text:
Q: Reset total sum if input changes with jquery change event I have a list of inputs that i'll be using to set values (0 to 100).
The total values from those inputs can't be more than 100, i have this done and it's working, but i need a way to subtract the total if i change one of those inputs and the total becomes < 100
Here's one example for what i have so far:
var soma_total = 0;
jQuery(function($){
    $('input[type=text]').each(function () {
        $(this).change(function(){

        var valor = $(this).val();
        valorPorcentagem = valor;
            eE = procPorcentagem(valorPorcentagem);

            eE = Math.ceil(eE);

            valorPorcentagem = parseInt(valorPorcentagem);

            if((parseInt(valorPorcentagem) + soma_total) > 100)
                valorPorcentagem = 100 - soma_total;
                $(this).val(valorPorcentagem);
                soma_total += valorPorcentagem;
console.log(soma_total);
                $('#final_sum').append('
'+soma_total+'
');

        });
    });
});

function procPorcentagem(entradaUsuario){
var resultadoPorcem = (entradaUsuario * 48) / 100;
return resultadoPorcem;
}

JSFiddle
Help please, thanks!

A: This demo might give you an idea on how to proceed:

$(function() {
    $(':text').val(0).on('change', function(e) {
        var i = $(':text'),
            total = 0;
        i.each(function() {
            total += +this.value;
        });
        if( total > 100 ) {
            this.value -= (total - 100);
        }
        total = 0;
        i.each(function() {
            total += +this.value;
        });
        $('#final_sum').text( total );
    });
});

<input type="text">
    <input type="text">
        <input type="text">

0

redpajama_set_name: RedPajamaStackExchange


Welcome to the IslandWood Garden!: Our Garden Blog has a new home!
Our Garden Blog has a new home!
Welcome! Our blog has a new "home" and a new address. You can now find Soil to Snack recipes, pictures, garden activities and more at the Blog section of the IslandWood Home page. Please let us re-direct you. Click Here to go to the new Blog.
And if you have any questions or comments, feel free to leave a comment here (I still monitor this page), or on our new blog page under the "comments" section. We love to hear from you!


A child's personality is affected by his/her choice of colour. A number of researches have been conducted to know the relation between one's behavioural traits and colour preferences. It has been found that colours strongly reflect upon the child's personality.
Knowing about your child's personality can be an added tool to enhance your parenting abilities. All parents wish to see their child realize his/her capabilities completely and become successful in life. Parents tend to experiment with many tricks that can help their child in his/her development. In this regard, if you know about the true colours of your child, you can definitely fare better as a parent.
Here we are going to discuss several colours and how they influence a child's overall persona.
Red: The inclination for the bright, lively red colour indicates that the child has a similar personality. The child wants to live fully and is quite extrovert. Other traits include being impulsive, furious, and aggressive. The child is moody and hates boredom and monotony.
Yellow: Yellow indicates calmness and consistency. These children are thoughtful and insist on planning before taking any action. They have great expectations but often do not carry them out due to lack of enthusiasm at a later stage. However, the child has a sharp mind.
Orange: The children that prefer orange colour are quite social and make friends easily. They are good- natured and have amicable terms with many. They prefer friendship in many relationships and also have great leadership traits. Such children can have a bright future in politics.
Green: Green is the colour of balance. These children often do not like major changes. They are sensible and like their privacy and freedom. They give importance to social reputation and respect from others over other issues. Hence it is important to be polite with such kids. Also, they have a fun side and like to party and eat. However, such children can be very possessive and jealous at times too.
Blue: Kids liking blue are generally introvert and calm. These kids want to be organized and neat. They are hard workers and put thought into what they are doing. Also, they tend to have a strong hold over their emotions and can be opinionated. They are good at handling responsibilities but do not trust others easily.
Purple: All people, in general, liking purple are said to have a mysterious personality. They are sensitive and temperamental. Often, such kids are found to be very creative and imaginative. They like to do meaningful things, and have great passion. Some of them can have a deep appreciation for art and become artists themselves when they grow up.
Indigo: Indigo indicates that the child is equally creative and disciplined. He/she also has good powers of intuition and is very sensible.
Brown: Brown is the colour of earth. Hence it indicates stability and support. Such kids are rational and sensible. They are determined in their approach and can be stubborn sometimes. They are careful in whatever they do, although their brain is not very quick.
Pink: Pink is generally considered a girly colour. However, contrary to popular belief, it is not so. Pink can be considered similar to red. It indicates affection and love. These kids should be treated with care and affection at all times. They tend to have the innocence of childhood at all times.
Based on the following analysis, you can judge your child better. Treat him/her accordingly and your child is surely going to benefit in the long run from your treatment. Your parenting tactics can encourage your child to become what he/she is truly capable of doing.


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Whether you need a tune-up, a flat repair or a bike overhaul, we're here to do the job right for you.


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Our America: A Photographic History
Ken Burns, with Susanna Steisel et al. Knopf, $60 (352p) ISBN 978-0-385-35301-4
Documentarian Burns (Country Music: An Illustrated History) presents a stunning collection of photographs chronicling American history from 1839 to 2019. In the book's intimate introduction, Burns traces the roots of his "life's calling" to seeing his father cry for the first time while watching a movie after his mother's death from cancer ("I understand instantly the power of film and the safe harbor it permitted him to have"), and explains the camera movements he uses to bring still photographs to life in his documentaries. The black-and-white photographs are presented one per page and captioned only with the date and location, fostering the viewer's deep engagement with each image. (Comprehensive illustration notes appear at the end of the book.) It's a powerful and moving collection, ranging from the obscure (a 1903 photo of the first Japanese American baseball team in the mainland U.S.) to the famous (Robert Frank's 1955 image of passengers on a segregated trolley in New Orleans). Celebrity faces—Charlie Chaplin, Mark Twain, Johnny Cash—appear in unguarded moments, alongside natural wonders—Niagara Falls, Yellowstone National Park, Bryce Canyon—and evidence of racial violence, including a formerly enslaved man's scarred back and the aftermath of the 1911 lynching of an Oklahoma mother and her son. Visually arresting and expertly curated, this is a must-have for fans of Burns's documentaries. (Oct.)
The Vietnam War: An Intimate History
Geoffrey C. Ward, Ken Burns
This lavishly illustrated large-format book from frequent collaborators Ward and Burns (The Roosevelts) serves as the companion volume to the eponymous 18-hour, 10-part PBS documentary from Continue reading »
Emmy Award–winning filmmaker Burns continues his tradition of narrating the audio abridgment of his documentary work, as he has done before with The Civil War, The National Parks, Continue reading »
Country Music: An Illustrated History
Ken Burns, Dayton Duncan
This voluminous and hugely entertaining introduction to country music coincides with the release of the eponymous PBS series, by producer and writer Duncan (Out West) and producer and Continue reading »
Featured Nonfiction Reviews
Benjamin Banneker and Us: Eleven Generations of an American Family
Rachel Webster
Poet Webster (Mary Is a River) offers a stunning meditation on race, identity, and achievement. At a family reunion in 2016, Webster, who is white, discovered that she was Continue reading »
Flight Paths: How a Passionate and Quirky Group of Pioneering Scientists Solved the Mystery of Bird Migration
Rebecca Heisman
Science writer Heisman debuts with a winning examination of the seasonal movements of birds, tracing how scientific understanding of bird migration has evolved and detailing the Continue reading »
Ghosts of the Orphanage: A Story of Mysterious Deaths, a Conspiracy of Silence, and a Search for Justice
Christine Kenneally
Journalist Kenneally (The Invisible History of the Human Race) paints a beyond disturbing picture of human cruelty in this shocking exposé of decades of abuse of children housed Continue reading »
Weathering: The Extraordinary Stress of Ordinary Life in an Unjust Society
Arline T Geronimus
Neither genetic differences nor unhealthy lifestyles are at the root of racial health disparities in the U.S., according to this powerhouse study. Geronimus, a professor of Continue reading »

