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|Touching cold objects causes my heart to beat wildly
With the Marfan Syndrome issues affecting my body, including extra height and long limbs, the heart inside has to work extra hard every moment just pump blood those extra long distances. But when cold affects my fingers and toes my heart sometimes goes crazy trying to figure out how to handle pumping blood through now constricted blood vessels way out there in the fingers and toes.
To put it simply, when my fingers and toes become cold my heart sometimes starts racing or jumping around with crazy atrial fibrillation, also know as cardiac arrhythmia.
My simple solution for avoiding this type of heart fluttering lies in warm socks, a pair of soft comfy gloves and warm weather.
Its that easy for me to avoid certain types of cardiac arrhythmias. Keep those toes and fingers warm. Don't let them get cold.
Our body has certain reactions to cold. One of the first things our body does when our peripheral temperature (temperature of toes, limbs, fingers, arms and ears) drops is to vaso-constrict blood vessels. There is a good, brief explanation about cold and our body's cardiovascular system on the Livestrong.com website.
An even more comprehensive and excellent brief, visually oriented website explaining the fundamentals of cardiovascular output and variables that can affect both blood pressure and heart rate is published by James Doohan and is a site I highly recommend.
As my curiosity concerning peripheral body temperature and arrhythmia grew, I wondered about my own body.
Judy says my fingers and toes are unusually cold and I agree. I hate the cold weather or touching anything cold or jumping water.
So I measured my body temperature orally with our medicine thermometer. The temperature in my mouth was 97.7 F, or 36.5 C. My fingers and toes were so cool that the digital medicine thermometer could not determine the temperature.
Not to be thwarted I found the industrial infra-red digital thermometer I had in the garage, installed a new 9 volt battery and pointed the laser at my toes. The readout told me why my feet felt like ice. Toe temperature was a cool 74.4 F or 23.6 C. My fingers were not much warmer at 76 F. The house temperature was a pleasant 79 F while the outside temperature hovered in the mid 80's F.
For comparison I measured my wife's and children's peripheral body temperatures, though the teens thought I was crazy.
Judy's finger and toe temperatures were in the low 90's F. The two marf teens, with their long limbs were more like me, with lower peripheral body temperatures.
These temperatures are no surprise to me because I know my heart has to pump blood extra long distances, all the while dealing with installed metal parts and foreign aortic components. The old clicker is also stressed from multiple open heart surgeries, functioning well below normal output.
So when the fingers and toes get cold and the skin vessels constrict as they do naturally to conserve body heat, the heart has a harder job pumping blood. At this point all the node chemicals and signals start to fire, diastolic pressure jumps and my heart attempts to increase output.
It is kind of like flooring the accelerator pedal in a car with an engine about to throw a rod. Motor starts shaking, clanging, huffing and puffing and, well you get the picture.
Of course there are many causes of arrhythmia.
But because they are so frightening to me with my beat up heart and aorta, controlling one cause is important. When my heart goes into erratic beat patterns I become concerned the dissected descending aorta will further aneuryze, dilate or even burst.
Fortunately warm comfortable socks, like those made for diabetic patients can moderate lower body peripheral temperatures and reduce the likelihood of signalling for increased cardiovascular output. Gloves too address the same issue on the hands.
Avoiding cold weather is my big strategy.
But wherever you live, keeping peripheral body temperature fluctuations to a minimum might help you solve some of your afib or arrhythmia problems. It is worth a try!


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David Jones occupies a unique place in 20th-century British art, and is often called the greatest painter-poet since William Blake.
Like Blake David Jones was a Londoner, born at Brockley, in north Kent. However he was the son of a Welsh father and an English mother, and the landscape, language, and myths of Wales were powerful influences upon his art.Amgueddfa Cymru has the principal public collection of Jones's work, but as he worked primarily in watercolour this is not on permanent display.This exhibition focuses on his work in that medium, and will be followed by another which examines his engravings, book illustrations, and inscriptions.

subset: commoncrawl


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Names changes have not always brought a rollicking success. Remember when the successful Nissan Pulsar became the unwanted Tiida. In the creation of fresh tags, there are other case histories of triumph seguing to disappointment: Iran transforming from Persia, and Todd Carney, now better known across Australia as D***head.
On the other hand, renewing names can hit the spot - ask Elton John, formerly Reggie Dwight. Or Eminem (born Marshall Bruce Mathers III). Or the Sydney Swans, identified in a previous life and location as South Melbourne.
BMW is hoping for similar success with its rebadging of its masterpiece, legend, dream material… We're talking about the BMW M3. Or is that the M4?
Branding is appearing just a little muddied at a time when BMW is keen to hit back at the tough competition from the Mercedes AMG cars and Audi's RS flyers.
Since the mid-1980s, the M3 Coupe has been the performance car that boys (and some girls) of all ages lusted after.
Across several generations, the M3 was the sizzling all-rounder that enthusiasts bought in droves, and BMWs in-house motorsport division, BMW M, used as the basis of many touring car variants.
Then, last year the marketing and branding chaps settled on a new nomenclature for BMW. Odd numbers were allocated to sedans; even numbers to coupes and convertibles. In one fell swoop, the M3 Coupe was no more. The last one was produced in July last year.
The new 3-Series M car in two-door coupe form is called the M4. Doesn't have the same ring to it, does it? In years past the M3 always carried an M3 badge, whether it was a coupe, a sedan or a drop top.
Boasting about their new weapon down at the pub, owners of the new M4 will now have to go into an elaborate explanation about how the M4 is really, truly the M3 of folklore, and that the new M3 sedan is really a….aaaagh. Confusing it is. And it will remain so until we all get our heads around it.
The M division's head of sales Jorg Bartles doesn't anticipate any lingering dramas.
"People will get used to the change," he says. "In any case, we [the M division] didn't have a choice. It was BMW's decision. But we still have the M letter."
While new buyers of the latest M3/M4 range hitting the local showrooms this month will perhaps stumble over the badge, they also need to decide to make a choice. Stay with the evocative old name attached to a more practical and not-so-sexy four-door shape, or go for the unfamiliar new name in the stirring coupe that traditionalists have adored for decades.
The decision-making process is difficult. From the driver's seat, it's nigh impossible to detect any differences. Around a racetrack, they are nigh identical. On some circuits, the coupe might just shade the sedan. Just. Both double-clutch transmission versions of the M3 and M4 do the zero to 100km/h burst in 4.1 secs.
The brilliant twin-turbocharged in-line six-cylinder engines in each produces 317kW, which is a little more power than the V8 its replaces. But check out the torque leap – up 38 per cent to 550Nm – which transforms the new M-and-M pair into track blasters that can also behave like princesses in a road environment. Fuel consumption (8.3 litres/100km) and emissions (194gkm) are 25 per cent better than the old 4.0-litre V8.
As is the case with all M cars, owners can also tailor engine, transmission, steering and dynamics to suit ability or tastes. From soft to brutal.
Purists who hanker for the traditional M3 performance might opt for the M4 two-door, believing that it may have the slightest edge in acceleration because it is lighter by 23 kg. The coupe is also not as tall as the sedan (by 41mm) and 7mm narrower, measurements that should hand it a teeny advantage at higher speeds.
The sedan, on the other hand, is probably an easier car to live with, seating five with the rear passengers benefiting from extra head room. It also has a bigger-capacity luggage area, 480 litres to the coupe's 445 litres.
Nominating which is the more awesome car is a tough call. Ahead of the Australian launch Drive was spirited across the Tasman to do some serious back-to-back motoring on some excellent rural roads, as well as two – yes, two – of New Zealand's tasty racing circuits.
First up, Hampton Downs, an undulating track designed with input from four-time Bathurst winner Greg Murphy. An excellent choice to check BMW's assertion that the M cars are track ready but to attempt to answer a pressing first world question: which of the two cars does Drive favour?
A dry track surface would be ideal to mount a comparison. But of course it's raining. Way harder to get clear impressions of the dynamics and balance.
The new electromechanical Servotronic steering offered for the first time in the M3/M4 impresses. Both cars gives the driver a choice of three settings – Comfort, Sport and Sport +. The tactile feedback of old is there in the last of those settings.
Similarly the standard Adaptive M suspension gives similar choices. Sport + is obvious for the track; Comfort more suited to the city and rural roads, where your kidneys vote for a suspension mode less rigid.
What is obvious from powering around slippery Hampton Downs is that, yes, it's quite reassuring to have the electronics on safety watch to catch any overly bold tail-out action. Use too much throttle at generous revs and the rear tyres – excellent 19-inch Michelin Pilots – spin up momentarily before traction is limited and composure restored.
Finally, there's a hint of a dry line appearing, and we get a healthier idea of the behaviour and character of the cars. Maybe the M3 is a little more poised. The rear end certainly seems to stick a little longer before the power overcomes grip.
While the newcomers do have a pleasant and obvious exhaust note, the twin-turbo doesn't growl in the same sensual way as the old V8, or as urgent as the glorious metallic blast of the last naturally aspirated E46 six-cylinder.
Next up is a 250km road drive to Taupo. It's still raining. But the beautiful power delivery and huge torque spread continue to impress in the real world. These new M cars are not out of place as daily transport. The made-for-the M3/M4 Michelins Pilots (not run flats, by the way) keep hanging on in the wet, when others might have lost their tenacity. The only jarring note is the high and intrusive levels of tyre roar on coarse tarmac.
A new day dawns with a similar weather scenario. It's still raining and its 3 degrees C. Off to the nearby Taupo race track, we're thankful for the wide layout, the heated seats and the blast from the climate control air cond. Lapping in both cars again serves to endorse the pair's under-bonnet performance, brakes, grip, active differential, steering and balance.
Manual gearbox cars which rev match (blip) on down changes, can be ordered specially at no extra charge, and have a 40kg advantage in weight. But the manual can't beat the standard-issue DCT, which is faster and more fuel efficient.
BMW Australia expects just a handful of orders for manuals. Unlike the case in Germany where the coupe is still very much the buyers' favourite, there is also a forecast that Aussies will be evenly split in their demands for M3 and M4.
Which would Drive choose? The M4 – the coupe – is a visual stunner, the pick of the two if styling is the criteria. But on the grounds of practicality I'd want the sedan, the M3, with DCT. The more compact and lighter doors are easier to manoeuvre when alighting. It'll carry a fifth passenger too.. At $156,000, the M3 is also 10 grand cheaper than the coupe.
And I won't need a whiteboard down at the pub to explain what an M4 is….
For its part, Mercedes Benz isn't in surrender mode, being on target to pass a milestone for its AMG prestige performance brand when it delivers the 10,000th AMG since the launch of the brand in Australia. (That was the C36 in 1995).
Currently AMG makes up an impressive nine per cent of Mercedes' local passenger car and SUV volumes. That's the highest penetration of any market in the world and the car maker is looking at delivering 2000 AMG units this year.
The direct competitor for the BMW M3/M4 is the Mercedes C63 AMG, which can now only be ordered in one guise - C63 AMG 507 Coupe (the sedan and wagon variants are out of production, with an all-new range imminent)
This week on the day of the launch of the new M3/M4, (a sheer coincidence, no doubt!), Mercedes-Benz Australia announced special pricing of $159,507 for the C63 AMG 507 Coupe, a cut of nearly $12,000. With 373 kW from its 6.3-litre V8 (which gets SLS pistons and rods), the model often referred to as the 'factory hot rod' is not merely fading away….
The 10,000th AMG will be delivered later this year and Mercedes promises it will be a special car of which more details will be released later.


