (12'1) x 4.47m (14'8)
Utility Room: 1.88m (6'2) x 1.88m (6'2)
Bedroom One: 3.18m (10'5) x 3.86m (12'8)
En Suite: 1.98m (6'6) x 2.06m (6'9)
Bedroom Two: 2.79m (9'2) x 3.56m (11'8)
Bedroom Three: 2.49m (8'2) x 2.87m (9'5)
Bathroom: 3.18m (10'5) x 1.75m (5'9)
Allocated Parking
Rear Garden
*All internal Photographs depict show unit.
*Service Charges Apply
*This document is intended to provide an indication of the general style of our development. Chase New Homes operate a policy of continuous development and individual features such as windows and elevational treatments may vary from time to time. Whilst every endeavour has been made to provide accurate information in relation to internal and external finishes, the Company reserves the right to change supplier and alter or vary the design and specification at any time for any reason without prior notice. Consequently these particulars should be treated as general guidance only and cannot be relied upon as accurately describing any of the Specified Matters prescribed by any Order made under the Property Misdescriptions Act 1991 or superseded by the Consumer Protection for Unfair Trading Regulations (CPRs). Nor do they constitute a contract, part of a contract or a warranty. An Energy Performance Certificate (EPC) is available for inspection on request and a copy is held by the selling agent. Danbury Palace is the marketing name and will not necessarily form part of the approved postal address. All details are correct at time of going to press, October 2015.
Consumer Protection from Unfair Trading Regulations 2008 and the Business Protection from Misleading Marketing Regulations 2008: Every effort has been made to ensure that consumers and or businesses are treated fairly and provided with accurate material information as required by law. It must be noted however that the agent has not tested any apparatus, equipment, fixture, fittings or services and does not verify they are in working order, fit for their purpose, or within the ownership of the seller or landlord, therefore the buyer or tenant must assume the information given is incorrect. Neither has the agent checked the legal documentation to verify the legal status of the property. A buyer or tenant must assume information is incorrect until it has been verified by their own solicitors or other advisers. Nothing concerning the type of construction, condition of the structure or its surroundings is to be implied from any image of the property.
More information from this agent
To view this media, please visit the on-line version of this page at www.rightmove.co.uk/new-homes-for-sale/property-44924229.html?premiumA=true
Listing History
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Market Info
Disclaimer - Property reference 405072. The information displayed about this property comprises a property advertisement. Rightmove.co.uk makes no warranty as to the accuracy or completeness of the advertisement or any linked or associated information, and Rightmove has no control over the content. This property advertisement does not constitute property particulars. The information is provided and maintained by Beresfords, at Chelmsford. Please contact the selling agent or developer directly to obtain any information which may be available under the terms of The Energy Performance of Buildings (Certificates and Inspections) (England and Wales) Regulations 2007 or the Home Report if in relation to a residential property in Scotland.
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Image Credit: Tibor Fazakas
Welcome to eParenting's colouring pictures section. We've got over 200 colouring pictures for children on all sorts of subjects as well as many of your favourite characters.
Plus we have a new section of more complicated colouring pictures for older kids and adults.
These printables are free for personal and educational use only. They are not to be copied, reproduced, sold or distributed without prior permission of eParenting.
About the Author: Jacqui O'Brien started eParenting in 2004. At the time her kids were 1 and 4 and kept her nice and busy. Now they are teenagers and still keeping her pretty busy!
Here she shares things that she has learnt along the way about looking after kids.


text: I have a question should i be able to use logic 7 when watching movies through my cable box? It's hooked up with a coax cable and i can choose DPL 2, but not L7, I can use L7 for DVD, CD ect.. but not through my cable box, it seems odd to me why DPL 2 works but not L7 please help. Craig


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Atlanta restaurant reviews and food guides from local Atlanta foodies. Read unbiased reviews and dining experience of the most popular Atlanta restaurants including Vortex grill, Marietta Diner, Après Diem Café Bistro, Empire State South and Canton cooks. Address : Atlanta, Georgia, 30302 USA
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"The most important aspect of commercial real estate is the people behind all the numbers. I enjoy communicating and building strong relationships with my clients."
"It is my commitment to maintain the highest level of service to my clients and to do what it takes to help them achieve their investment goals."
After serving in the Israeli Air Force, Roee and Leeor decided to focus solely on the commercial real estate industry, with primary emphasis on the ownership and brokerage of commercial real estate. Today, with their combined 20-year experience in the field, Roee and Leeor have had valuable experience in the industry that allows each to provide clients with the highest quality service.
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text: I have posted some questions here regarding my search for a crank for my 76 90S. The bike is one I restored a couple of years ago, but was never happy with the level of vibration in the foot pegs. One of the things I like about the 90 motors is they are almost as smooth as a 75, but this one vibrated as much or more than the 100s I've ridden. So finally this winter I tore it back apart to find the crank was out of spec. So the search began for a replacement. I looked at five that for one reason or more felt weren't suitable. One of the most disappointing was from regular seller on IBMW, who turned out to be not only incompetent, but also dishonest. So finally I just started emailing people I had had contact with, who might have a lead on one. One such email went to our own Robert the Wirewerker. He said he had one but he would need to take it out and measure it. Measure it? This was something I had not heard from a seller before. So a couple of days later I hear back that it checks out to be very good. By this time I felt like UH HUH, we'll see. But a few days later Robert had the crank at my door and to my pleasant surprise I found the rod throws at the upper end of the spec, the mains fell into one of the color codes and they were all very round. Yesterday I took the bike out for a test run and found it to be a very smoooth running R90S. Up until then my 74 90S was the smoothest airhead I have ridden, now I'm not so sure. Oh, and many thanks to BMW Wrench for all the fitment clearance tips.