redpajama_set_name: RedPajamaCommonCrawl


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So simply do a brainstorming session and make your kids bedroom attention-grabbing and colorful. Use shiny and interesting colors in your kids bedroom as it will make the environment lively and cozy. They'll easily make use of the minimalist design. You can also have a look at just a few house design and plan, for some inspiration. An on-site designer creates your room's design idea, which includes a space plan, coloration palette and product suggestions. A web based designer usually doesn't prepare architectural drawings that require exact on-site measuring. A web-based designer guides you in conducting your own inventory, measuring and images, which you then submit, usually via e-mail. If you're looking for contemporary home designs particularly designed for fashion and performance, then choosing Minimalist home designs and plans is right for you. But in relation to your kids room then you definately need to be further cautious as your kids bedroom design ought to go effectively with the likes and dislikes of your baby.
It pays attention to the cleanliness of the joints of the walls as well. With the deluge of DIY shelter magazines, house-decorating Tv, and easy online entry to home furnishings, it was solely a matter of time before the interior design business could be pressured to evolve as effectively. An internet designer means that you can take your mission at your personal pace, implementing your purchasing and set up as your finances and time enable. An on-site designer implements and coordinates the buying and installation course of, with bespoke, antique and/or customized To-The-Trade objects not out there to the general public. An on-site designer helps you outline your needs, preferences and price range via on-site consultations. An internet designer does the same by way of a questionnaire, phone consultations and in some instances, companies corresponding to Skype. A web based designer does the identical. An on-site designer sets the pace for the buying and set up course of. An online designer guides you in implementing the buying and installation of products from properly-established online-retailers and, in some circumstances, purchases To-The-Trade gadgets directly for you.
An on-site designer inventories, measures and images your area. An on-site designer prepares interior architectural drawings for the development of the space and or constructed-ins. You'll be capable of make full use of all of the space. That is great for house design with restricted area area. Bright colours like crimson, yellow and orange provide an fascinating and aesthetically pleasing contrast to the overall design of the home. While decorating your youngsters bedroom due consideration ought to be given to all side like bedding, wall colour, decor and other. If you are on a slim funds, don't thoughts doing somewhat leg-work, and like initiating new projects by yourself, consider e-Decorating services. Wondering how e-Decorating works? You'll be able to take a look at their numerous home designs and plans to see which one works for you. You may also paint the room with blue sky, rainbows and birds which is not going to only look engaging but will even give a soothing feeling. It makes use of unpolluted, geometric strains to create a sleek look. It makes use of only prime quality lights, as a result of the concept is to create a easy effect.
That is to additional create a simple impact. They normally take the type of vases, artworks, or simple pieces of show furniture. Besides wall decor and paint the furnishings and accessories also plays a significant position while designing your youngsters bedroom. The theme will additional make it easier to to determine upon the wall decor and accessories used within the room. An interesting theme will provide help to to make your kid's room attractive and colorful. You may simply get your dream minimalist house and land bundle with the assistance of a very good, dependable residence builder. They will design properties for you in any fashion you want. You'll be able to paint the room with varied photos of plants, animals, flowers and other objects. The wall paint color also plays a serious position within the decoration of your kids room. Each and every room of your private home is undoubtedly very important and desires special care and a focus in its decoration.
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Below are 25 best pictures collection of leather sofa design ideas photo in high resolution. Click the image for larger image size and more details.


Before the era of top ten listicles, marketing labels and the best-of-genre trailers, these films were seen and circulated within the cinephile world as examples of "great (art) films," not "great science fiction films."What apocalypse stories tend to share is a theme of faith: what it is to have it, what it is to lose it, and how the object of that faith is both constructed and reconstructed in a changing environment.The first book enchanted with under-explored glimpses of otter islands and hints of Earth origins; this volume continues to offer glimmers of recognition coupled with enough strangeness and unanswered questions to keep readers invested.
Both Danielewski's fans do and his professional critics consider his work as a particularly intricate key with eyes toward a potential lock; the frame, instead, allows us to situate it on a keyring, and go from there.