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Over half a million Internet of Things (IoT) devices could end up captured and leveraged by botnets, researchers said.
This all came about when Mirai and at least one other botnet released huge distributed denial-of-service (DDoS) attacks against the website of journalist Brian Krebs and hosting provider OVH. The attack on OVH was said to have exceeded 1Tbps.
Switch in Malware Distribution
3 Botnets Unite in Huge DDoS Attack
Botnet Targets Linux Platforms
Botnet Branches Out into Ransomware
It appeared these attacks ended up powered by compromised IoT devices protected by weak or default credentials.
The author of Mirai releases the source code of the malware, claiming he had made enough money. The source code includes a list of 60 username and password combinations the Mirai botnet has been using to hack IoT devices.
Devices associated with this username and password combination actually make up a significant portion of the Mirai botnet, said researchers from Flashpoint.
Experts reported video surveillance products from Dahua Technology accounted for the highest percentage of compromised devices. However, Flashpoint traced other hacked devices, which may not appear related, but really are. They devices all went back to one vendor.
Many DVR, NVR and IP camera manufacturers get their hardware and software components from a China-based company called XiongMai Technologies. XiongMai shipped vulnerable software that ended up in at least half a million devices worldwide.
The fact you can gain access to these devices with default credentials should not pose a major risk as long as they are not accessible from the Internet. The problem is the firmware provided by the Chinese manufacturer also includes a telnet service active by default and which allows easy remote access to the devices.
On top of that, the default credentials cannot end up changed as they are hardcoded in the firmware and there are no options for disabling them. The telnet service is also difficult to disable.
A scan Flashpoint conducted using Shodan found over 500,000 devices with the vulnerabilities, making them an easy target for Mirai and other botnets.


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hygroscopic(redirected from hygroscopical)
Also found in: Dictionary, Thesaurus, Medical.
(of a substance) tending to absorb water from the air
Being sensitive to moisture, such as certain tissues.
Possessing a marked ability to accelerate the condensation of water vapor; applied to condensation nuclei composed of salts which yield aqueous solutions of a very low equilibrium vapor pressure compared with that of pure water at the same temperature.
Pertaining to a substance whose physical characteristics are appreciably altered by effects of water vapor.
Pertaining to water absorbed by dry soil minerals from the atmosphere; the amounts depend on the physicochemical character of the surfaces, and increase with rising relative humidity.
Readily absorbing and retaining moisture from the air.


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2019 Kansas City Heart & Stroke Walk/5K Run
Kansas City, MO
Saturday, June 15, 2019
Life is why we walk.
Thanks to all our walkers, donors and volunteers who have accepted the challenge to help fight heart disease and stroke. We cannot achieve our mission without each one of you!
Date & Time
Check-In Festivities begin at 7:00am
Starts 5K Begins at 7:30am & Walk Begins at 8:00am
Length of Walk 5K timed run, 3 mile walk and 1 mile walk
Power and Light District
13th & Grand Blvd
Kansas City, MO 64106
Get Directions
Your Heart Walk Team
Email Your Heart Walk Team
By participating in the Heart Walk, you're joining a million Heart Walk Heroes from across the nation raising funds for lifesaving science. Science that can teach us all how to live longer and be Healthy For Good.
Take a few minutes to consider the lives you are going to help change for the better through your leadership and donations. We're talking more moms, dads, brothers, aunts and babies' lives saved. Help keep hearts everywhere beating. Let's take steps together to cure heart disease and stroke.


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Monk fruit is a small sub-tropical melon that has been cultivated in the remote mountains of Southern China for centuries. According to legend, monk fruit is named after the Lou Han group of people who were Buddhist monks that first cultivated the fruit over a thousand years. In the practice of Traditional Chinese Medicine, Luo Han Guo is considered to be a longevity aid and is associated with longevity in populations that live for one hundred years or more in Southern China.
Hill Pharma, Inc. is an industry leader in the production of high quality botanical extracts. Our Magou-V™ is naturally extracted from the monk monk fruit. Hill Pharma, Inc. controls the cultivation and proprietary production in a process that is vertically integrated. Magou-V™ is available in both USDA Organic and Non-GMO natural options.
The monk fruit was discovered over a thousand years ago, and has been treasured for its medicinal and sweetening properties ever since. The sweetness of the monk fruit comes from antioxidants called mogrosides. Mogroside V has the highest sweetness level and most health benefits. Magou-V™ has zero calories, is nearly 300+ times sweeter than cane sugar, does not raise glucose levels, and provides a clean label alternative for formulators.
With FDA Nutritional labeling taking effect, all sugars found in products need to be identified. Having a healthy, sweet alternative is a priority for may consumers. Artificial sweeteners can be harmful to our health Magou-V™ is a solution, providing natural sweetness with no after taste.
Hill Pharma, Inc. is proud to offer the following products in both USDA Organic and natural non-GMO options.


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recipe: Monster Apple Bites
The Halloween food, and an everyday snack to keep (scare) the doctor away! 😉
Prep time: 10 minutes
Green apple – Mouth
Strawberries – Tongue
Peanut butter – Glue
Salted caramel sun seeds – Teeth
Banana pecan crumble – Eyes & Hair
1 tbsp Melted dark chocolate – Eyes
Prep work
Mouth: slice apple into a quarter and cut the centre of it to form the shape of a mouth
Tongue: Slice strawberries into thin strips
Creating your monster:
1. Coat the insides of the mouth with peanut butter
2. Place salted caramel sun seeds on the top of the mouth
3. Place a strip of strawberry at the bottom
4. Glue the eyes on with peanut butter
Other ways you can enjoy it
Instead of peanut butter, you can also spread yogurt in the apple's mouth for a little extra protein, calcium, and YUMZ!
Here's another idea: If you are serving it on Halloween, use red jam for a bloodier mess.
Leah's healthy tips
More than half of the apple's vitamins and fibre are in its skin – don't peel it away!!
Did you know?
Unlike red apples, green apples take a longer time to go brown once you've cut it.