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UP Board Application Form 2017- 18 Private Regular 10th/12th Board has dispatched a latest notification regarding Compartment Form of UP Board for high school & intermediate exams in this month. This exam will be similar to the regular board exam. Those students who appeared in UP Board as private students may also fill UP Board Compartment Form. UP Board exam was conducted in the month of February and March.
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Organization Name: The Board of High School & Intermediate Education (BHSIE)
Uttar Pradesh Board 10th/ 12th Examination Fees:- The students have to submit an amount of money as Examination Fees till 10th August 2017. The examination fees can be submitted with Rs 100 extra as late fees till 16th August 2017
Type of Announcement: Compartment Form
Application Mode Online
Official Website: upmsp.nic.in
Last Date to Apply 16th August 2017
Eligibility: candidates who haven't pass in the 10th/ 12th annual examination conducted by the UP Board in March Compartment Exam they eligible to be part of UP Board Compartment Form.
How to Apply :-Go Official Web Site Follow step by step for helping the candidates First of all, go to the official website and that is www.upmsp.edu.in. You may also click on the direct links at the end of this web page. Click on the link High school and Intermediate Registration 2017 and download the official notification. and then click on option and fill all the details like user Id, Password, Security code etc and click on submit button. Fill all the details in the application form and click on the make a payment of examination fees. Click on final submit button after rechecking the details.
Click Here For This Blogger www.jobinfo4u.in


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Tuesday, April 7, 2009
Snowman WIP Part 2
Here's my work-in-progress for the dialogue scene involving the snowman (see previous post). Actually, for now I don't have the snowman in the scene! Just got the husband and wife going, but I'll work on their frosty house guest in the near future. Enjoy!
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Each year, a dreamer longs to do something of epic proportions. Jump out of airplanes, quit the day job, chase after the one great love, and the list goes on. Mine, however, was an ode to the dauntlessness of my ancestors. Albeit less maverick, it sure carried more weight for me. (way more for the boylove […]View post →
Let me let you in on a secret: the secret to sensible packing is photographing what you pack. For hand-carry bags, for instance, it is imperative not to overstuff lest your shoulder is prepared to bear the yoke of overpacking. So how does photographing helps? Whatever doesn't look good in the photo, goes. Genius, right? […]View post →
When asked about my travels, I can only tell stories. How I ate fried grasshoppers in Vietnam or drank my way through Laos, for example. I suck at giving structured information like budget and itinerary. But here's an attempt at a Baguio-Sagada Travel Guide that really, is just Sagada. Don't judge 😛 This guide is based […]View post →
Leaving Sagada before daybreak, I tiptoed downstairs to the unmanned reception counter, ridden by guilt from another alcohol-fueled sleep. Sobriety would've reminded me to settle the hostel bill the night prior. But I wasn't sober, and had to be on the first jeepney to Bontoc before fruit and vege sellers beat me to the terminal. […]View post →


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The Bourne Ultimatum
About The Bourne Ultimatum
The Bourne Ultimatum is a 2007 English movie. The book stood at #3 in Amazon's 2007 book and DVD best-sellers lists.
The Bourne Ultimatum in news
Accomplished Media Executives Rick Hack and Linda Benjamin Join Truli Media Group
Truli Media Group, Inc. (OTCQB: TRLI), parent company of Truli.com, a global, faith and family friendly media content platform and social community hub, today announced that Rick Hack has signed on as Director of Brand Development for the company and Linda Benjamin has joined its advisory board of directors.
Matt Damon would love to do another Bourne movie
Matt Damon has said that he would love to do a fifth movie in the Bourne franchise.


text:
Robert Blair Kaiser
Smashwords Edition
Copyright 2012 Robert Blair Kaiser
This a piece of "reality fiction," a mixture of fact and fiction that uses the names of some real persons and places to give the tale an air of reality. But it is a tale. The characters in this book are fictional and any similarity to real persons (other than their names), living or dead, is coincidental and not intended by the author. The plot is fiction. Obviously. The story is set in the future.
This ebook is licensed for your personal enjoyment only. It may not be re-sold or given away to other people. If you would like to share this book with another person, please purchase an additional copy for each recipient. If you're reading this book and did not purchase it, or if it was not purchased for your use only, then please purchase your own copy at http://www.smashwords.com/books/view/140288
Thank you for respecting the hard work of this author.


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The Ataxia-Telangiectasia mutated (ATM) kinase is regarded as the major regulator of the cellular response to DNA double strand breaks (DSBs). In response to DSBs, ATM dimers dissociate into active monomers in a process promoted by the Mre11-Rad50-Nbs1 (MRN) complex. ATM can also be activated by oxidative stress directly in the form of exposure to H2O2. The active ATM in this case is a disulfide-crosslinked dimer containing two or more disulfide bonds. Mutation of a critical cysteine residue in the FATC domain involved in disulfide bond formation specifically blocks ATM activation by oxidative stress. Here we show that ATM activation by DSB s is inhibited in the presence of H2O2 because oxidation blocks the ability of MRN to bind to DNA . However, ATM activation via direct oxidation by H2O2 complements the loss of MRN/DSB-dependent activation and contributes significantly to the overall level of ATM activity in the presence of both DSB s and oxidative stress.
Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disorder (1 in 40,000 to 100,000 live births worldwide).1 The most striking clinical manifestation of A-T is neurodegeneration, which is characterized by progressive difficulty with motor coordination beginning in early childhood (progressive cerebellar ataxia). A-T patients also have small clusters of enlarged ocular blood vessels (oculocutaneous telangiectasia), a weakened immune system and increased risk of developing cancer, particularly lymphomas and leukemias.2,3
The ATM kinase was identified as the product of the gene that is mutated in A-T.4 Over 400 ATM mutations have been identified in A-T patients, most of which are truncating mutations which generate shorter and unstable forms of the ATM protein. Cells from A-T patients are hypersensitive to ionizing radiation (IR) and deficient in DNA damage-induced checkpoint activation at the G1/S, intra-S and G2/M phases of the cell cycle.3
ATM is a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family, which also includes ATM and Rad3-related-protein kinase (ATR), the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), and mammalian target of rapamycin (mTOR).5 ATM regulates the DNA damage response by phosphorylating its downstream targets at specific S/T(Q) sites in response to DSBs. ATM also responds to physiological DNA breaks during the development and differentiation of lymphocytes. Chromosomal abnormalities and accumulation of unrepaired ends during V(D)J recombination and class switch recombination were observed in B cells from A-T patients and ATM-deficient mice, indicating that ATM deficiency impairs site-specific recombination in cells of the immune system.6,7 The increased frequency of defective repair during these processes may explain the high incidence of lymphoid cancer among A-T patients.8
ATM safeguards genome integrity in mammalian cells by regulating the activation of cell cycle checkpoints. p53 was the first substrate of ATM to be identified,9,10 and ATM-mediated phosphorylation of p53 on Ser15 is important for the G1/S cell cycle checkpoint.11 ATM also phosphorylates and activates checkpoint kinase 2 (Chk2),12 which in turn phosphorylates several substrates including p53, BRCA1, CDC25A and CDC25C.13,14 ATM can also regulate the intra-S checkpoint by phosphorylating the SMC1 component of cohesin, and inhibition of this phosphorylation abrogates the S-phase checkpoint.15 A recent combined proteomic and functional checkpoint screen showed that nine proteins of the ubiquitin-proteasome system (UPS) were also phosphorylated by ATM and that they are also required for mammalian DNA damage checkpoint control, particularly the G1/S cell cycle checkpoint.16 A global analysis of protein phosphorylation induced by DSBs showed that over 700 proteins are targeted by ATM following DNA damage, including many proteins involved in DNA repair and cell cycle regulation, but also many with no obvious link to the DNA damage response.17
The primary role of ATM in the DNA damage response is checkpoint signaling, and for many years ATM was thought to have no role in repair because A-T cells show nearly wild-type levels of DNA repair under normal conditions.18 But ATM has been shown to contribute to the repair of DSBs after IR. In the absence of ATM, approximately 10% of DSBs are left unrepaired in A-T cells after IR exposure.19 One explanation for this observation is that a subset of DSBs localized to heterochromatin require ATM to facilitate entry of the DNA-repair machinery by phosphorylating the transcriptional corepressor Kruppel-associated box (KRAB)-associated protein-1 (KAP1). In addition, the high level of unresolved DNA breaks created during V(D)J and class switch recombination in A-T cells suggest that there is also an important role for ATM in non-homologous end joining (NHEJ), but the underlying mechanisms are not understood. DNA breaks that form in A-T cells by any pathway are much more likely to persist through multiple cell cycles compared to wild-type cells since ATM is responsible for directing cells into senescence or apoptosis in response to DSBs.20,21
The neurodegenerative phenotype in A-T patients has been attributed to the genomic instability caused by ATM deficiency. However, in post-mitotic neurons, ATM is not required to stop cell cycle progression in response to DNA damage. In the absence of cell cycle progression, ATM deficiency should have a limited impact on genomic stability because A-T cells show nearly normal levels of DNA repair. Thus, the loss of differentiated non-dividing neuronal cells in A-T patients cannot be explained by genomic instability alone.
The primary site of cellular degeneration in A-T patients is the cerebellum.1 Considering the high level of metabolism in neuronal cells and high oxygen concentration in brain tissue, it is possible that oxidative stress could significantly contribute to the degenerative process. Abnormal control of reactive oxygen species (ROS) has been reported in A-T based on the observations showing that the levels and function of antioxidant systems are lower in A-T cells compared to normal cells.22 Clinical research has shown that A-T patients have significantly reduced levels of total plasma antioxidants to about 77% of normal capacity.23 A-T cells have reduced levels of the important antioxidants vitamin A and E, impaired GSH biosynthesis and reduced levels of NADH and NADPH.22,24,25 A-T fibroblasts are also more sensitive to oxidative stress than healthy fibroblasts,22 and increased levels of ROS generated in ATM-deficient brain tissue under physiological conditions are correlated with increased levels of protein and lipid damage.26 Progressive deterioration of redox balance was also observed in stem cell populations from ATM-deficient mice.25 These mice showed progressive bone marrow failure resulting from a defect in the function of haematopoietic stem cells (HSC) that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of HSC and prevented bone marrow failure.27 Observations from several laboratories have shown that oxidative stress in ATM-deficient cells can be alleviated by the antioxidants catalase and N-acetyl cysteine (NAC) which neutralize ROS production.27,28
Why does the loss of ATM, a regulator of the cellular DSBs response, lead to oxidative stress? Our recent work shows that ATM acts as a redox sensor in addition to its role as a sensor of DSBs.29 We hypothesize that the changes in redox balance observed in cells from A-T patients are a result of an inability to sense ROS and may be responsible for the neurodegeneration and other unexplained phenotypes observed in A-T patients.