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Republicans in Disarray
Shane Goldmacher writes in the New York Times:
While all parties go through reckonings after losing power, the G.O.P. has lost the popular vote in seven of the last eight presidential elections and, for the first time since Herbert Hoover, ceded the White House, Senate and House in a single term.
That's got to hurt.
I have no doubt Republicans are already looking to take Congress back in the midterms. Dems hold the houses by a hair, and the president's party usually loses seats in midterm elections. Even so, I bet the Republican establishment right now wishes it had never heard the name "Donald Trump."
The base, however, may not let them forget.
But the most acute danger for the health of the party, and its electoral prospects to retake the House and Senate in 2022, is the growing chasm between the pro-Trump voter base and the many Republican leaders and strategists who want to reorient for a post-Trump era.
"Have you heard what some of these folks waving MAGA flags are saying about Republicans?" said Representative Peter Meijer, Republican of Michigan, whose first days in Congress this month were marked by evacuations to escape from a mob. "They don't identify themselves as Republicans." …
… Some party leaders fret that as of now, they cannot win with Mr. Trump, and they cannot win without him. Right-wing voters have signaled that they will abandon the party if it turns on Mr. Trump, and more traditional Republicans will sour if it sticks by him.
It's obvious to me that the Republican Party would be best off in the long run if it let Trumpism go and resigned itself to being in the wilderness for awhile. For one, the big donors have turned against Trumpism. It's possible they would return in time, but for now they are clearly signalling they want the pre-Trump GOP back.
It's also the case that the Trump base has revealed itself to be a tad, um, unstable, and not necessarily interested in the serious issue of protecting the wealth of the wealthy, which has been dear to the hearts of Republicans since McKinley. The GOP has long had to pull the scam of firing up the base with culture war issues — fighting racial integration, women's lib, affirmative action, gay marriage, etc. — and pushing different issues in government policies — deregulation; tax cuts for the wealthy. But QAnon is like an alien life form that keeps mutating out of control. There is no guarantee that it won't work against the Republican Party in the future.
Paul Krugman:
… it would be a foolhardy prophet indeed who looked at the Jan. 6 riot at the Capitol and assumed that this time, under this pressure, the conservative coalition will finally break apart, sending the Republican Party deep into the wilderness and reshaping American ideological debates along new lines.
But breaking points do come, and the violent endgame of the Trump presidency has exposed a new divide in the conservative coalition — not a normal ideological division or an argument about strategy or tactics, but a split between reality and fantasy that may be uniquely hard for either self-interest or statesmanship to bridge.
The other problem for Republicans is that while it might be best for the party to move away from Trumpism, a whole lot of individual elected officials owe their relatively new careers to Trumpism. Will the likes of Josh Hawley or Marjorie Taylor Greene be willing to step away from the brink?
Of course, I'm also hoping that Democrats will use its majority to jump on election reform, and fast. No more voter suppression. And if they can do something about political gerrymandering that would be peachy.
It's also the case that we haven't yet gone through all of the fallout from the January 6 insurrection. Facts are still coming out. Today we learned that the FBI was given a stark warning about what would happen —
A day before rioters stormed Congress, an FBI office in Virginia issued an explicit internal warning that extremists were preparing to travel to Washington to commit violence and "war," according to an internal document reviewed by The Washington Post that contradicts a senior official's declaration the bureau had no intelligence indicating anyone at last week's pro-Trump protest planned to do harm.
Yet, obviously, preparations were not made. Requests for National Guard were denied six times while the riot was happening. It appears that people in the Pentagon and in Homeland Security made a deliberate decision to let the insurrection take place. Possibly that's not true, but that's what it looks like. We need to know. It's all still very muddy right now.
And there could still be more violence from Trump supporters, which would dig the hole for Republicans much deeper.
Oh, and Chad Wolf resigned in the middle of overseeing security for the inauguration. Way to go.
But back to the Republicans — This afternoon, the New York Times published a story by Jonathan Martin and Maggie Haberman saying that Mitch McConnell is pleased about impeachment.
Senator Mitch McConnell of Kentucky, the Republican leader, has told associates that he believes President Trump committed impeachable offenses and that he is pleased that Democrats are moving to impeach him, believing that it will make it easier to purge him from the party, according to people familiar with his thinking.
Interesting. And Liz Cheney says she will vote to impeach Trump. So these signs point to a break between the old guard and Trump. I can also see the possibility that the Trumpers could form a third party that would spllit the right-wing vote for awhile. We'll see.


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Slogan polityczny – krótkie wyrażenie (czasem jedno słowo), mające na celu wypromowanie partii politycznej (lub osoby, czy jej poglądów). Slogan taki ma najczęściej charakter propagandowy. Często spotykane są również slogany negatywne - mające na celu zdyskredytowanie innych partii (przeciwników politycznych).

Propaganda polityczna

redpajama_set_name: RedPajamaWikipedia


GlaxoSmithKline plc (LSE/NYSE: GSK) today announced that it has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for GSK2857916 monotherapy in patients with multiple myeloma who have failed at least three prior lines of therapy, including an anti-CD38 antibody and are refractory to a proteasome inhibitor and an immunomodulatory agent.
In October, the European Medicines Agency (EMA) granted PRIME designation to GSK2857916 for the treatment of relapsed and refractory multiple myeloma patients whose prior therapy included a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody. GSK2857916 is an anti B-cell maturation agent (BCMA) monoclonal antibody-drug conjugate.
GSK2857916 has also received orphan drug designation from the EMA and FDA for multiple myeloma.
The PRIME and Breakthrough Therapy Designations are based on results from a phase 1 open-label, dose escalation and expansion study in patients with relapsed/refractory multiple myeloma, irrespective of BCMA expression. Data from this ongoing trial will be presented on 11th December in an oral presentation at the 59th annual meeting of the American Society of Hematology meeting in Atlanta.
Orphan designation may be granted for therapies intended to treat conditions that affect fewer than 200,000 people in the U.S. The designation qualifies the sponsor of the drug for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing[iii].
GSK2857916 is a humanised anti BCMA monoclonal antibody conjugated to the cytotoxic agent monomethyl auristatin-F, via non-cleavable linker (drug linker technology in-licensed from Seattle Genetics).
GSK2857916 is currently in phase 1 clinical development (NCT02064387) in patients with relapsed/refractory multiple myeloma and other advanced haematologic malignancies expressing BCMA.
GSK2857916 is not approved for use anywhere in the world.
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Principal risks and uncertainties' in the company's Annual Report on Form 20-F for 2016.


10-16. June, the Tornado Worlds were held in Lindau, Germany. We know quite well the place as we were racing a lot there with Libera in the good old times during the Libera Cup and Rund ums.
Mainly it is a light wind place with flat water, but we know very well that some strange things can happen there.
We have started to work on the new sails just after the 2015 Worlds. We knew that we need something new for really light wind.
We have made changes on the batten placing, draft positions and luff curve and a little bit of twist.
We have ended up in a totally, radically new mainsail.
"It is a lot different to my current main. The draft is further back, and the sail is more sensitive. It was only 4-6 knots, so it was easy to over sheet the sail and make it too flat, but I think the top 3 battens were to stiff.
The sail was very responsive once I found the "sweet spot", and only had to make minor sheeting adjustments to keep optimum speed.
We won all three races on yardstick over the f18's, winning one race by over 1 leg.
Very interested in how it would handle 15+ knots."
Brett started to play with the battens, and his choice was very stiff carbon rods for the Worlds.
Just about a month before the Worlds, Gavin Colby the current Hobie 16 World Champion came to me that he had downwind speed problems and he need a good kite. He ended up on the new 1D kite and he changed the jib too.
On the practice race day, I got the info from the great friend and partner Roland Gaebler, that Brett has a really impressive speed.
"Very flat but we sail with no cunningham and as long as we do not oversheet we are fast in flat water and light winds. Our speed was really pretty good, we were leading most of the race but lost out protecting the right on the last downwind although tthe final winner went even more right and passed us all.!!"
We had to make some changes on Gav's jib battens before the regatta to fit better to the light wind.
"The spinnaker certainly helped us immensely and we were never slow downwind."
We had an interesting week during the regatta, from 1-3kts up to 20+. It is nice to see that our sail worked really well and in the hands of real pros and in different conditions.
This regatta was very important to us. When we started our brand last February, we made a plan to finish as high as possible on big regattas. In 2015 the 2nd place on the F16 Europeans was really fine which was followed by 4th place on the Tornado Worlds. We saw that we have the opportunity to go higher so started to focus and develop. We knew that, so it was the proof too.
The Tornado class is very important to us as well. Not only, because we sail this boat, but it was the one of the most important classes for Giorgio and Pablo.