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Rajagopal V. Sekhar, MD; J. Clay Goodman, MD; Ashok Balasubramanyam, MD; Jeffrey B. Tatro, PhD; Emese Mihaly, PhD
Editor's Note: The lead author of the following Clinical Observation was one of a dozen Associates of the American College of Physicians selected to present a clinical vignette at the 2003 Annual Session in San Diego. We are proud to present this case report through a special arrangement with the Council of Associates of the College.
Acknowledgment: The authors thank Margaret Entwistle for technical expertise.
Grant Support: By National Institutes of Health grants DK59537 and HL73696 to Dr. Balasubramanyam and grant MH44694 to Dr. Tatro.
Potential Financial Conflicts of Interest: None disclosed.
Sekhar RV, Goodman JC, Balasubramanyam A, et al. Regulation of Body Weight by Proopiomelanocortin Peptides in Humans: Lessons from the Nelson Syndrome. Ann Intern Med. 2005;143:238–239. doi: https://doi.org/10.7326/0003-4819-143-3-200508020-00021
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© 2019
Published: Ann Intern Med. 2005;143(3):238-239.
Copyright © 2019 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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Gene name - E2F transcription factor 1
Synonyms -
Cytological map position - 93E8--93E9
Function - transcription factor
Keywords - cell cycle
Symbol - E2f1
FlyBase ID:FBgn0011766
Genetic map position -
Classification - multifunctional
Cellular location - nuclear
|Recent literature
|Bradley-Gill, M.R., Kim, M., Feingold, D., Yergeau, C., Houde, J. and Moon, N.S. (2016). Alternate transcripts of the Drosophila "activator" E2F are necessary for maintenance of cell cycle exit during development Dev Biol [Epub ahead of print]. PubMed ID: 26859702
The E2F family of transcription factors are evolutionarily conserved regulators of the cell cycle that can be divided into two groups based on their ability to either activate or repress transcription. In Drosophila, there is only one "activator" E2F, dE2F1, which provides all of the pro-proliferative activity of E2F during development. Interestingly, the de2f1 gene can be transcribed from multiple promoters resulting in six alternate transcripts. This study investigated the biological significance of the alternate transcriptional start sites. The de2f1 promoter region shows tissue and cell-type specific enhancer activities at the larval stage. While a genomic deletion of this region, de2f1ΔRA, decreases the overall expression level of dE2F1, flies develop normally with no obvious proliferation defects. However, a detailed analysis of the de2f1ΔRA mutant eye imaginal discs revealed that dE2F1 is needed for proper cell cycle exit. dE2F1 expression during G1 arrest prior to the differentiation process of the developing eye is important for maintaining cell cycle arrest at a later stage of the eye development. Overall, this study suggests that specific alternate transcripts of "activator" E2F, dE2F1, may have a dual function on cell cycle progression and cannot simply be viewed as a pro-proliferative transcription factor.
|Zappia, M.P. and Frolov, M.V. (2016). E2F function in muscle growth is necessary and sufficient for viability in Drosophila. Nat Commun 7: 10509. PubMed ID: 26823289
The E2F transcription factor is a key cell cycle regulator. However, the inactivation of the entire E2F family in Drosophila is permissive throughout most of animal development until pupation when lethality occurs. This study shows that E2F function in the adult skeletal muscle is essential for animal viability since providing E2F function in muscles rescues the lethality of the whole-body E2F-deficient animals. Muscle-specific loss of E2F results in a significant reduction in muscle mass and thinner myofibrils. It was demonstrated that E2F is dispensable for proliferation of muscle progenitor cells, but is required during late myogenesis to directly control the expression of a set of muscle-specific genes. Interestingly, E2f1 provides a major contribution to the regulation of myogenic function, while E2f2 appears to be less important. These findings identify a key function of E2F in skeletal muscle required for animal viability, and illustrate how the cell cycle regulator is repurposed in post-mitotic cells.
|Flegel, K., Grushko, O., Bolin, K., Griggs, E. and Buttitta, L. (2016). The role of the histone modifying and exchange complex NuA4 in cell cycle progression in Drosophila melanogaster. Genetics [Epub ahead of print]. PubMed ID: 27184390
Robust and synchronous repression of E2F-dependent gene expression is critical to the proper timing of cell cycle exit when cells transition to a post-mitotic state. Previously histone Modifying and Exchange Complex NuA4 was suggested to act as a barrier to proliferation in Drosophila, by repressing E2F-dependent gene expression. This study shows that NuA4 activity is required for proper cell cycle exit and the repression of cell cycle genes during the transition to a post-mitotic state in vivo However, the delay of cell cycle exit caused by compromising NuA4 is not due to additional proliferation or effects on E2F activity. Instead NuA4 inhibition results in slowed cell cycle progression through late S and G2 phases due to aberrant activation of an intrinsic p53-independent DNA damage response. A reduction in NuA4 function ultimately produces a paradoxical cell cycle gene expression program, where certain cell cycle genes become de-repressed in cells that are delayed during the G2 phase of the final cell cycle. Bypassing the G2 delay when NuA4 is inhibited leads to abnormal mitoses and results in severe tissue defects. NuA4 physically and genetically interacts with components of the E2F complex termed DREAM/MMB (Rbf, E2F and Myb/Multi-vulva class B), and modulates a DREAM/MMB-dependent ectopic neuron phenotype in the posterior wing margin. However, this effect is also likely due to the cell cycle delay, as simply reducing Cdk1 is sufficient to generate a similar phenotype. This work reveals that the major requirement for NuA4 in the cell cycle in vivo is to suppress an endogenous DNA damage response, which is required to coordinate proper S and G2 cell cycle progression with differentiation and cell cycle gene expression.
|Hinnant, T. D., Alvarez, A. A. and Ables, E. T. (2017). Temporal remodeling of the cell cycle accompanies differentiation in the Drosophila germline. Dev Biol 429(1): 118-131. PubMed ID: 28711427
During Drosophila oogenesis, mature oocytes are created through a series of precisely controlled division and differentiation steps, originating from a single tissue-specific stem cell. To describe how the cell cycle is remodeled in germ cells as they differentiate in situ, the Drosophila Fluorescence Ubiquitin-based Cell Cycle Indicator (Fly-FUCCI) system was used, in which degradable versions of GFP::E2f1 and RFP::CycB fluorescently label cells in each phase of the cell cycle. The lengths of the G1, S, and G2 phases of the cell cycle were found to change dramatically over the course of differentiation, and the 4/8-cell cyst was identified as a key developmental transition state in which cells prepare for specialized cell cycles. The data suggest that the transcriptional activator E2f1, which controls the transition from G1 to S phase, is a key regulator of mitotic divisions in the early germline. These data support the model that E2f1 is necessary for proper GSC proliferation, self-renewal, and daughter cell development. In contrast, while E2f1 degradation by the Cullin 4 (Cul4)-containing ubiquitin E3 ligase (CRL4) is essential for developmental transitions in the early germline, the data do not support a role for E2f1 degradation as a mechanism to limit GSC proliferation or self-renewal. Taken together, these findings provide further insight into the regulation of cell proliferation and the acquisition of differentiated cell fate, with broad implications across developing tissues.
|Zhang, P., Pei, C., Wang, X., Xiang, J., Sun, B. F., Cheng, Y., Qi, X., Marchetti, M., Xu, J. W., Sun, Y. P., Edgar, B. A. and Yuan, Z. (2017). A balance of Yki/Sd activator and E2F1/Sd repressor complexes controls cell survival and affects organ size. Dev Cell 43(5): 603-617.e605. PubMed ID: 29207260
The Hippo/Yki and RB/E2F pathways both regulate tissue growth by affecting cell proliferation and survival, but interactions between these parallel control systems are poorly defined. This study demonstrates that interaction between Drosophila E2F1 and Sd disrupts Yki/Sd complex formation and thereby suppresses Yki target gene expression. RBF modifies these effects by reducing E2F1/Sd interaction. This regulation has significant effects on apoptosis, organ size, and progenitor cell proliferation. Using a combination of DamID-seq and RNA-seq, this study identified a set of Yki targets that play a diversity of roles during development and are suppressed by E2F1. Further, it was found that human E2F1 competes with YAP for TEAD1 binding, affecting YAP activity, indicating that this mode of cross-regulation is conserved. In sum, this study uncovers a previously unknown mechanism in which RBF and E2F1 modify Hippo signaling responses to modulate apoptosis, organ growth, and homeostasis.
|Kim, M., Tang, J. P. and Moon, N. S. (2018). An alternatively spliced form affecting the Marked Box domain of Drosophila E2F1 is required for proper cell cycle regulation. PLoS Genet 14(2): e1007204. PubMed ID: 29420631
Across metazoans, cell cycle progression is regulated by E2F family transcription factors that can function as either transcriptional activators or repressors. For decades, the Drosophila E2F family has been viewed as a streamlined RB/E2F network, consisting of one activator (dE2F1) and one repressor (dE2F2). This study reports that an uncharacterized isoform of dE2F1, hereon called dE2F1b, plays an important function during development and is functionally distinct from the widely-studied dE2F1 isoform, dE2F1a. dE2F1b contains an additional exon that inserts 16 amino acids to the evolutionarily conserved Marked Box domain. Analysis of de2f1b-specific mutants generated via CRISPR/Cas9 indicates that dE2F1b is a critical regulator of the cell cycle during development. This is particularly evident in endocycling salivary glands in which a tight control of dE2F1 activity is required. Interestingly, close examination of mitotic tissues such as eye and wing imaginal discs suggests that dE2F1b plays a repressive function as cells exit from the cell cycle. Evidence is also provided demonstrating that dE2F1b differentially interacts with RBF1 and alters the recruitment of RBF1 and dE2F1 to promoters. Collectively, these data suggest that dE2F1b is a novel member of the E2F family, revealing a previously unappreciated complexity in the Drosophila RB/E2F network.
|Song, F., Li, D., Wang, Y. and Bi, X. (2018). Drosophila Caliban mediates G1-S transition and ionizing radiation induced S phase checkpoint. Cell Cycle: 1-12. PubMed ID: 30231800
Cell cycle progression is precisely regulated by diverse extrinsic and intrinsic cellular factors. Understanding the underlying mechanisms of cell cycle regulation is essential to address how normal development and tissue homeostasis are achieved. This study presents a novel cell cycle regulator Caliban (Clbn), the Drosophila ortholog of human Serologically defined colon cancer antigen 1 (SDCCAG1) gene. Ionizing radiation induces expression of clbn, and over-expression of clbn blocks G1-to-S cell cycle transition in Drosophila, while flies loss of clbn have defective S phase checkpoint in response to irradiation. Mechanistically, induced expression of clbn suppressed E2F1 activity and down-regulates the DNA replication and expression of its downstream target cyclin E, a key regulator of G1-to-S transition. Meanwhile, clbn over-expression leads to upregulation of the CDK inhibitor Dacapo (Dap), and upregulated Dap is decreased when e2f1 is over-expressed. Furthermore, expression of clbn is down-regulated in cells with e2f1 over-expression or rbf1 knockdown, indicating that Clbn and E2F1 act antagonistically in mediating G1-to-S transition. Thus this study provides genetic evidence that Clbn works together with E2F1 in regulating cell cycle progression, and Clbn is required for S phase cell cycle checkpoint in response to DNA damage.
The E2F protein is a critical component for normal cell cycle regulation. As a transcription factor, it positively regulates many of the genes required for initiation of S phase (the DNA synthetic phase). The complexity of E2F regulation is fairly well understood in human biology, while the availability of mutations makes it a prime target for investigation in Drosophila.
Drosophila E2F mutants complete early cell cycles, using maternal gene products, but DNA synthesis fails in cycle 17. Instead of undergoing their normal proliferation during a rapid cycle lasting about 40 minutes, cell cycles in the CNS of E2F mutants gradually decrease DNA synthesis after stage 12. Abdominal histoblasts also cease DNA replication in E2F mutants. Messenger RNAs coding for proteins required for DNA synthesis disappear in E2F mutants (Duronio, 1995a).
Interactions with cyclin E are especially complex. Cyclin E, which is the regulatory subunit of the cyclin E/cdc2c kinase heterodimer, regulates entry in S by phosphorylation of target substrates. Cyclin E expression at G1-S requires E2F. Activation of E2F without cyclin E is not sufficient for S phase. Early in G1, ectopic expression of cyclin E alone can bypass E2F and induce S phase. Thus cyclin E is a downstream target of E2F, coupling E2F activity to G1 control (Duronio, 1995b).
How is E2F regulated? In mammalian systems E2F is held inactive by the retinoblastoma (Rb) family of pocket proteins (See Drosophila Retinoblastoma-family protein). Hypophosphorylated Rb can interact with E2F during G1. This complex can bind to DNA and repress transcription of E2F target genes. A chain of events leads first to sequestration and ultimately the release of E2F. The sequestering of E2F is actively carried out by Rb family members until Rb is inactivated by hyperphosphorylation, carried out by cyclin dependent kinases. At this point, E2F is released allowing it to activate genes required for DNA synthesis and entry into S (Zhu, 1995 a and b).
An additional factor conspires to hold E2F inactive in G1 phase: the association of E2F with p53. As a consequence of its ability to physically associate with E2F, the expression of wild-type p53 can inhibit transcriptional activation by E2F. The expression of both E2F1 and DP1 (E2F's dimerization partner) can also downregulate p53-dependent transcriptional activation (O'Conner, 1995).
Equally important as the G1 phase regulation of E2F is the inactivation of E2F during S phase, when it is no longer required for gene activation. In mammalian systems the inactivation of E2F is again carried out by cyclin A dependent kinase activity. Just as there is a physical association of E2F with the Retinoblastoma protein in G1, there is an association of cyclin A with E2F in S phase (Kitagawa, 1995). These G1 and S phase interactions of E2B have yet to be documented in Drosophila. In Drosophila cyclin A is not synthesized until G2, too late to inactivate E2F in S phase.
E2F is capable of driving the G1-S transition of the cell cycle. However, mice in which the E2F-1 gene has been disrupted develop tumors, suggesting a negative role for E2F in controlling cell proliferation in some tissues. The consequences of disrupting the DP genes have not been reported. A screen was carried out for mutations that disrupt G1-S transcription late in Drosophila embryogenesis and five mutations in the dDP gene (DP transcription factor) were identified. Sequencing of dDP reveals the presence of several important motifs, including the DNA-binding region, the DEF box that is predicted to be required for DP/E2F heterodimerization, and three other highly homologous regions named DP-conserved box 1 (DCB1), DCB2, and negatively charged box (NCB). Although mutations in dDP or dE2F nearly eliminate E2F-dependent G1-S transcription, S-phase still occurs. Cyclin E has been shown to be essential for S-phase in late embryogenesis, but in dDP and dE2F mutants the peaks of G1-S transcription of cyclin E are missing. Thus, greatly reduced levels of cyclin E transcript suffice for DNA replication until late in development. Both dDP and dE2F are necessary for viability, and mutations in the genes cause lethality at the late larval/pupal stage. The mutant phenotypes reveal that both genes promote progression of the cell cycle (Royzman, 1997).
Although the dE2F mutant animals survive through larval life, a dramatic delay is observed in larval growth. It takes between 288 and 432 hr for the dE2F mutant larvae to pupate, compared to 120 hr for heterozygous sibling controls. Five days after egg laying (AEL) the dE2F mutant larvae are very sluggish and much smaller in size than their wild-type counterparts. The polytene salivary gland and diploid imaginal discs can not be identified in the 5-day-old dE2F mutant larvae, presumably because they are so small. The brains are also greatly reduced in size as compared to wild type. The size of the dE2F mutant larvae increases over time, and the internal tissues approached wild-type size. Therefore, DNA replication can occur during this larval period, but it is slow. Replication in the absence of dE2F is further evidenced by the formation of banded polytene salivary gland chromosomes in some of the 12- to 18-day larvae. Although the polytene chromosomes from the dE2F mutant larvae are smaller and more fragile than normal they are clearly visible. Thus, it is concluded that S phase occurs in the absence of dE2F, but dE2F is necessary for timely replication and growth. In addition to the growth delay, the dE2F mutant larvae had another striking phenotype: melanotic pseudotumors are formed. Melanotic tumors are groups of cells within the larvae that are recognized by the immune system and encapsulated in melanized cuticle. They are referred to as pseudotumors to emphasize that they are not necessarily the consequence of hyperproliferation but can be abnormal cells recognized by the immune cells. Small pseudotumors were first observed in the dE2F mutants 7 days AEL, and these early pseudotumors grow and darken as the larvae age. In the dE2F mutants that initiate pupation, numerous additional small pseudotumors form (Royzman, 1997).
Approximately half of the dDP mutant pupae reach adulthood in the pupal case. These adults struggled to eclose but ultimately die. Organisms dissected from the pupal case have essentially normal heads and thoraxes. However, their abdominal defects are severe. This is informative as the head and thorax are derived from imaginal discs, whereas the abdomen arises from the abdominal histoblast nests. The imaginal discs proliferate during larval stages, but the abdominal histoblast nests proliferate during pupal development. Thus, pupal lethality may result from a defect in abdomen formation that occurs during pupal development. Having shown that heat shock dDP rescues the dDP mutants, the developmental period during which ectopic dDP expression is capable of rescuing the lethality of the dDP mutants was defined. Ectopic expression of dDP results in 100% rescue of dDP mutant animals. Thus, the late lethality of dDP mutants is not a manifestation of a defect in the early development of the organism, but rather it stems from defects in larval/pupal life (Royzman, 1997).
The striking observation from the Drosophila dDP and dE2F mutants is that although cyclic transcription of cyclin E, PCNA, and ribonucleotide reductase 2 (RNR2) is not detectable, S phase still occurs. Although the possibility that cyclic transcription of these genes occurs at a low level driven by maternal pools of dDP and dE2F cannot be excluded, the bursts of transcription that normally precede S phase are not essential for the G1-S transition. In these mutants the cell cycle may be driven by basal levels of transcripts and post-transcriptional regulation. The maternal pools of components of the replication machinery can persist until late in development, as evidenced by the fact that mutations in PCNA and MCM2 cause late larval lethality (Royzman, 1997 and references).