There are many observations in the literature that link ATM with oxidative stress but it has not been clear if the association is indirect through the formation of DNA damage.22,30 To test our hypothesis that ATM can be activated by ROS directly, we treated primary human fibroblasts with the stable oxidant H2O2 in comparison to treatment with bleomycin, a genotoxic agent that induces DSBs. The hallmark of ATM activation, ATM autophosphorylation,31 occurred in response to H2O2 as well as to bleomycin treatment.29 p53 and Chk2 phosphorylation by ATM were also observed, but histone H2AX phosphorylation, a marker for DNA DSBs, occurred only with bleomycin treatment. Thus, ATM activation induced by H2O2 can occur in the apparent absence of DSBs. Similar to histone H2AX, the heterochromatin protein Kap1 was phosphorylated after bleomycin exposure but not after H2O2 treatment. ATM-dependent p53 phosphorylation was also observed in ATLD cells which are deficient in DSBinduced ATM signaling.32 These results suggested that ATM can be activated directly by oxidative stress independent of DSBs and the activation mechanism is distinct from MRN/DSB-dependent activation.
In mammalian cells, ATM is initially an inactive, noncovalently-associated dimer31 but converts to an active monomer upon DNA damage in the presence of the Mre11/Rad50/Nbs1 (MRN) complex. Our laboratory has previously reconstituted DNA-dependent ATM activation in vitro with purified recombinant proteins, demonstrating that inactive ATM can be strongly activated by the addition of both MRN complex and linear DNA ends.33,34 In our experiments investigating the effects of oxidation on ATM, we found that the addition of H2O2 to purified dimeric ATM in vitro stimulates its activity on a p53 substrate even in the absence of MRN and DNA.29 The magnitude of this stimulation was similar to that observed with MRN and DNA; however, ATM activation by H2O2 could be completely inhibited by the reducing reagent NAC, while the stimulation by MRN and DNA was unaffected. Unlike the MRN/DNA stimulation that induces ATM monomerization, ATM treated with H2O2 formed covalent dimers that were sensitive to reducing reagents, showing that intermolecular disulfide bonds form between ATM monomers and suggesting that these are important for the activation of ATM by oxidative stress.29
Since ATM responds to DSBs and oxidative stress with distinct activation mechanisms, we reasoned that we might be able to identify a mutation that specifically blocks the oxidation pathway. Mutation of cysteine residue 2991, the only cysteine in the FRAP/ATM/TRRAP C-terminal (FATC) domain (Fig. 1A), resulted in an ATM mutant that could be fully activated by MRN and DNA, but could not be activated by H2O2 in vitro.29 Expression of this allele (C2991L) in human lymphocytes lacking wild-type ATM completely blocked the apoptosis response to ROS while remaining competent for apoptosis in response to DNA damage, confirming that this allele specifically blocks oxidation-induced ATM activation in human cells as well.
Similar to the C2991L ATM protein, a mutant lacking the last ten amino acids of the ATM C-terminus results in a mutant protein (R3047X, Fig. 1A) that can be fully activated by MRN and DNA but cannot be activated by oxidation in vitro.29 Interestingly, R3047X has been identified as a causative mutation in several A-T patients.35–37 These patients exhibit ataxia, but in some cases were classified as A-T "variants" because they did not exhibit immunodeficiency and cells from these patients only showed moderate radiosensitivity, perhaps indicating a normal response to DSBs. Consistent with this hypothesis, we found that cells from an A-T patient expressing the R3047X allele were also specifically deficient in oxidative activation of ATM but showed normal ATM activation in response to DNA damage.29 These results suggest that the clinical manifestations of A-T, including neurodegeneration and ataxia, may be primarily due to the loss of oxidationdependent ATM signaling.
The FATC domains comprise the C-terminal regions of PIKKs. In some studies, FATC domains referred to the C-terminal, highly conserved domains of approximately 20–30 amino acids, and the regions between these FATC domains and the kinase domains were called the regulatory domains. Here we consider the entire C terminus adjacent to the kinase domains as FATC domains because they were proposed to be critical for kinase activity of PIKKs.38,39 A recent crystal structure of DNA-PKcs showed that the α-helical FATC domain protrudes from the kinase domain and interacts with the FAT domain, consistent with previous studies with low resolution electron microscopy.40–42 Acetylation of lysine 3016 in the FATC domain of ATM by histone acetyltransferase Tip60 also has been shown to activate the kinase activity of ATM in response to DNA damage.43 To test the role of the FATC domain of ATM, we expressed and purified an ATM mutant that lacks the entire FATC domain (N2963X). In vitro kinase assays comparing the N2963X mutant with wild-type ATM showed that neither DSBs nor H2O2 can activate ATM lacking the entire FATC domain (Fig. 1B).