The organic cotton used in Justfog P16A coils are chemically bleached and are 100% natural. Most importantly, it yields better flavor and vapor production than coils made of silica.
Unlike top-coil type clearomizers, Justfog 16 series clearomizers are all bottom-coil type which do not need to be held upside down before use. And they use every last drop of e-liquid.


Aksel Watch | Dane Dapper | In stock!
Dashing in navy and white, this Danish design is more than just about looks. Features a slim black dial with sleek silver-toned hands and markers and the one and only NATO nylon strap, offering unparalleled quality, strength and flexibility. So comfortable and lightweight, you'll forget you have it on.
The strap is easily detachable and can be swapped for another if you wish.


Maqbool has devoted his life to both learning about international development and working in it as a development practitioner. The last decade, he's worked in governance, rule of law, and counter-extremism. In his most recent role he served as project manager for USAID's two year program, "Citizen's engagement for effective legislative governance." Maqbool feels there is a significant portion of Pakistanis who are unable to exercise their civic rights and believes it is his and other government officials' job to advocate for them. Through the Accountability Incubator, he will move beyond volunteering his time and expertise into developing a system of government reviews and community empowerment.


text:
Creating dramatic impact around the world with lighting from Signify
Feburary 7, 2019
Fasten your seat belt it's going to be a luminous ride as we visit three lighting installations on three different continents. Color Kinetics dynamic lighting systems helped to create a nighttime identity for these three amazing cities.
The Orb, Adelaide, Australia
First destination takes us down under to Australia, as we start with a look at the 'Orb', the Adelaide Entertainment Centre.
The Orb creates a spectacular experience for visitors. The domed entry has been completely transformed with a customised LED lighting installation engineered to deliver maximum visual impact.
Conceptualised by international lighting designer, Lighting Design Partnership (LDP), the Orb's customised LED lighting installation has been engineered to deliver maximum visual impact, while also providing a wide variety of lighting scene choice and operational flexibility.
To achieve the sophisticated lighting effects, each of the Orb's 140 ETFE pillows has been fitted with six Color Kinetics ColorGraze Powercore linear colour-changing LED fixtures, with 30-degree or 60-degree beam-angle lensing. Over 800 LED lighting fixtures are deployed throughout the Orb, providing over 3500 individually controllable lighting addresses.
Read more on the Adelaide Entertainment Centre
Place de la Comédie, Montpellier, France
Place de la Comédie is the main focus point of Montpellier with the Opera being center stage. The historic character of this public space, and the numerous architectural elements that surround it, make it a special place for people to meet and tourists to gather. It is accessible by streetcar with the railway station and shops close by.
The concept for the nighttime lighting design was the mission of Yann Kersalé, lighting designer and artist. The color blue was chosen as a metaphor for water, symbolic of the river Lez that runs through the city.
The tall light columns that tower over the streetcar line are lit in blue and at the top are multiple lighting sources of white light that illuminate the public space.
These high mast columns are spaced out at regular intervals to help guide our sightline all the way to the façade of the opera house. The window mouldings of the edifice are lit in blue while white light accentuates the horizontal lines for a dramatic look.
The Hollywood Bowl, Los Angeles, California
Photo © Andy Kassen, Jay Winters
With its unmistakable signature shell, the Hollywood Bowl is one of world's largest natural amphitheaters, and a famed American landmark. It is home to the Hollywood Bowl Orchestra, the summer home of the Los Angeles Philharmonic, and the host venue for hundreds of musical events each year.
The Hollywood Bowl had a lighting makeover with the help of Color Kinetics LED lighting solution. The team was led by lighting designer Jay Winters of JK Design Group, and Paul Geller, Los Angeles Philharmonic Director of Production. Their goal was to seamlessly illuminate the entire arch of the shell with concealed, color-changing fixtures. Previously, color-changing effects were achieved using conventional light sources with scrolling color changers or dichroic color-mixing fixtures.
When considering a new shell lighting system, the team compared several technologies and determined that an LED-based approach was the way to go. According to Winters, "The move to Color Kinetics' LED-based system allowed not only the ability for straight color changes, but also an unlimited variety of sequenced effects and an amazing range of effects in terms of how we moved from one color to another."
The team chose iColor Cove MX Powercore high-output linear LED luminaires, and mounted them in custom, 1.2 m (4 ft) long sheet metal channels. The metal channels provided the proper cut-off to control the luminaires' wide beam dispersion, ensuring the effective illumination of each surface of the shell's concentric baffles with no light spilling onto the other surfaces of the stage area. The luminaires were compatible with the Hollywood Bowl's existing theatrical DMX console, which made the switch to the new system seamless.
Read more about the Hollywood Bowl installation
Orb, Adelaide Entertainment Centre, LED lighting, Color Kinetics, ColorGraze Powercore, LED fixtures, iColor Cove, Hollywood Bowl, amphitheater, Place de la Comédie, dynamic lighting, Los Angeles Philharmonic
5 tricks for a Halloween treat with Philips Hue
Read the blog post
SandRidge Commons: Innovative illuminations and big energy savings in the heart of downtown Oklahoma City
The Seattle Seahawks and CenturyLink Field shine bright from the rooftop with connected lighting from Signify
Interact Light play – Transform your architectural lighting into an interactive experience
Montreal's Luminothérapie celebrates its 10th anniversary with POP!
Creating organic serenity in a concrete jungle
Vaya Flood Series Expands to G3 RGBW
Zero 88 celebrates 50 years
US Conference of Mayors Report Prioritizes Infrastructure Investments for Cities