E2F positively regulates many of the genes required for initiation of S phase (the DNA synthetic phase). In mammals, the tumor suppressor RB interacts with, and negatively regulates, E2F, but it is not clear whether the function of pRB is solely mediated by E2F. In addition, E2F has been shown to mediate both transcription activation and repression; it remains to be tested which function of E2F is critical for normal development. Drosophila homologs of the RB and E2F family of proteins Rbf and E2f have been identified. The genetic interactions between Rbf and E2f were analyzed during Drosophila development, and the results show that Rbf is required at multiple stages of development. Unexpectedly, Rbf null mutants can develop until late pupae stage when the activity of E2f is experimentally reduced, and can develop into viable adults with normal adult appendages in the presence of an E2f mutation that retains the DNA binding domain but lacks the transactivation domain. These results indicate that most, if not all, of the function of Rbf during development is mediated through E2f. In turn, the genetic interactions shown here also suggest that E2f functions primarily as a transcription activator rather than a co-repressor of Rbf during Drosophila development. Analysis of the expression of an E2F target gene Pcna in eye discs shows that the expression of PCNA is activated by E2f in the second mitotic wave and repressed in the morphogenetic furrow and posterior to the second mitotic wave by Rbf. Interestingly, reducing the level of Rbf restores the normal pattern of cell proliferation in E2f mutant eye discs but not the expression of E2f target genes, suggesting that the coordinated transcription of E2f target genes does not significantly affect the pattern of cell proliferation (Du, 2000).
Given that E2f is just one of many potential targets of Rbf, the dramatic suppression of the rbf mutant phenotypes by E2f mutants is very unexpected. (1) Lowering the activity of E2f can suppress the early larval lethality of the rbf mutants as well as the developmental phenotypes observed in the adult eyes and bristles. (2) An allele of E2f with an intact DNA binding domain but with no transactivation domain or Rbf binding domain can suppress the lethality of rbf null mutants, allowing the double mutant flies to develop into viable adults. Furthermore, these suppressed rbf null adults show normal adult structures. Thus the uninhibited E2f in rbf mutants mediates both the lethality as well as the observed eye and bristle phenotypes in adults. These observations provide strong evidence that E2F mediates most, if not all, of the phenotypes of rbf during development (Du, 2000).
Interestingly, lowering the activity of Rbf can also partially suppress the E2f null phenotypes. There are at least two possible explanations for this observation. One possibility is that Rbf has a function downstream of E2f; the other possibility is that Rbf can affect the E2f mutant phenotypes through a parallel pathway (for example Rbf may be able to regulate the expression of E2f target genes through another target such as dE2F2). The second explanation seems to be more likely for the following reasons: (1) in the suppressed E2f null mutants, the expression of E2f target genes is not restored, and the larvae growth is still greatly retarded, suggesting that reducing the level of Rbf bypasses rather than restores the function lost by E2f mutation; (2) the rbf null mutant phenotype is fully suppressed by an E2f mutant that lacks transcription activation and an Rbf binding domain, demonstrating that Rbf functions upstream of E2f. In summary, these results do not point to a role for Rb downstream of E2f. In contrast, loss of Rbf indeed causes deregulation of the expression of PCNA even in the absence of transcription activation by E2f, supporting the notion that Rbf can regulate the expression of PCNA by targets other than E2f (Du, 2000).
E2F transcription factors can function both to activate transcription and to repress transcription by recruiting RB family proteins to specific promoters. Although analysis of E2f mutants shows that E2f is required for the coordinated expression of replication functions such as PCNA and Ribonucleoside diphosphate reductase small subunit (RnrS), it is not clear whether the lack of transcription of these set of genes is the cause of the larval lethality. It is formally possible that the lethality of E2f mutant is caused by the failure to repress certain critical E2f target genes. Depending on the function of E2f as a transcription activator or a co-repressor of Rbf, completely different predications are expected regarding the genetic interaction between Rbf and E2f. The observation that lowering the level of Rbf can suppress the larval lethality of E2f mutants and allow the E2f mutants to develop into pharate adults, suggests that during Drosophila development, the function of E2f is mainly to activate transcription and not to recruit Rbf to repress transcription (Du, 2000).
In addition to the first E2f to be identified in Drosophila, a second, termed E2f2, has been identified (Sawado, 1998). Interestingly, E2f2 can bind to E2F binding sites, but the function of E2f2 appears to be distinct from that of E2f. Cotransfection of E2f2 represses the expression from the PCNA gene promoter while cotransfection of E2f activates the expression (Sawado, 1998). Similar findings are also observed in transfection experiments in which E2f strongly activates transcription, while E2f2 fails to activate a reporter with E2F binding sites. These results suggest that E2f2 may function mainly to repress transcription while E2f functions mainly to activate transcription. Taken together, these data suggest a model for the function of Rbf, E2f and E2f2. In this model, E2f functions mainly to activate transcription of the E2f target genes. Rbf negatively regulates the activity of E2f to inhibit the expression of E2f target genes. In addition, Rbf can also repress the expression of E2F targets genes through other targets of Rbf such as E2f2. Thus the expression of E2F target genes will have three different states: activated, when there is free E2f/Dp to activate transcription; repressed, when there is E2f2/Dp/Rbf (and possibly E2f/Dp/Rbf) to repress transcription; and basal, when there is neither activation nor repression. At present, it is not clear whether E2f also has a function to repress transcription during development, nor is it is clear about the function of free E2f2/Dp (Du, 2000).
Precise control of cell cycle regulators is critical for normal development and tissue homeostasis. E2F transcription factors are activated during G1 to drive the G1-S transition and are then inhibited during S phase by a variety of mechanisms. The single Drosophila activator E2F (E2f1) was genetically manipulate to explore the developmental requirement for S phase-coupled E2F down-regulation. Expression of an E2f1 mutant that is not destroyed during S phase drives cell cycle progression and causes apoptosis. Interestingly, this apoptosis is not exclusively the result of inappropriate cell cycle progression, because a stable E2f1 mutant that cannot function as a transcription factor or drive cell cycle progression also triggers apoptosis. This observation suggests that the inappropriate presence of E2f1 protein during S phase can trigger apoptosis by mechanisms that are independent of E2F acting directly at target genes. The ability of S phase-stabilized E2f1 to trigger apoptosis requires an interaction between E2f1 and the Drosophila pRb homolog, Rbf1, and involves induction of the pro-apoptotic gene, hid. Simultaneously blocking E2f1 destruction during S phase and inhibiting the induction of apoptosis results in tissue overgrowth and lethality. It is proposed that inappropriate accumulation of E2f1 protein during S phase triggers the elimination of potentially hyperplastic cells via apoptosis in order to ensure normal development of rapidly proliferating tissues (Davidson, 2012).
Thus stabilizing the single Drosophila activator E2f1 in S phase results in apoptosis is necessary to prevent hypertrophy of wing imaginal discs. It is concluded from these data that hyper-accumulation of E2f1 during S phase represents a form of proliferative stress during development that is sensed by the apoptotic machinery and results in the elimination of cells with excess E2f1 activity to maintain homeostasis during tissue growth (Davidson, 2012).
What might be the function of a Drosophila cell's ability to detect abnormal accumulation of E2f1 protein during S phase and subsequently trigger apoptosis? One possibility is that accumulation of E2f1 during S phase resembles instances of abnormally high E2f1 activity that might occur sporadically during rapid growth of a population of precursor cells such as those in the wing imaginal disc. These events could be caused by stochastic or even genetic changes that affect either E2f1 gene transcription or the ability of the CRL4Cdt2/PCNA pathway to destroy E2f1 after replication factor genes are activated in late G1. The cell's ability to detect E2f1 accumulation in S phase clears these potentially hyperplastic cells from developing tissues via apoptosis, consequently contributing to the balance between cell proliferation and cell death that is necessary for normal tissue growth (Davidson, 2012).
Growing Drosophila imaginal discs possess another mechanism of homeostasis in which a process of compensatory proliferation is activated in order to achieve normal tissue development when as many as 50% of cells are killed by external stimuli like radiation-induced DNA damage. Indeed, in spite of high levels of apoptosis (15% of the cells), 50% of en-Gal4>E2f1Stable progeny survive until adulthood with about 2/3 of these surviving flies containing wings with somewhat mild morphological defects. Blocking apoptosis with baculovirus p35 when E2f1Stable is expressed shifts the cell proliferation/apoptosis balance too strongly in favor of cell proliferation, resulting in massive hypertrophy and 100% lethality (Davidson, 2012).
p35 is a broad caspase inhibitor that blocks effector caspase activity at a step downstream of their proteolytic activation. Therefore, cells expressing p35 can initiate apoptosis, but lack the capacity to complete it and are referred to as 'undead cells.' These undead cells produce signals that stimulate unaffected neighboring cells to proliferate. Thus, the dramatic hypertrophy seen in E2f1Stable/p35 wing discs might be the result of two synergizing growth signals: hyper-active E2f1 and compensatory proliferation from undead cells. The current experiments cannot precisely discern the relative contribution of these two inputs, but E2f1 activity appears to make a larger contribution because E2f1Stable/DBD Mut expression does not cause dramatic overgrowth (Davidson, 2012).
What might explain the 32% of en-Gal4>E2f1Stable discs that displayed a reduced posterior compartment rather than an overgrown one? The DNA damage observed in eye discs experiments provides a possible answer. Perhaps early in development the 'arrest' class of wing discs sustained enough genomic damage to prevent proliferation, resulting in too small a pool of cells that could respond to the hyper-active E2f1 and undead cell signals to support disc overgrowth. Thus, the wide range of phenotypes that were observed in E2f1Stable/p35 wing discs may result from multiple influences that act stochastically within the population (Davidson, 2012).
Because endogenous E2f1 is quantitatively destroyed only in S phase, the relative amount of hyper-accumulation of E2f1Stable is greater during S phase than during any other stage of the cell cycle. Therefore, one possibility is that E2f1Stable-induced phenotypes result from the stability of E2f1 protein in S phase, and not from general over-expression throughout the cell cycle. Failure to detect E2f1Stable induced apoptosis in G1-arrested embryonic cells is consistent with this possibility. However, another difference between these embryonic cells and wing discs cells is that the former are cell cycle arrested and the latter are continuingly proliferating during larval development. Thus, another possibility is that S phase-destruction of E2f1 modulates the levels of E2f1 in proliferating cells, and cells that fail to destroy E2f1 during S phase have an increased chance of activating apoptosis at any point in the cell cycle. In either model, S phase E2f1 destruction is not essential for proliferation per se. In marked contrast, E2f1Stable expression blocks endocycle progression, suggesting that knocking in E2f1Stable to the endogenous locus would be lethal during development, perhaps even dominant lethal (Davidson, 2012).
E2f1Stable induces apoptosis at least in part through expression of the pro-apoptotic gene hid. Surprisingly, these events still occur after expression of an E2f1Stable variant that cannot bind DNA and therefore lacks the ability to stimulate transcription of replication factor genes or cell cycle progression. Instead, E2f1Stable requires the ability to bind Rbf1 to induce hid gene expression and apoptosis. Genetic disruption of Rbf1 is well known to result in increased hid expression. It is therefore proposed that the inappropriate accumulation of E2f1 in S phase disrupts some aspect of Rbf1 function leading to hid expression and apoptosis (Davidson, 2012).
The data do not discern either the function of Rbf1 that is disrupted by E2f1Stable or the mechanism of hid induction. While the mechanism connecting Rbf1/E2f1 function and hid may be indirect, some studies suggest that Rbf1 and/or E2f1 could regulate hid directly. It has been demonstrated that Drosophila wing disc cells undergo apoptosis in response to ionizing radiation independently of p53 and that this response requires E2f1 and is triggered by hid expression. In eye discs, loss of Rbf1 function in the MF results in apoptosis that requires E2f1 transactivation function and is accompanied by hid expression. However, whether these effects represent a direct induction of hid by E2f1 is not clear. E2f1 binding at the hid locus has been observed, but the binding site is located ~1.4 kb upstream of the of the start of hid transcription, which is more distal than in well characterized E2F-regulated promoters. When located this far upstream the hid E2f1 binding site fails to activate gene expression in S2 cell reporter assays. hid is also a target of p53, and so any DNA damage resulting from stabilizing E2f1 during S phase, as was observed in eye discs, may also contribute to the activation of hid expression via p53-mediated DNA damage response pathways (Davidson, 2012).
Another possibility is that E2f1, in combination with Rbf1, plays primarily a repressive role at the hid locus. In this model, the result that E2f1Stable or E2f1Stable/DBD Mut both induce apoptosis would be explained by disruption of Rbf1/E2f1 repressive complexes at the hid locus causing de-repression of hid expression. This model has interesting caveats: what protects the Rbf1/E2f1 complex at the hid locus from being disrupted by Cyclin E/Cdk2, which is active during S phase and inactivates Rbf1-mediated repression of E2f1, or by CRL4Cdt2-mediate destruction of E2f1? Recent data indicate that the dREAM/MMB complex is required for the stability of E2F/Rbf1 repressive complexes in S phase, and acts to protect these complexes from CDK-mediated phosphorylation at non-cell cycle-regulated genes. While there is yet no evidence that dREAM/MMB regulates hid , this work provides precedent for gene specific Rbf1 regulation during S phase (Davidson, 2012).
Finally, while hid might be a critical player in the response to E2f1Stable, there are likely other mechanisms responsible for sensing and modulating the apoptotic response to E2f1 levels. For instance, it has been demonstrated that a micro-RNA, mir-11, which is located within the last intron of the Drosophila E2f1 gene, acts to dampen expression of pro-apoptotic E2f1 target genes following DNA damage. In this way, the normal controls of E2f1 gene expression modulate apoptosis. In addition, transgenic constructs lack the normal E2f1 3' UTR, which serves as a site for suppression of E2f1 expression by pumilio translational repressor complexes. Thus, several modes of E2f1 regulation have been bypassed via transgenic expression of E2f1Stable (Davidson, 2012).
The finding that stabilized Drosophila E2f1 can induce apoptosis independently of transcription and cell cycle progression parallels previous observations made in mammalian cells, albeit with important differences. In mammalian cells, E2F1 can induce apoptosis independently of transcription and cell cycle progression, but apoptosis required E2F1 DNA binding activity, unlike in the current experiments. These studies suggested that DNA binding by E2F1 prevented pro-apoptotic promoters from binding repressor E2F family members (Davidson, 2012).
This comparison of results highlights the way similar phenotypic outcomes in different species can arise from different mechanisms. While mammalian activator E2Fs are also inhibited during S phase, they are not subject to CRL4Cdt2-mediated, S phase-coupled destruction like Drosophila E2f1. Instead, mammalian activator E2Fs are inhibited by direct Cyclin A/Cdk2 phosphorylation, targeted for destruction by SCFSkp2, and functionally antagonized by E2F7 and E2F8. The regulation provided by E2F7 and E2F8 is of particular note, as it is essential for mouse development. These atypical E2Fs homo and hetero-dimerize and act redundantly to repress E2F1 target genes independently of pRb family proteins, thus blocking E2F1 from inducing apoptosis. Moreover, the E2F7 and E2F8 genes are E2F1 targets, consequently creating a negative feedback loop that limits E2F1 activity after the G1/S transition. A similar negative feedback loop among factors that regulate G1/S transcription exists in yeast. The analogous Drosophila negative feedback loop involves E2f1 inducing its own destruction by stimulating Cyclin E transcription, which triggers S phase. Therefore, the evolution of eukaryotes has resulted in the use of different molecular mechanism to achieve negative feedback regulation of G1/S-regulated transcription, and in the case of activator E2Fs this regulation is essential for normal development (Davidson, 2012).
Bases 5' UTR -701
Bases in 3' UTR - 1261
Although Drosophila and human proteins share three regions with a high degree of homology, the fly protein is much larger, in part due to the insertion of a 300-aa block with a unique sequence between the two homologous blocks closest to the C-terminal. The Drosophila gene is equally related to each of the human family members. Amino acids 249-318 of the fly protein share a striking homology with DNA-binding domains of the human E2F genes. In addition, a region termed the "marked box" is highly conserved. This domain may function in protein dimerization. The C-terminal Rb-binding domain has also been largely conserved in the fly protein, sharing 56% similarity to the human proteins (Dynlacht, 1994 and Ohtani, 1994).
date revised: 2 December 2018
Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.
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Wednesday, September 6, 2017
God's Will For Your Life
"God's will for your life is not very complicated. Obviously, living a Christlike life is hard work, and what following Jesus entails is not clear in every situation. But as an overarching principle, the will of God for your life is pretty straightforward: Be holy like Jesus, by the power of the Spirit, for the glory of God." ~ Kevin DeYoung, "Just Do Something"
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A member of an alien species is being interrogated and tortured by a machine.
"Caught in a large-scale and endless war, the sophisticated and utterly unstoppable machines seem to be winning the battle against their adversaries: a proud alien species. As a result, a technologically perfect robot interrogates a captive alien with the intention to locate the rest of his race's survivors, pressing on with more and more unrelenting and horrible tortures. But the alien knows that he holds his species' last chance of survival and he won't go down without a fight." Written by Nick Riganas
Written – directed – animated by Kaleb Lechowski (C) Kaleb Lechowski
Hartmut Zeller – Sound
Dave Masterson – Voice acting
IMDb: http://www.imdb.com/title/tt2624672/
Scott Glassgold / IAM Entertainment – Representation
This description is from the short film's original source, which can be found here: R´ha