Our recent work identified cysteine 2991 in the FATC domain as a crucial residue for the activation of ATM via oxidation.29 This residue is conserved in terrestrial vertebrates but not in marine animals, and is not present in lower eukaryotes (Fig. 2C and D). The land invasion by vertebrates during late Paleozoic time period coincides with the spike of atmospheric oxygen to nearly 35 percent,44 perhaps suggesting that gaining the function of oxidative stress sensing by ATM might contribute to the survival of terrestrial vertebrates in a high oxygen environment.
The protein kinase mTOR, a member of the PIKK family that regulates cell growth and proliferation in response to cellular nutrition and energy level, was also shown to be oxidized at two conserved cysteines within the C-terminal FATC domain.45 An intramolecular disulfide bond between these cysteines was demonstrated in vitro, and mutation of these cysteines altered the stability of mTOR in budding yeast. These results suggest that cellular redox potential could affect the amount of the mTOR protein by influencing its degradation, and is consistent with the FATC domain playing an important role in regulation of the PIKK family.
Interestingly, the ATM FATC domain was proposed to contain a peroxisome localization signal, and ATM has been observed in the cytoplasm co-localizing with peroxisomes.26 Significantly decreased catalase activity and increased lipid peroxidation in several A-T cell lines suggests that ATM might affect peroxisome functions. Previous reports have also suggested the existence of extranuclear ATM46 but this has been a controversial topic and is not fully resolved. More recent evidence suggests that ATM is predominantly cytoplasmic in neuronal cells, for example, slices of cerebella from mice confirmed the existence of cytoplasmic ATM,47,48 and ATM was shown to translocate from the nucleus to the cytoplasm in neuronal cells upon differentiation.49 Additionally, after the induction of DSBs, a subset of ATM is exported to the cytoplasm in a manner depending on the NF?B essential modulator (NEMO).50,51
Ionizing radiation (IR) induces DSBs by direct deposition of energy to the sugar-phosphate backbone. IR can also ionize H2O and generate ROS, which accumulate to induce oxidative stress when rapidly produced.52 Many groups use IR to induce DSBs, but the effects of the radiation on oxidation of cellular compounds are rarely investigated. Oxidative stress and DNA damage are generally experienced simultaneously in cell populations, considering that high levels of ROS also cause DSBs as well as a variety of base and backbone modifications.30 DNA damage responses that occur under oxidative stress conditions may be very different from responses under normal conditions, however, because oxidative stress has been shown to reduce the activity of many proteins. The Ku heterodimer, for instance, was shown to be functionally inactivated after oxidation.53
To determine the effect of oxidative stress on MRN/DNA-dependent ATM activation, we performed ATM kinase assays with MRN and DNA in the presence of varying amounts of H2O2. In the reactions with wild-type ATM, H2O2 had no obvious effect on overall ATM activity (Fig. 2A). However, in the reactions with the C2991L ATM mutant, ATM activation was completely inhibited by H2O2. Because C2991L ATM is deficient in oxidative activation and can only be activated by MRN and DNA, the loss of ATM activation is due to the loss of MRN/DSB-dependent ATM activation under oxidative conditions. In the case of wild-type ATM, although H2O2 can inhibit MRN/DNA-dependent ATM activation, it also is capable of being activated through oxidation, which complements the loss of MRN/DNA-dependent activation.
The MRN complex acts as a sensor for DSBs, and is essential for the activation of ATM by DSBs. Shortly after DSBs occur, ATM is recruited to DSB sites.31,54 The MRN complex binds to ATM, recruits ATM to broken DNA ends, and is essential for ATM activation in vivo and in vitro.34,55 A direct pull-down assay was used to determine if the interaction between ATM and MRN is affected by oxidation. This experiment showed that immobilized MRN complex can bind ATM efficiently even in the presence of H2O2 (Fig. 2B), indicating that oxidative stress does not affect the interaction between MRN and ATM.
To determine if the ability of MRN to recognize DSBs is altered by oxidation, we performed a gel mobility shift assay with purified MRN complex in the presence of H2O2 (Fig. 2C). This result shows that, under oxidative conditions, MRN does not bind efficiently to DNA.
Based on these results, we propose that oxidative activation of ATM contributes significantly to overall ATM activity in the presence of both DNA damage and oxidative stress, and its role increases with ROS concentration. During ionizing radiation, the oxidative activation may dominate at very early time points because direct oxidation is instantaneous and does not require other factors to facilitate activation. After a brief exposure to radiation, the reducing environment inside cells could reverse the oxidative activation of ATM after the elimination of the short-lived ROS by cellular antioxidants. Subsequently, the MRN/DSB-dependent activation pathway is likely to generate longer-lasting ATM activation by continual recruitment of DNA damage response proteins to persistent DSB foci. Evidence of such phenomenon may have been shown in previous research; for instance, pan-nuclear ATM autophosphorylation was observed immediately after IR.31 This might be the result of very early ATM activation by oxidative stress induced by IR. At later time points, activated ATM was only observed in DSB foci, indicating primarily MRN/DNA-dependent ATM activation.
ATM is thought to safeguard genomic integrity by sensing the generation of DSBs. Our studies with ATM oxidation showed that this enzyme is also an important sensor of ROS.29 In the absence of ATM, mammalian cells exhibit significantly higher levels of ROS,26 suggesting that there may be ATM targets that regulate antioxidant systems. The highly toxic ROS generated in the absence of ATM can damage proteins, lipids and DNA, ultimately leading to cell death in some tissues (Fig. 3).