Get the latest cybersecurity news.
In this week's roundup we've got news about a massive data breach at a major British company that could result in a huge fine for a General Data Protection Regulation (GDPR) violation. It's one of the first major breaches announced since the regulation went into effect in May.
Elsewhere, municipalities in the US are attempting to get ahead of cyberattacks, there's more news on the efforts to thwart attacks on the upcoming midterm elections and a curious new strain of ransomware includes the face of an extremely famous individual.
Learn more in this week's edition of Cyber Resilience News.
FOIA.gov is for people to learn about how to submit a Freedom of Information Act (FOIA) request. Its home page states that the "basic function of the Freedom of Information Act is to ensure informed citizens, vital to the functioning of a democratic society." The site is run by the Environmental Protection Agency and seemed innocent enough until it was discovered there was a software bug in the site's search facility.
British Airways revealed it's been the subject of a massive data breach thought to have affected hundreds of thousands of customers over a two week-period last month. It has now recruited the help of the National Crime Agency and National Cyber Security Centre to investigate into how the incident happened.
A campaign recently reported by Farsight Security involved an internationalized domain name "homograph-based" phishing website that tricked mobile users into inputting their personal information. The suspected phishing websites presented as commercial airline carriers and offered free tickets, fooling users with the age-old bait-and-switch technique.
A couple recent unsuccessful cyberattacks on Dickinson County, Kan.'s computer system has spurred an investment in new antivirus software. "We've had a couple attempted attacks come through our firewall and into the software. Luckily, staff were able to deal with those," County Administrator Brad Homman told commissioners on Aug. 23.
Cybercriminals often use the threat of the FBI and law enforcement to frighten victims enough to pay up. It's unusual, though, to see the face of a former head of a country as a brand of malware. Barack Obama's Everlasting Blue Blackmail Virus Ransomware, is perhaps one of the more peculiar strains of ransomware which have emerged over the course of this year.
Banking malware, including Trojans which steal your online credentials and screen grabbers, usually place heavy emphasis on remaining undetected for as long a period of time as possible. TrickBot, Emotet, BackSwap and the experimental MysteryBot are only a handful of the countless forms that banking malware can take.
More secure keys protecting the directory name system (DNS) are ready to deploy, but for those using DNS servers that haven't been upgraded, it could cause problems reaching websites. Changing these keys and making them stronger is an essential security step.
A new financial malware camouflaged as a security module and dubbed "CamuBot" is targeting Brazilian Banking customers. The malware was first spotted in Brazil in August 2018 in a series of targeted attacks against business banking users and has been since been actively used to target companies and public sector organizations, IBM X-Force researchers said in a Sept. 4 blog post.
Working to deliver on one of five goals set earlier this year with the debut of the new Mayor's Office of Equity, Diversity and Inclusion, Atlanta officials gathered to mark the debut of a portal aimed at tracking city funds Sept. 4. The initiative known as Open Checkbook was announced on April 10, less than a month after the city suffered a debilitating ransomware cyberattack.
Hackers are constantly probing for "the one flaw overlooked" in Houston's computer networks, the official responsible for safeguarding the fourth-largest US city's system said. His presentation helped persuade local lawmakers they needed a $30 million cybersecurity insurance plan with a $471,400 premium, an example of a burgeoning trend across the country.
Researchers have seen an uptick in a new ransomware strain similar to the notorious SamSam virus, warned the US Department of Health and Human Services Healthcare Cybersecurity Communications and Integration Center in an alert. Ryuk isn't technically advanced, but the highly targeted, planned ransomware variant has several interesting features that ensures its victims are hit hard, according to research from Check Point.
When Russian hackers successfully attacked Hillary Clinton's presidential campaign chairman John Podesta in 2016, they didn't need to use crippling ransomware or a complex zero-day exploit. Instead, the Russians used one of the oldest tricks in the hacker playbook: Email phishing.
A pair of Russian-speaking hackers, likely working in legitimate information security roles, has quietly emerged as a major threat to banks in Russia and numerous other former Soviet republics in recent months. The duo, called "Silence," is known to have stolen at least $800,000 from banks in Russia, Ukraine, Belarus, Poland, Kazakhstan and Azerbaijan over the past year.
Researchers from software security company SureCloud recently published a report about a security flaw in Chromium-based browsers, like Chrome and Opera. The issue appears to revolve around a browser's password autosaving features and the way home routers use unsecured HTTP connections on their administration pages.


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UN calls for 'independent' probe into death of Egypt's Morsi
The UN human rights office called Tuesday for an "independent inquiry" into former Egyptian president Mohamed Morsi's death while in state custody.
"Any sudden death in custody must be followed by a prompt, impartial, thorough and transparent investigation carried out by an independent body to clarify the cause of death," said Rupert Colville, spokesman for the UN High Commissioner for Human Rights.
Morsi, Egypt's first democratically elected president in 2012 after the Arab Spring uprisings, was overthrown in 2013 after a brief, turbulent term in power.
He died Monday after collapsing during a trial hearing in a Cairo court.
"Concerns have been raised regarding the conditions of Mr. Morsi's detention, including access to adequate medical care, as well as sufficient access to his lawyers and family, during his nearly six years in custody," Colville said.
He noted that Morsi "also appears to have been held in prolonged solitary confinement," and said the investigation must "encompass all aspects of the authorities' treatment of Mr. Morsi to examine whether the conditions of his detention had an impact on his death."


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RIBA to celebrate women in the field by remembering trailblazer Ethel Charles, the first woman to join the organization
Jun 16, '17 12:39 PM EST
Image via RIBA
At the turn of the century, women were rare in the field of architecture—something that, while certainly improved, remains a deeply unfortunate reality of the profession that urgently requires attention and remediation.
A notable exception was Ethel Mary Charles, the first women to join the Royal Institute of British Architects (RIBA), helping pave the way for the thousands of women who've followed in her footsteps. On July 5, 2017, RIBA celebrates Charles with #EthelDay, a day of international social media campaigning to recognize the indelible mark that women have left in the field since her day.
RIBA encourages everyone to share a picture of a film of a woman architect you find inspiring (and/or one of their designs), with the hashtag #EthelDay.
"I encourage architects, students and their educators, design professionals and enthusiasts from around the world to join me in celebrating the contribution of women in architecture," states Jane Duncan, RIBA President and founder of International Women in Architecture Day. "Whether you participate on social media with our #EthelDay campaign by sharing a photograph of an inspiring woman architect, host a Wikipedia 'edit-a-thon' to improve the visibility of women architects, or host a special event in your office or college, I can't wait to hear about it. Let's get the world celebrating the talent, ideas and creations of inspiring women in architecture."
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ribawomenwomen in architectureinternational women in architecture dayethel mary charlesroyal institute of british architects


At last the flight ticket for an unforgettable journey to Australia is in your hands. Travel to Australia is a great experience!
It's not a journey planned in a hurry, not an escape of some days. It's a studied journey, scheduled, well-considered and planned in every detail. Maybe it's a honeymoon or an important anniversary. All is perfect to travel to Australia.
Whatever the reason is, we know well that often the little details miss.
I know a lot of people that near the impending leaving have checked thousands of times the same things and then they have forgotten the most important ones.
If you are obviously tested travellers and you are not anxious, these indications are not for you. But if you are novice travellers and you have some more anxiety (due to the important amount of a such journey), my post is whole for you.
Did you remember to get the visa?
Whether you travel to Australia for tourism or for business, you need to get the visa to Australia. How do that? You can get the visa from the official channels or by an easier and quicker way from the agencies offering a valid support to get the visa.
Why choose their services? Easy. To stay calm.
The visa to Australia can be a tourist or business visa but pay attention to the differences.
The business visa to Australia doesn't allow to work for a company nor to sell services to the public.
The correct definition of the visa is EVISITOR subclass 651, commonly known as ETA to Australia (not to confuse with the one to Canada that has the same name).
One of their most interesting services, besides the help, the correction of data if wrong, the notifications about the papers' progress and sent by PDF, according to me is the complete refund if the ETA visa for Australia is refused.
The visa lasts 90 days max and it has to be required for each family's member.
Now we're ready to plan our journey. There are endless things to see and however long the journey may be, I assure you it won't be enough.
Sydney will astonish you by its liveliness.
A nice walk along the harbour and the majesty of the Opera House seen from the sea and from the bridge.
The uncontaminated nature, the great plains, the desert, the animals will astonish you. You know well that Australia is not only kangaroos.
You cannot miss to take photos of a very beautiful koala at close. Do you?
Kangaroo Island certainly deserves to be visited, as well Tasmania: islands always have a particular charm.
The Ocean Road is really famous and is known everywhere as one of the most beautiful ocean roads in the world. Don't you believe it? Look at these photos!
In sunny days the colours and the blue shades are incredible.
Then there are the deserts with their rock formations, perfect hexagonal natural frameworks with seals basking in the sun.
On the very long and uncontaminated ocean beaches, mostly deserted, you can sunbathe, swim or surf.
At every corner a multicoloured parrot, a Tasmanian devil, a lavender field or many wild kangaroos for unique shoots you'll look at excited for the rest of your life.
We left it the end one of the main attractions.
You know well that the Australian Coral Reef is the greatest in the world.
With its colours it allows to admire unique seabed, whether you are keen on snorkelling or diving.
You know well how much we love seabed, colours, animals…whether they are in the Maldives or in Florida with the Christ of the Abyss…we have to dive!
So there is nothing left to do but finish this post about the wonderful journey to Australia which is ahead of you with a dive together with these wonderful dolphins! Enjoy your journey!
This entry was posted in Australia, Oceania and tagged eta, on the road, tanzania, tour. Bookmark the permalink.