text:
Kevin R. Carey
Kevin R. Carey
Kevin R. Carey is a Senior Managing Director with the Fixed Income Group at First Republic Investment Management.
Mr. Carey joined First Republic Investment Management in 2012. In his role he specializes in the design and management of income-oriented portfolios for Ultra-High Net Worth individuals, Institutions, Trusts, Endowments and Foundations. Mr. Carey is a member of the firm's Asset Allocation Committee, Alternative Investment and Fixed Income Strategy team.
Prior to joining First Republic, he was a Managing Director and head of the Fixed Income Group at Deutsche Bank, formerly Banker's Trust. Mr. Carey's most recent roles at Deutsche Bank were Chair of the Fixed Income Strategy group and a member of the domestic and global Investment Strategy Group. He began his career with the firm in the capital markets and funding area. Mr. Carey moved to the Private Banking division of Banker's Trust and later went on to become a Portfolio Manager in the Fixed Income group, which he went on to lead.
Mr. Carey earned his BBA in Finance and an MBA from Pace University.
Wealth Management Experience: Since 1989
Check the background of this investment professional on FINRA's BrokerCheck.


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The Room
Why bother paying a tenner to see a decent film when you can sit in the comfort of your living room and snark at a really, really terrible one? "American" director and actor Tommy Wiseau is the perpetrator of The Room, a crime against acting and cinematography. YouTube it, and prepare for "I DID NAAAAAAAAAAT" to be your new catchphrase.
Dum dum di da dum dum di dum dum… Observia! That's how the national anthem of Observia – a new independent state deep in the heart of Student Centre territory – goes. We've finally declared independence from the tyrannical Students' Union, hurrah! But we're still a welfare state, of course, since we have no weather and our only natural resource is snark.
It's a restaurant where all the main courses cost a tenner! See what they did there? With the punning? Yes. Not only is it a lovely, spacious restaurant in nearby Donnybrook, but the food is delicious and only a tenner. Go, eat, come home without that horrible I-shouldn't-be-eating-out-in-a-recession guilt.
RIP Bebo
Yes, it's where we all cut our social networking teeth; but have you looked at it lately? It's a graveyard littered with embarrassing old photos, flashing backgrounds, 'luv'; and home to the functionally illiterate. Burn it. Burn it to the ground. And let's work on making sure Facebook doesn't make the same mistakes.
The disclaimer says "do NOT watch this video if you are under 18". We'd amend that to do not watch this video if you have eyes. Especially if you have eyes and you've just had lunch. It's the new Two Girls One Cup, and we at otwo are simply baffled as to why people continue to make this shit. Pun very much intended.
We wuz robbed. The Observer's fantastical Fantasy Girls have not been nominated for a Student Media Award in the blogging category. Infamy! Blasphemy! Fix! No fairsies! Clearly our ditzy, girlish, sometimes drunken ramblings about things we don't know an awful lot about are more deserving of Smedia glory than well-thought-out posts about serious stuff, and stuff. Boo-urns.
Ads on YouTube
The most annoying thing on the internet since RickRolling, YouTube channels are now showing non-skippable ads in front of certain videos. Why, YouTube, why? The reason we look things up there is so we can skip the boring bits and get straight to the good stuff – not look at ads for products that aren't even available in Ireland. Sort it out.
Issue 12
And now, the end is near, and so we face the final curtain… sniffle, sob and crysies, Volume 16 is coming to a close. No longer will this writer be able to dispense the wisdom of what is hot and what is not to eager ears, shaping the coolness of a future generation. And no longer will this writer receive snarky texts, emails and glares from the editorial team when articles are many, many days late.