The discovery of the ATM oxidative activation pathway has implications beyond the A-T disorder. Redox balance plays an important role in regulating cell cycle progression, proliferation and survival. ATM functions as a redox sensor to regulate cell cycle checkpoints, apoptosis and very likely the cellular antioxidant systems. Indeed, ATM was recently shown to regulate mTORC1 signaling through LKB1/TSC256 and HIF-1α57 in response to changes in cellular redox state. Oxidative activation of ATM is also known to be critical for the survival of neuronal cells and hematopoietic stem cell populations that are hypersensitive to ROS.27 Tumorigenesis also involves the generation of ROS, and the ability of antioxidants to block formation of T cell lymphomas in ATM-deficient mice suggests that excess ROS contributes to tumorigenesis in the absence of ATM.58 Aneuploidy, a hallmark of cancer cells, was recently shown to induce ROS and the loss of ATM was shown to drastically accelerate aneuploidy-induced tumorigenesis.59 This makes the ATM oxidative activation pathway a potential therapeutic target for cancer as well as oxidative stress-related neurodegeneration diseases.
Protein purification and ATM kinase assays were performed as described in reference 29. Biotinylated MRN was purified as described previously in reference 60 and incubated with ATM (100 nM MRN, 7.1 nM ATM) in the presence or absence of H2O2 (0.5 mM) in a buffer containing 25 mM Tris-HCl pH 8.0, 100 mM NaCl, 10% glycerol and 1 mM DTT for 10 min at 30°C before isolating MRN with streptavidin-coated magnetic beads (Invitrogen). Proteins bound to the beads were separated by SDS-PAGE and analyzed by western blotting for Mre11 (Genetex, GTX70212) and ATM (Genetex, GTX70103). Gel shift assays were performed as previously described in reference 61, with purified human MRN and a dsDNA (41 bp, 3′ labeled with Cy5). MRN preincubated with H2O2 was bound to DNA (5 nM) in a buffer containing 25 mM MOPS, pH 7.0, 5 mM MgCl2 and 0.5 mM AMP-PNP for 10 minutes at 37°C, and protein-DNA complexes were separated by native agarose gel electrophoresis. The labeled DNA was analyzed in the gel using a Typhoon imager (GE).
We are grateful to the members of the Paull lab for useful suggestions. Funding was provided by the National Institutes of Health, NIH CA132813 and CA92584.
Previously published online: www.landesbioscience.com/journals/cc/article/14323
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Surprising Information About Quality Parenting
A lot of daddies as well as mothers have to have child-rearing recommendations regarding children and also preteens. A child's younger years will certainly mold and mildew him into that and just how he will certainly be as grownups, and it's this that makes this certain period really essential. The toddler as well as teen years furthermore provide their very own categories of troubles as well as grabs, which tends to make this sort of topic stuffed with important truths in addition to smart assistance.
You will most likely agree that being a mother or dad is typically complicated yet fulfilling. If we're making the finest phone calls in relationship to our youngsters, it's not normally very easy to figure out. The most beneficial recommendations that a person can provide is that no matter what you are executing, if it concerns your young person, make certain to do it due to actual love. When punishing your child, do refrain from doing so due to anger; do it because you enjoy him. The best point that us moms and dads can perhaps provide for our child is love him.
For parents who have a toddler, there are certain things that you need to recognize. A kid could often break down and also have an emotional fit. The best way to handle this is to quit it until it in fact commences. Whenever a young child or woman goes to house the entire day with her or his father and also mama, it's a great idea to opt for a stroll or do various other satisfying tasks to provide them both physical as well as psychological workout. Furthermore, have fun with your child and spend quality time with him, as high as you realistically can.
It is crucial to stimulate your little child's intellect as well as physical abilities. The kid can be quite very easy to take care of if he is busy as well as nurtured, and the little one's emotional fits will not manifest as typically as it once did. A precise routine could also aid the avoidance of outbursts, taking into consideration that a lot of more youthful kids favor recognizing exactly what they could anticipate. A clear routine will offer your young kid a sensation of protection, as well as they'll have snoozes as well as comply with bedtime better as well as with much less meltdowns.
Points will certainly start to alter for you as well as your tot when he has moved past the young child years and also attained education age. A kid that is only simply beginning to head to school will most definitely feel like a big youngster, and also you need to start treating your youngster like one. One specific little guidance would be to mark to your daughter or kid a number of fast house work; this will educate him responsibility. It is advisable to think about the kid's age when you are marking to him a particular chore; as an example, you must not at all need a 5-year-old to scrub your entire kitchen area.
You'll most definitely deal with plenty of temper tantrums when you try to educate your fast-growing youngster, significantly whenever he or she has just began attending institution. A youngster still hasn't fairly surpassed his previous means, and also she or he might just begin throwing a temper tantrum any time he does not get just what he expects. This could be the ideal time to start showing to your little boy or girl the right ways to articulate out his views. You should say to your child that it is great for him to tell you of his anger or stress, yet guarantee that it is crystal clear that she or he should do it with regard for authority.