ShockCast Episode 114 - "Doki Doki Panic Time"
I know. That's the most ridiculous title that we've had for the ShockCast but once you listen to the episode, it will all make perfect sense to you. For this week's first main topic we talk video game sequels. Whether they're a "must have" or a "dont want" and how they affect a particular series. For our second topic we discuss the week that was E3 and whether or not the show is still worth having considering that much of it is instantly available for non-show goers to consume. All that and the week in news makes this week's show another must listen!


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2 Hour Sunset Guided Walk
Home to rugged peaks, deep crater lakes, and beautiful volcanic landscapes, the Tongariro National Park ranks among the North Island's top natural attractions. On this evening tour, follow your guide along hiking trails to Mt. Ruapehu or the Taranaki Falls, and learn of Tongariro's rich geology. As the sun sinks on the horizon, sip a glass of New Zealand wine and soak up spectacular views over the rugged scenery.
Taupo Self-Guided Audio Tour
Download a vibrantly-narrated mp3 audio guide combined with a map detailing the area of your tour. Enjoy the action packed city of Taupo on this self-guided audio tour of the city. You will see how the stunning lake city of Taupo has gently transformed by taking you on a journey which will highlight its geothermal history and the massive lake on which it sits where water based and adrenaline activities keep many tourists busy.
What Nature Walks in Tongariro National Park are taking additional safety precautions?
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Wider highways … info only!
JACKSON, Wyo. – Information highways? Yes! Four-lane highways? No! That would seem to be the common theme in rural parts of the West. Those that are lagging in bandwidth want more, more, more. Not so much highways.
State highway officials in Wyoming's Teton County want to expand the existing two-lane highway south of Jackson to five lanes. County commissioners instead see a medley of three, four and five lanes. They may sue the state.
They are particularly concerned that the wider highway would be less permeable to wildlife. Local officials, meanwhile, are also considering a proposal for 120 miles of fiber-optic line across the county and into Idaho.
The new line would increase Internet speeds 5-fold to 100-fold, reports the Jackson Hole News&Guide. It would also provide redundancy. Earlier this year, cell phone service was lost for 26 hours when a flash flood several hundred miles away severed a cable.
In Colorado, the Silverton community, located high and remote in the San Juan Mountains, also seeks redundancy – and, for that matter, a fiber optic line of its own. The existing fiber optic line stops 16 miles short of the town near Molas Divide.
Town officials say microwave, the community's existing link to the outside world, delivers too little bandwidth. "Nobody is putting in microwave," says Patrick Swonger, a town councilman. "Nobody is doing that. It's all fiber optic. Those are the highways of the future."
Community officials charge that they were promised fiber-optic connection under a Colorado program launched in 2002 to connect all county seats, including Silverton. Instead of delivering an information highway, says San Juan County Administrator Will Tookery, "They barely widened the existing mule train."
Aspen plans more housing
ASPEN, Colo. – Aspen and Snowmass Village have plenty of spare bedrooms at the moment. So, the Aspen Skiing Co. had no trouble filling out its peak season employment roster of 3,500 for its four ski areas and associated enterprises.
Just the same, the company continues its effort to add employee housing, reports The Aspen Times. The company plans to add 600 "beds" to the existing 550 in Aspen and other locations in the Roaring Fork Valley. Some units are for seasonal employees, but the company also has built single-family and other housing types for year-round workers.
Company officials tell the newspaper that when the national unemployment rate falls below 6 percent, Aspen has trouble filling all its positions. The national rate currently hovers at slightly less than 10 percent.
The Times notes that tight housing has been the norm in Aspen for decades, and those periods of easy vacancies are rare and short-lasting.
Backcountry gates closed
TELLURIDE, Colo.—Skiers who use the lifts of Telluride to gain the powder stashes of the Bear Creek area are miffed. The Forest Service announced that three backcountry gates from atop the ski area were being closed, and one more was being relocated.
All this has been in response to the purchase earlier this year of three mining parcels in the valley by Tom Chapman. Chapman has made a name for himself in Colorado during the last 15 years by repeatedly purchasing mining claims amid sensitive public lands, such as wilderness areas, then threatening development.
In this case, he warns of encroachment on his property by customers of the Telluride Ski and Golf Co. which is contemplating developed skiing in the basin. The property doesn't seem to be marked, however.
Locals tell The Telluride Watch that they believe the Forest Service has essentially taken the side of Chapman in the dispute. The gates should be left open, to provide public access to public lands, they say.
"Those gates access much more area than the private claims, and the Forest Service has a legal obligation to provide access to public lands," said Tor Anderson, director of the Telluride Mountain Club. He went on to question whether access to public land elsewhere would be closed – for fear of public intrusion on private lands.
New lights in Durango
DURANGO, Colo. – For those in Durango distressed by the encroachment of city lights into the night sky, there's a margin of good news. All 765 of the city's overhead street lights have been changed out to fixtures that are compliant with dark-sky regulations adopted by the city in 2003.
Dark-sky fixtures contain the light and focus it downward toward the streets and pathways, instead of allowing the light to pollute surrounding hillsides and the sky.
Manes in Park City
PARK CITY, Utah –A proposal to allow horse-drawn carriages on Park City's Main Street is being reviewed by city officials. The local newspaper calls it "Manes on Main." The street is steep, but horses seem to handle the grade just fine. They certainly did so during the Olympics in 2002, when the Budweiser Clydesdales were brought in. But the street was closed to automobiles then. The question seems to be whether steeds and steel can coexist.
The big get bigger … and wealthier
TRUCKEE, Calif. – The sale of Squaw Valley by Nancy Cushing, widow of the resort's founder, Alex Cushing, has once again put a spotlight on the finances of ski areas. Earlier this year, Northstar-at-Tahoe was sold to Vail Resorts, giving it two ski areas in the Tahoe Basin. Now, Squaw Valley has been sold to KSL Capital Partners, which is composed of two former executives from Vail Resorts.
"It's a business with significant cash flows," Michael Berry, president of the National Ski Areas Association told the Northern Nevada Business Weekly. "By and large the industry does very well from a financial standpoint, and that is why we are seeing interest from groups such as Vail and KSL, who have looked around and chosen to be involved in major destination resorts."
After a long period of stagnation, the U.S. ski industry has spurted in recent years from about 52 million annual skier days to 60 million skier days.
Larger corporations can do well because of the benefits of buying power.
Eric Resnick, managing director for KSL Capital Partners, tells the newspaper, "If you have a loyal following and put out a good product, you will be successful," he said. "It's simply a matter of scale."
Twilight zone of benefit 13 Jan, 2012
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Alabama Gov. Robert Bentley speaks during the annual State of the State address at the Capitol, Feb. 2, 2016, in Montgomery, Ala.
Photo by Brynn Anderson/AP
Sex scandal gets even worse for Alabama governor
When we last checked in on Alabama Gov. Robert Bentley, the "family values" Republican was facing accusations from the former head of the Alabama Law Enforcement Agency about an alleged extra-marital affair. The officer held a press conference to say he'd been fired for failing to go along with a scheme to hide the governor's personal misdeeds.
Bentley held a strange press conference soon after to apologize – though it was unclear to whom he was apologizing and for what. The governor acknowledged his role in inappropriate communications with his top political aide, but he denied having a "physical relationship" with her.
An audio recording surfaced soon after in which Bentley is overheard describing what sounded like a "physical relationship" with his staffer.
A week later, the questions are only growing louder; the list of Republicans calling for Bob Bentley's resignation is growing longer; and the governor's future is looking bleaker.
Gov. Robert Bentley sidestepped questions about an alleged affair with senior political adviser Rebekah Caldwell Mason during a visit Monday to a rural health center in Centreville – his first public appearance since sexually explicit recordings of the governor talking to Mason were made public last week.
If he's come up with a defense or any new talking points, the governor kept them to himself. "We have made our statement last week and that's all we're going to say about that," he said.
But there is no scenario in which Bentley's odd, literally unbelievable statement from last week makes his scandal go away. On the contrary, today's headlines make clear this controversy goes well beyond an inappropriate workplace romance.
* A local NBC affiliate reported that State Auditor Jim Zeilger is leading an Ethics Commission review of Bentley's conduct, and he believes the matter may lead to possible criminal charges.
* No one seems able to explain how Bentley's top political staffer, his alleged mistress, is paid.
* The Alabama Political Reporter published a piece alleging that the governor "pressured law enforcement officers to use federal and state resources to target" critics of his extra-marital relationship.
* Bentley has even apparently been kicked out of his church.
The Birmingham News' John Archibald published a brutal column today noting that Alabama's state government is simply unraveling: the governor is mired in scandal; the lieutenant governor is widely seen as "unfit to serve"; the state House Speaker is currently awaiting trial on 23 felony counts; and the state Supreme Court's chief justice is Roy Moore, whose crackpot views have already forced his ouster once, and who can hardly be counted on to adjudicate responsibly going forward.
"This is not a war," Archibald concluded. "It's a massacre, and annihilation. The very people Alabama elected to manage the state and help it to prosper are the ones who burned our village to the ground and salted the fields."
Look for more on this on tonight's show.
The MaddowBlog, Alabama and Scandals
Supreme Court fiasco weighs on key...
Alabama and Scandals