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GERALD EVE STRENGTHENS MANCHESTER PLANNING and DEVELOPMENT TEAM
Leading property consultancy Gerald Eve has strengthened its national planning and development team with the recruitment of Thomas Relph as a senior planning consultant at the firm's Manchester office.
Thomas graduated from Sheffield University in 2010 with an MPlan in Town and Regional Planning and is a Member of the Royal Town Planning Institute. He arrives from the Manchester office of Nexus Planning, where he advised clients including Countryside Properties, Infrared Partners and UK Power Reserve.
He joins Gerald Eve's national planning and development team – which has now grown to more than 80 people – with current clients and projects including: Jaguar Land Rover, Redrow Homes and Hiscox. Thomas is the twelfth new recruit to Gerald Eve's Manchester office in the past year, bringing the number of employees based there to 27 across eight departments offering planning, development, investment, agency, rating, valuation, building consultancy and corporate advisory expertise.
Harry Spawton, partner at Gerald Eve, said: "Thomas' arrival underlines not just the ambitions for the firm's national planning and development team, but also the increasingly strong nature of the regional development market. He brings with him a host of specialist experience and further strengthens our market-leading team, helping Gerald Eve offer clients an even better level of service."
Thomas can be contacted via email (email@example.com) or at Gerald Eve's Manchester office.