Occasionally, the non aggressive method will not deal with any kind of kid, as well as it could be called for to penalize your young person in a tougher fashion. No matter whether you are handling a child or an older child, as his mum or father, it is your duty to put your foot down and also clearly reveal when no means no. Naturally, you need to be comprehending and also client with your children, but every so often, difficult love might just be exactly what they call for.
There are various other techniques for carrying out self-control to your boy or woman without needing to paddle him; in fact, lots of people choose to never hit their daughters as well as children. A break is a great way of punishing toddlers as well as smaller sized kids. Nevertheless, this may not really deal with per-adolescents. The most helpful type of penalty for a kid of that age is understand one point they use each day and also like or regularly, and remove it temporarily. To put an end to their unfavorable conduct, you can take away their mobile phone, internet and also television opportunities, or implement a very early time limit.


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APG RealEstate is located in the city of sydney that helps you find dream home and fiancial free in property investment.APG does not stop service until your property sold in the market as we promised that we will help you rent out,resale and also redesign until your property sold.
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Fifthly, we will keep supporting you after your property settlement when you meet new issues in the property.


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Movie Star Hotel Guangzhou
No.350,Xin Gang Zhong Road, Guangzhou, China
The business Movie Star Hotel offers air-conditioned guest rooms close to Taikoo Hui, Guangzhou Opera House and Zhujiang New City.
The property is set in Hai Zhu in Guangzhou that provides fast access to business centers and exhibition centers as well as museums, the opera house and the tower. The venue is set within 7 km from Guangzhou city center.
This hotel comprises 115 rooms featuring Deluxe Business Double Room, Business Single Room and Deluxe Twin Room. They also feature en suite bathrooms fitted with a hairdryer, a shower and free toiletries.
Breakfast is served in the restaurant each morning. The restaurant serves Chinese dishes.
A 20-minute walk to Opera House subway station. 35 minutes' drive from New Baiyun airport.
Guests can benefit from car rentals available at the hotel.
Important information
- Children and extra beds
- One child under the age of 10 may stay free of charge when using existing bedding.
- There are no extra beds provided in a room.
- On-Site Parking
- Wi-Fi in public areas
- Express Check-In/Check-Out
- 24-Hour Front Desk
- Non-Smoking Rooms
- Designated Smoking Area
- Executive/club floor
- Safety Deposit Box
- Business Center
- Luggage Storage
- Elevator
- Coffee Shop
- Credit Card Accepted
- No Pets Allowed
- A la carte restaurant
Leisure & Sports
- Casino
- Beauty salon
- Sauna
- Karaoke
- 24-Hour Room Service
- Breakfast in the Room
- Tours/ticket assistance
- Meeting/Banquet Facilities
- Fax/Photocopying
- Currency Exchange
- Shops/Commercial Services
- Car Rental
- Laundry
- Dry Cleaning
- Ironing Service
Room Amenities
- Air Conditioning
- Sitting Area
- Carpeted floor
- Kettle
- Shared bathroom
- AM/FM Alarm Clock
No.350,Xin Gang Zhong Road, Guangzhou, China
This hotel comprises 115 rooms featuring Deluxe Business Double Room, Business Single Room and Deluxe Twin Room. They also feature en suite bathrooms fitted with a hairdryer, a shower and free toiletries.
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Movie Star Hotel
No.350,Xin Gang Zhong Road, Guangzhou, China
What's nearby
- Local attractions
- Canton Tower1.4 km
- Guangdong Museum of Art1.7 km
- Xinghai Concert Hall1.8 km
- Pearl River-InBev International Beer Museum2.0 km
- Guangdong Zhongshan University2.1 km
- Guangzhou Opera House2.5 km
- Zhujiang New City2.8 km
- Pazhou Intl Exhibition Center3.9 km
- Sun-Yat-Sen University2.4 km
- City Center4.0 km
- Haiyin Park3.2 km
- Mall of the World3.0 km
- Guangzhou GT Land Plaza2.7 km
- Airports
- New Baiyun33.1 km
- Train stations
- Guangzhou East Railway Station5.5 km


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Last night, rapper Jay-Z gave a message to all haters who has been talking sh*t about him along with his ownership of the Brooklyn Nets team during his third performance at the new Barclays Center in Brooklyn.
"We still got a long way to go because everybody wanna diminish your accomplishment. When I look at the paper and I see them talking, 'Ehh.. he owns one-fifteenth.' First of all, I don't know where they get that number from but I'm cool with it. I know it's not about me, it's about y'all.
What I mean by that is, it's not personal to me. They know that if you see me standing here that you know it's possible to achieve great things. Don't let anybody diminish your accomplishments. It's our motherf-cking time now."
And according to NecoleBitchie, despite his club 40/40 being located inside of the Barclays– Jigga's Rocawear store, a bar that sells his Ace Of Spades champagne, and an advertising agency hired by the Brooklyn Nets in which he co-owns is also located inside.
Plus, the Brooklyn Nets players shared a pic of them today all suited up in their brand new "Black & White" jersey's.
And the team is part owned by Jay-Z with their coach being Avery Johnson. With the "B.N's" first game against the 76er's on October 13.


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From the Editor: A Public Service Announcement Regarding PETA
Senior Editor Roman King warns against donating to PETA.
From the Editor: Common Sense Isn't So Common Anymore — Here's Why
Senior Editor Roman King returns from nowhere with an article on common sense.
From the Editor: The Art of the Dox — Internet Vigilantism on the Rise
Roman King gives a scathing opinion of people responsible for dox attacks on the Internet.