Are you looking for clearer skin? Decreased skin sensitivity, redness and inflammation? Reduced appearance of fine lines and wrinkles? Increased elasticity? A healthier you not just on the inside, but on the outside too? Topical probiotics are one of the new beauty breakthroughs proven to help our skin!


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Pakistani military says Indian fire kills soldier in Kashmir
Jan. 14, 2021 Updated: Jan. 14, 2021 6:09 a.m.
MUZAFFARABAD, Pakistan (AP) — Pakistan's military said Indian troops opened fire across the border in the disputed Himalayan region of Kashmir on Thursday, killing a Pakistani soldier, the latest in continued tensions between the two South Asian nuclear rivals.
A statement from the military condemned what it described as India's unprovoked violation of the 2003 cease-fire agreement along the Line of Control, which separates Kashmir between the two sides. The Pakistani troops returned fire, it added.
There was no immediate comment from New Delhi but the the two sides routinely accuse each other of unprovoked attacks in Kashmir, which is a split between them and claimed by both in its entirety.
Pakistan and India have fought two of their three wars over Kashmir since gaining independence from British rule in 1947.
Shopping The best streaming services in 2021, and why
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There are many theories on the battered landmark's origin story.


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The REPROCELL Blog
In Clinical Capabilities
Will mRNA change medicine for good?
By Zara Puckrin, BSc / 12 August 2021
In 2020, the first-ever mRNA vaccine was approved for clinical use: the BNT162B2 coronavirus vaccine. At the time, few laypeople had heard of mRNA - but the therapeutic potential of this molecule had been recognized by scientists for decades. In this article, we will explore mRNA's rise to fame in 2020 and the potential of this molecule in regenerative medicine.
How mRNA became a vaccine game-changer
Messenger ribonucleic acid (mRNA) is a single-stranded molecule best known for its essential role in protein expression. It was first discovered by scientists in the summer of 19611. Three decades later, a research group from the University of Wisconsin demonstrated that foreign mRNA could induce protein production in vivo2, and in 1993 mRNA was used to immunize mice against influenza3.
However, when the idea of using nucleic acids for vaccination was borne, it was originally thought that DNA would be best suited to therapeutic application. It was soon discovered that DNA was expensive to manufacture and was found to cause heritable changes in cellular DNA4. Due to the risk of tumor formation, DNA-based treatments were considered unsuitable for clinical use.
Scientists then turned to mRNA, DNA's single-stranded partner. It turned out that mRNA posed no threat of genomic integration4 and was quicker, and much more cost-effective to manufacture6. The biggest obstacle to the introduction of mRNA-based vaccines was the instability of this molecule, which made it difficult to store and transport compared with conventional vaccines. Innovations such as lipid encapsulation7 negated this problem, and the first successful mRNA immunization attempt was published in 19933. Thirty years later, the first mRNA vaccine was approved for clinical use during the coronavirus pandemic8. And today, it is thought that this molecule could solve many issues facing conventional vaccine development9.
mRNA: is it safe?
The safety requirements for vaccines are extremely high, and the FDA and EMA agree that mRNA vaccines are safe for human use. Some authors even argue that they are safer than conventional vaccinations9 because there are no cell cultures used in the mRNA manufacturing process. As a result, mRNA-based therapies are at reduced risk of viral contamination, are absent of viruses, and have a shorter manufacturing period.
Thanks to mRNA's non-integrative nature, it is also the preferred vector for the reprogramming of induced pluripotent stem cells (iPSCs). Compared with viral and DNA-based reprogramming techniques, mRNA reprogramming is more efficient, flexible, safer, and best suited to the production of iPSCs for clinical use4.
Will mRNA help with other diseases?
RNA was used clinically decades before the first successful vaccination attempt in 1990. In the 1980s, the RNA therapeutic Ampligen was shown to block the growth of transplanted tumors in mice10, and in later clinical trials, produced promising results for cancer10 and HIV patients11.
Thanks to recent advances in mRNA technologies, we have reached the point where customized, nucleotide-based therapies for other diseases are conceivable5. Because any protein can be encoded using mRNA, these vaccines can be created more rapidly, making it possible to design custom vaccinations against patient-specific antigens12. BioNTech is currently pursuing personalized cancer treatments using mRNA vaccines13, and Cure Vac AG has an extensive range of therapeutic targets for mRNA-based drug treatments in development14. And Moderna has at least 9 clinical trials ongoing15 for antiviral vaccines and cancer therapies in areas such as influenza and melanoma.
Yet the capabilities of mRNA extend beyond drug development. Perhaps the most exciting and intriguing potential of this molecule is its use in the development of autologous cell therapies16, or personalized regenerative treatments derived from a patient's own cells.
mRNA can do much more for medicine