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Now that we have celebrated the first days of Passover, let's revisit the story of Exodus with Rabbi Dr. Paul Shrell-Fox, Looking at the events of the Exodus and our knowledge of Egyptian deities, God's role as described in the Haggadah and around the seder table takes on new meaning.
How Can One Sell Hametz Which is in a Different Time Zone? Responsa in a Moment: Vol. 12, No. 3, March 2018
Question from a rabbi in Jerusalem: I am taking care of "Reuven"'s apartment in Jerusalem, but "Reuven" lives in New York. Reuven asked me to sell his hametz to a non-Jew. But Pesah in Israel ends 31 hours before it ends in New York – a seven-hour time difference plus an additional day of Yom Tov Sheni (the additional day of the Festival in the Diaspora). In other words, the hametz will revert to his possession in Jerusalem when it is still Pesah in New York. How, then, can I sell his hametz?
Are you Ready to Leave Egypt? Rabbi Professor David Golinkin Takes the Passover Stage
Lights Camera Action! Drama doesn't just take place in the movies, on Passover we remember that we too were brought out of Egypt. In preparation for your own seder Rabbi Professor David Golinkin, President of The Schechter Institutes, tells of the custom of reenacting the story of the Exodus and offers a way of bringing the drama to your own seder.
Rav or Rabbah: Choosing Titles in the Rabbinate
Midrash Sifre teaches that the Israelites left Egypt with Miriam at their lead: "when you left Egypt": the time of your redemption, the tribes traveled only when Miriam preceded them (Sifre Deut. 275). She is one of the important women in the Passover story. In her essay, Rabbi Sara Cohen, ordained in 2017 by the Schechter Rabbinical Seminary discussed the different titles Israeli women take on when they become rabbis.
Passover for the Soul Bringing spirituality to our seder celebration
Israelis celebrate Passover in one of two ways: either by closely sticking to laws of Pesach related to hametz and the Seder, or by hiking in nature and joining family for a relaxed festive meal. This year experience the family Seder meal as a celebration of a new beginning, and find personal meaning in the story of Exodus from Egypt.
The Drama of the Seder What a Pesah Custom Can Teach Us about Jewish Education Today
Bringing the Seder to life- there is one custom which is very common today among Jews from Islamic lands, which uses drama in order to arouse the interest of children and bring the Exodus to life.
Why do we spill 16 drops of wine while reciting the Ten Plagues during the Seder? Responsa in a Moment: Volume 10, Issue No. 6, April 2016
In addition to providing the origin of this specific custom, I will give the sources for the custom of sprinkling or spilling drops of wine while reciting the Ten Plagues, the reasons that have been given for the custom, and the various permutations of the custom.
The Book of Chronicles and the Ephraimites that Never Went to Egypt
Did the story of the exodus really happen? Did the entire Israelite people suffer slavery in Egypt before arriving in the land of Canaan? Many historians question this. They point to the lack of solid archeological evidence. More traditional scholars argue that the lack of evidence is an argument from silence. It is only natural that the Egyptian kings and scribes would fail to document the humiliating story of the Israelite rebellion and exodus. There is, however, a third alternative to the question of the exodus' historicity.
Visual Midrash on the Parting of the Red Sea: Parashah Beshalach
The splitting of the Red Sea and the Children of Israel's rescue from Egypt in Exodus 13-16 is the climax and conclusion of the long episode of the Exodus from Egypt that starts in Exodus 4. The Children of Israel's escape from the Egyptians is described as a double miracle – God "split" the sea to enable the Children of Israel to cross it and then brought the waters down to finish off the Egyptians. The Children of Israel are commanded to observe this double miracle in order to testify to future generations about the Divine salvation they were privileged to experience. They respond to the event by singing the "Song of the Sea", which expresses the greatness of the miracle, the survivors' joy and the praise for God in their hearts. Jewish, Christian and Muslim artists throughout history dealt with the splitting of the Red Sea. The great interest in this episode surely stems from its inherent drama and visual elements. But as we will see below, artists interpret the event very differently emphasizing various themes.
The Circle of the Seder Plate; The Cycle of Our Fortunes
When recalling my Jewish childhood, the first memory that comes to mind is from Seder night – the immaculate house, the set table covered with a white tablecloth, the taste of the holiday foods, and primarily the feeling of contentment after long days of hard work and preparation. The stars of the evening were the children, for whom the Seder was fashioned as a unique and fascinating experience, engaging all of the senses in order to allow us to absorb both the explicit and hidden messages of the Haggadah. The telling of the story was led by my grandfather, who would stand and hold the full Seder plate over the heads of the participants, as a symbol of abundance, blessings and success, while those seated would sing with great fervor, "This is the bread of our affliction… all who are hungry may come and eat…next year we shall be free."


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I have stopped pretending to know what I don't. Instead, I tell people: "I'm sorry, I don't know. Why don't you try Google?"
I have learned that some lessons in life will cost you your time, money and emotion. That would include lending money to people and never getting it back, or making a wrong move at your workplace.
I finally recognized that it's okay to ask for help. Because there are plenty of generous people around to help you too.
I know that I need to be fair to myself, instead of being constantly bullied into doing things I don't wish to do.
Letting go is really one of the ways to resolve a naggling problem.
Stick around with your friends. Thick and Thin. Point out to them where they have went wrong, no matter how much it'll hurt them.
Honesty is still the best policy. Because lying and coming up with the lies to cover up the previous lie is seriously exhausting.
Defend anything you love. Your chosen set of best friends. Your favourite band. Your parents. Of course, defend reasonably. Like "I love the Red Hot Chili Peppers, but I think some of their lyrics is crap."
I have oily scalp. My hair needs constant wash. At least twice a day. Without a wash, I look like I haven't bathe in days.
Be adventurous. Audrey and I hopped on a cab in Johor Bahru, and we met the nicest Taxi Driver whom gave a jumpstart guide to the place. Going to JB might be nothing to some of you, but well, it's somewhere to start, right?
Love your parents. Just because.
See through all your projects. Work wise, personal projects. The feeling after you finish is shiok lah.
Prove to people who don't believe in you that you can do it. Also shiok feeling lah.
It's a superficial world. Look presentable.
It's okay to point out to your boss where they have went wrong. Because they are human after all.
Saturday, December 26, 2009
Some lessons I've learnt.
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More Celebrity News ►►
After taking a three month hiatus from the public to focus on her health and well being, Selena Gomez has returned to social media with her Wizards of Waverly Place co-star David Henrie.
As if Selena's social media return isn't already exciting enough, add in the fact that she was hanging out with David Henrie talking about a possible Wizards of Waverly Place reunion!
Alex and Justin Russo reunited on Selena's instagram and if you were a Wizards of Waverly Place fan back in the day, knowing that Selena and David are still friends is magical. Pun intended. Selena created her first ever instagram story with Henrie while dreaming about a Wizards of Waverly Place reunion and Henrie jokingly claiming that he founded Selena's social media presence.
Selena and Henrie joked about what their characters on Wizards of Waverly Place would be up to all these years later and decided that Justin definitely would have about 15 children by now, Alex is single, trying to figure things out and killing it, while their little brother Max is lucky if he even found himself. Henrie added that Max is literally lost and for sure just making sandwiches on the street because the family restaurant went out of business. Selena proceeded to ask her followers if they would be down for a Wizard's reunion, adding that she thinks they should do it! Henrie posted a photo of his adorable reunion with Selena on instagram saying QUOTE – "We had the best time last night. We dreamed up what our wizards characters are doing present day lol, and talked about the fact that I started all of @selenagomez social media platforms."
Selena also posted two instagram pics that many are suspecting may be teasing at the new music she is said to be creating with Paulina Rubio seeing as though she captioned the photo, "come over here" which is the title of Ricky Martin's single. So lots of exciting potential projects to look forward to.
But I want to hear what you guys think about a possible Wizards of Waverly Place reunion. Sound off in the comment section below and then once you're done with that, click right over here for a winners recap of the Golden Globes. Thanks for watching Clevver News, I'm your host Jackie Iadonisi and I'll see you next time.
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The news that legendary actor Tom Hanks would be playing Fred Rogers in a biopic about the esteemed host of 'Mister Rogers' Neighborhood' reminded me of something.
Do you remember when we were kids and there was a rumor that Mr. Rogers was an insane Vietnam Vet who had killed hundreds of people in the war and was covered in tattoos? That's why he had to wear the sweaters.
Well, it turns out it's not true. Or at least Wikipedia says it's not. The fucking internet strikes again and ruins a perfectly good urban legend.