From the Editor: I Am My Own Worst Enemy – Depression, And How I've (Almost) Conquered It
Senior Editor Roman King shares a personal account of the mind's ability to be self-destructive, and how to persevere through it.
From the Editor: The American High School System Is Seriously Screwed Up
Senior Editor Roman King returns to From the Editor with a commentary on the average American high school.
From the Editor: Stagnation and Apathy Are Extremely Destructive — Here's Why
In this edition of From the Editor, Roman King warns the general population not to accept a mediocre life.
Venezuelan Crisis Reaches A New Apex
Venezuela's political crisis is reaching an apex, and the tension is beginning to become unbearable.
From the Editor: In The Age of Information, Ignorance is a Choice
Senior Editor Roman King takes an intensive look at the societal paradigms of ignorance in the modern era
From the Editor: Illinois Can't Keep Their Ducks in a Row
On our first From the Editor, Roman King takes a hard look at the Illinois economic crisis.
Janet Yellen Testifies Before House Banking Committee, DOW Hits Record High
The economy is robust and in good shape, according to Janet Yellen, current Federal Reserve chair.


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Nótaí Scór Chiarraí:
2016-02-10 19:51:00
Nótaí Scór Chiarraí:
SCÓR NA bPÁISTÍ DISTRICT FINALS:
North Kerry Football Area
Date: Sunday 20th March 2016
Time: 2pm sharp
Venue: Marian Hall, Moyvane.
South Kerry
Date: 11th March
East Kerry
Dáta: 11th March
Dáta: 11th March
Greater Tralee Area (Trá Lí & Naomh Breandán)
Date: Friday 11th March 2016
Am: 7pm
Ionad: ITT (Tralee IT), North Campus.
SCÓR NA bPÁISTÍ INFO:
(i) After each district final, the qualifiers' names and registration numbers should be forwarded, le bhur dtoil, to firstname.lastname@example.com before 31st March.
(ii) N.B. No DISTRICT ROUND Quiz will be held this year; all quiz teams may go straight to the county final on 17th April. All quiz entries (names and GAA registration numbers) should be forwarded to firstname.lastname@example.com by Saturday April 2nd.
(iii) The County Semi-finals will be held at 4pm on 9th April in Foilmore (for South Kerry) and at 2pm on 10th April (for North Kerry - venue to be decided).
(iv) The County Final will take place on 17th April.
Quiz: No Quiz in District Areas; County Quiz for all Kerry Clubs on 17th April.
CULTÚR - SCÓR - KERRY SCÓR NA bPÁISTÍ RULES
Amendments to rules for 2016
The quiz will have 30 questions made up of ten rounds of three. The rule book, which can be found on the kerry GAA website, outlines the question categories and the following categories will have one question as Gaeilge which must be answered as Gaeilge.
Round 1 Gaelic football
Round 3 General GAA
Round 5 World history and World geography
Round 7 Irish current affairs
Round 9 Irish culture
Please note that this year (2016) EVERY SINGLE CLUB may enter a 4-person table quiz team in the COUNTY FINAL of Scór na bPáistí. All entries, with names and GAA registration numbers, should be forwarded to email@example.com by Saturday April 2nd. Beidh an craobh-bhabhta ar siúl ar 17ú Aibreán. Scór na bPáistí ends with the Kerry final.
SENIOR SCÓR - Crème de la crème na Ríochta:
Best wishes to the Kerry Senior Scór competitors in the Munster semi-final on February 20th (Saturday) in Kanturk: Rince Foirne: An Spá - Sinéad Ní Chróinín, Pádraigín Ní Mhurchú, Clár Ní Mhuimhneacháin, Céití Ní Chonchúir, Fiona Ní Cheallaigh, Ciara Ní Shé, Mairéad Ní Mhongáin, Áine Máire Ní Niallagáin, Máire Masún. Amhránaíocht [SOLO SINGING]:Gleann Fleisce – Eibhlín Ní Chróinín; Aithriseoireacht [RECITATION/STORYTELLING]: An Spá – Ray Ó Súilleabháin; Bailéadghrúpa [BALLAD GROUP]: Na Gaeil – Treasa Céitinn, Pádraig Mac Síthigh, Tracey Uí Mhuirthile, Rachel Uí Mhuimhneacháin, Tadhg Ó Loinsigh; Léiriú Stáitse [STAGE PRESENTATION]: Fosadh – Eibhlín Uí Luasaigh, Proinsiasa Ní Éilí, Treasa Uí Chíosáin, Mícheál Ó Grífín, Eoghan Ó Muircheartaigh, Maidhc Ó Síoráin; An Seit [SET DANCE]: An Spá - Céití Ní Chonchúir, Ailís Ní Chullota, Pádraigín Ní Mhurchú, Sorcha Sinéad Ní Tháilliúir, Clár Ní Mhuimhneacháin, Máire Ní Mhathúna, Niamh Ní Fhiannachta, Sinéad Ní Chróinín; An Quiz: The Brothers Pearse Club (Cnoc na hEaglaise) - Alex Ó Dónaill, Seán Ó Flaithearta', Pól Ó Cullota, Mícheál Mag Fhionnbhair. The go directly to the All-Ireland which will be held in the INEC (Cill Airne) on 2nd April. Gach rath ar mhuintir Chiarraí.