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Zyloware Eyeglasses: Zyloware Eyewear is one of the world's largest makers of eyeglasses and sunglasses. Zyloware makes eyeglasses and sunglasses for Stetson and many other of the top eyewear labels. Zyloware also makes a full line of "house" eyeglasses models, under several names like "Zyloware" Eyeglasses and others.
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text: Last night my school had it's annual Halloween dance, which I don't normally dress up for, but decided that it would be more fun if I put together a fun costume. I bought this psychedelic dress from Goodwill for $5 and I already had the shoes. I found some fake eyelashes for a few bucks, used a TON of hairspray...and voila! A cute mod 60's look for under $10! What's even better? I won a category for the costume contest and got an iTunes gift card for $10! My Halloween trick-putting together a cheap costume that looked pricier than it was...my Halloween treat-relaxing on the night of Halloween and buying songs from Uffie, Lissy Trullie, Goldfrapp, Anjulie, Kate Earl, and Lucy Schwartz!


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£6,460,000 to spend
There already has been much said about the news that MPs have awarded themselves £10,000 to spend improving the public understanding of parliament. MySociety have added to the noise with a very sound request for MPs to sign a pledge on Pledgebank saying they will give £2,000 of the allowance to a competition pot to be spent on joint tools. As the cost of selling is such a large part of the cost of projects like I'm a Councillor, I think this approach could be beneficial and I hope a MP kicks it all off very soon. A link to the pledge will hopefully follow.


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Local Information: Castletroy, Co. Limerick
Great National Kilmurry Lodge Hotel is a 5-minute walk from the University of Limerick and the National Technological Park, Castletroy, just 10 minutes from Limerick's vibrant city centre.
Note: Map is an approximate indication ONLY. Please contact Kilmurry Lodge Hotel for directions and precise location prior to your visit.


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Journalists, explore this publication-ready project. Create a free v2com media account to download high-resolution images.Create a media account
Press Kit | no. 990-04
Press release only in English
KAYIWA, the inventor of the diamond-shaped glassware that has been copied the world over, continues to push boundaries with the introduction of CARAT light fixtures. These new pendant lamps serve more than their functional purpose and move into artistic territory.
"Lighting can change the entire ambience of a room, not just by providing the appropriate light," says designer/artist Lincoln Kayiwa. "The right fixtures can create the perfect fusion of functionality and style, even when they are turned off."
So whether it's on or off, the CARAT pendant lamp is always eye candy. It makes a minimalistic yet powerful impression when installed, either singly or grouped together.
Endless possibilities
Each piece has a transformative quality. Through variations in size, color and configuration, the collection can solve any number of aesthetic and functional needs for residential, hospitality, and contract settings.
CARAT lamps can be selected to match or accent the overall décor in any room. In addition to the classic De Stijl colors, the glass shades are obtainable in various hues, the ceiling roses exist in three color options, and the textile cable cords are available in various colors as well as patterns, all of which customers can select online.
Nevertheless, under our customized service, we can design and produce individual options tailor-made for specific needs, which offers a multitude of possibilities for designers, architects and anyone with a personal vision for exceptional lighting.
This includes, but is not limited to, longer textile cord length, other textile cord color and pattern options, custom glass shade hues, or integrating the Casambi Technologies' lighting control solution.
The fixtures are suitable for indoor use in most countries. The standard light source for all the CARAT luminaire models is a custom-designed 6 W, 400-lumen LED, with a color temperature of 4000 K. However, in addition to other features, it is possible to vary the light color temperature or lumens, as well as dim the light to create the perfect lighting for any application, with an optional Casambi lighting control system – using a smartphone, tablet or smartwatch – or even by good, old fashioned wall switches.
Traditional craftsmanship, modern design and technology
Just like its CARAT barware cousins, the light fixtures are created with skilled craftsmanship and a respectful use of materials. Passing through a total of seven craftsmen and taking hours to create and perfect, each piece in the collection is one-of-a-kind.
The CARAT pendant lamp collection's unique approach to the materials creates a contemporary, sculptural and visually stimulating concept that fuses both aesthetics and practicality into a distinctive creation. For instance, the diamond-faceted glass is sandblasted and brushed with pumice, creating an extraordinary texture that diffuses the light into a soft glow.
Moreover, the pendant lamps incorporate a silicone ceiling rose that adapts to any type of ceiling – horizontal or inclined. The soft plastic folds up against the ceiling to fit snugly and achieve perfect results. Further still, it being malleable makes it possible to turn inside out, which allows full view of cables and fittings, to make it easier to mount the lamps.
This sustainable, environmentally friendly LED lighting will last for over 50,000 hours, but KAYIWA even turns it up a whole notch by offering a lifetime warranty, as these collectible pieces are new classics that will last a lifetime.
About KAYIWA
KAYIWA's portfolio is diverse – ranging from furniture to housewares. With a witty yet elegant disregard for convention, the studio's collectibles are exquisite sculptures in their own right. At the same time, KAYIWA is passionate about fusing art with design to create functional solutions for everyday needs. The resulting limited edition objets d'art are genuine collectors' items, which continue to appreciate in value over time.
For our most discerning clientele, KAYIWA offers customized service. All the existing works may be commissioned in a range of colors, sizes, material and finishes to create personalized, one-off pieces. Likewise, our atelier can also make a completely new creation made to the client's exact specifications.
KAYIWA's Finnish-Ugandan designer/artist borrows principles and aesthetic elements from the rich cultures and traditions of African and Nordic art, craft and design. His creations acquire a story and become a heritage to pass down to the next generation.
Each artifact balances the latest technology with the best of artisan skill. All the works are realized with very high standards, and we guarantee that they will perform well for many years. Accordingly, we warranty all our collectibles against manufacturing defects in material and workmanship for a minimum period of 10 years.
About Designer/Artist Lincoln Kayiwa
Lincoln Kayiwa was born in 1979 into an architectural family in Kampala, Uganda. He graduated as a Master of Arts from the Aalto University School of Arts, Design and Architecture in Helsinki, Finland in 2007. Upon graduating, he founded his own studio, KAYIWA.
Kayiwa's Ugandan roots and Nordic life blend into a unique approach. He shows us that design can be bold and playful, yet still aesthetic, fully functional and durable. His uncompromising, innovative works make Lincoln Kayiwa a pioneer in creating limited edition, usable art pieces for collectors and galleries across the world.
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When it comes to making an impact in the lives of the students and communities we serve, we wouldn't be able to do it without the dedication and devotion of our City Year AmeriCorps members.
Our Benefits
As you make measurable impact in the lives of the students and communities we serve, we aim to provide a transformative experience for our City Year AmeriCorps Members. During your time with us, you'll be compensated with financial benefits, like total compensation for your service, as well as with life skills that will help you well beyond your year with us.
"Ms. Monisha, you made learning English easier for me to understand this year!" #sadgoodbyes #makebetterhappen #sweeps @Staples @CityYear


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Anglo trial: In quotes
A round-up of quotes from the Anglo trial
- "A lot of people if they were on holidays and saw their bank manager might head for the nearest sand dune," Prosecuting counsel Paul O'Higgins SC on how one of the Maple 10 was in Nice, France when approached by Anglo officials about the deal.
- "He told me that you will probably make no money in this transaction, but you will be a friend to the bank." Maple 10 Brian O'Farrell on Drumm's selling him the loan for shares deal.
- "If the bank went, I went." - Maple 10 borrower Brian O'Farrell on his motivation for helping Anglo.
- "Sean Quinn needed to be reined in" - Mr Quinn referring to himself in the third person regarding the CFD position he had built up.
- "I was at home looking after the children, I have no involvement with anything here, I'm sorry." - Patricia Quinn when asked what she knew about the lending.
- "It was one of those moments you will never forget in your life." – Former Anglo Divisional Director of Lending Michael O'Sullivan on hearing about the extent of Mr Quinn's control of Anglo.
- "I saw it very vividly. The problem was we had a loose cannon that had invested for the purpose of a financial gamble," Anglo director Michael Jacob on Mr Quinn's CFDs.
- "I was never in his house, he was never in my house, we never socialised together." Mr FitzPatrick on his relationship with Mr Drumm.
- "If I tried to run the show with senior executives there would be absolute disharmony, murder and divided loyalty and they would be telling me to bugger off," Mr FitzPatrick on letting Mr Drumm assume power as the bank's new CEO.
- "He asked, as if talking out loud, 'I wonder was that the right transaction to do', specifically in respect of the recourse to the ten borrowers," Anglo Chief Financial Officer Matt Moran describes what Sean FitzPatrick said to him after the Maple Ten went through.
- Matt, I spoke to Willie about moving the game forward tomorrow with a select group of clients - he will brief you. Time for Action". Email from Mr Drumm to Mr Moran July 8, 2008 regarding on Maple plan
- "I could have signed off on them but I could also have been on holidays." - William McAteer when asked if he approved the July 2008 loans.
- "Mr Quinn was entitled as a private citizen to have all the investments he wanted to have. I respect that and I did not feel it would be fair or appropriate for me to tackle a person about his own investment portfolio." – Former Financial Regulator Patrick Neary on why he did not question Mr Quinn about his control of Anglo.
- "I also take the view that the Financial Regulator took no steps to discourage the scheme or in anyway stop it. And it seems from regulator witnesses that they were somewhat relieved when the scheme went through and that the CFD issue was alleviated and regularised." – Judge Nolan's view on the role of the regulator.
Online Editors


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We supply your razor blades on a subscription. This means every month you will receive a new set of razor cartridges to refresh your blade arsenal. We deliver to your home right away so you need not worry about forgetting your refills, we sort out the remembering for you. All you need to do is sit back are relax to know that all your needs are taken cared.
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Cancelling your subscription is easy. You may cancel it by visiting your account page or just email us at email@example.com
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Unfortunate no, you would have to go through the whole process again. Its not that difficult anyways.
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