First coined in 199217, regenerative medicine was defined as "a new branch of medicine that attempts to change the course of chronic disease and will regenerate tired and failing organ systems". Using stem cells to regenerate lost or damaged tissues would enable us to cure the incurable and dramatically improve human quality of life. However, due to ethical considerations18 and the risk of immune rejection19 associated with embryonic stem cells (ESCs), regenerative medicine was considered science-fiction for a long time.
Fifteen years later, Professor Shinya Yamanaka changed everything by creating pluripotent human stem cells from mature adult tissues20. Generated from a single skin biopsy, these induced pluripotent stem cells (iPSCs) negated the use of ESCs and made the concept of autologous stem cell therapies tangible. With just a small piece of skin, replacement blood, tissues, and even whole organs could be created in vitro. Once transplanted back into the patient, there would be a reduced risk of immune rejection compared with allogenic cell therapies, like those currently used to treat blood cancers.
At the time, our biggest barrier to the introduction of these autologous cell therapies was safety. Because DNA vectors were used to create iPSCs, there was a risk of genomic integration which could result in tumor formation4. While this was acceptable for iPSCs used in research, it was a barrier for clinical applications4. So researchers set out to create a vector that was DNA-free and, like the drug developers years before them, they turned to mRNA.
Today, mRNA reprogramming is one of the safest and effective ways to produce iPSCs. It obliterates the need to screen cells for residual vectors and is superior in speed and efficacy compared with conventional techniques. These benefits, plus the unrivaled control it affords over reprogramming factor dosing21, have made mRNA reprogramming the most promising way to produce iPSCs for regenerative medicine4.
However, there are a few caveats that make clinical-grade iPSCs unsuitable for some applications. It has proved challenging to create stem cells from donor blood using mRNA reprogramming techniques. While there are some exceptions, like endothelial progenitor cells (EPCs)22, a key limitation of DNA-free reprogramming is that not all cells can be reprogrammed. This being said, there are a variety of donor materials that can be used for clinical-grade iPSC generation including skin, urine23, and dental pulp.
The future of mRNA and regenerative medicine
The ability to make any kind of human tissue has many exciting medical applications; to name a few, it could eradicate donor blood shortages, improve cancer survival, and obliterate age-related degeneration. Already, iPSC-based cell therapies are being developed for Parkinson's disease24 and spinocerebellar ataxia. The biggest barrier to the introduction of these therapies is regulatory obstacles25. We, therefore, believe it is only a matter of time before mRNA-based cell therapies become a reality.
Cobb. Who discovered messenger RNA? Current Biology 25:13 pp526-532 (2015)
Wolff et al. Direct gene transfer into mouse muscle in vivo. Science 247 pp1465–1468 (1990)
Martinon et al . Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. European journal of immunology, 23(7), 1719–1722 (1993)
Warren et al. mRNA-Based Genetic Reprogramming. Molecular Therapy 27:4 pp729-734 (2019)
Kallen et al. A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. Therapeutic advances in vaccines 2:1 pp10-31 (2014)
Pascolo. Messenger RNA-based vaccines. Expert Opinion on Biological Therapy 4 pp1285–1294 (2004)
Nature Editorial. Let's talk about lipid nanoparticles. Nature Reviews, Materials 6:99 (2021)
FDA press release Comirnaty and Pfizer-BioNTech COVID-19 Vaccine (2021)
Pardi et al. mRNA vaccines — a new era in vaccinology. Nature Reviews, Drug Discovery 17 pp261–279 (2018)
Carter et al. Preclinical studies with Ampligen (mismatched double-stranded RNA). Journal of Biological Response Modifiers. 4:5 pp495-502 (1985)
Carter et al. Clinical, immunological, and virological effects of ampligen, a mismatched double-stranded RNA, in patients with AIDS or AIDS-related complex. Lancet 1:8545 pp1286-92 (1987)
Kreiter et al. Targeting the tumor mutanome for personalized vaccination therapy. Oncoimmunology 1:5 pp768-769 (2012)
Bol et al. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity. Cancer immunology, immunotherapy: CII 65:3 pp327-39 (2016)
CureVac pipeline
Moderna current clinical trials
Mandal et al. Reprogramming human fibroblasts to pluripotency using modified mRNA. Nature Protocols 8:3 pp568-82 (2013)
Kaiser. The future of multihospital systems . Topics in Health Care Financing. 18:4 pp32–45 (1992)
Giacomini et al. Banking on it: public policy and the ethics of stem cell research and development. Social Science Medicine 65:7 pp1490-500 (2007)
Sarić et al. Immunological barriers to embryonic stem cell-derived therapies.Cells Tissues Organs 188:1-2 pp78-90 (2008)
Takahashi et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 131:5 pp861-872 (2007)
Bernal. RNA-based tools for nuclear reprogramming and lineage-conversion: towards clinical applications. Journal of Cardiovascular Translational Research 6:6 pp956-968 (2013)
Poleganov et al. Efficient Reprogramming of Human Fibroblasts and Blood-Derived Endothelial Progenitor Cells Using Nonmodified RNA for Reprogramming and Immune Evasion. Human Gene Therapy 26:11 pp751-766 (2015)
Gaignerie et al. Urine-derived cells provide a readily accessible cell type for feeder-free mRNA reprogramming. Scientific Reports 8:14363 (2018)
Dennis Normal First-of-its-kind clinical trial will use reprogrammed adult stem cells to treat Parkinson's Science article (2018)
Nair. Retrovirus-induced oncogenesis and safety of retroviral vectors. Current Opinion in Molecular Therapeutics 210:5 pp431-438 (2008)
Zara Puckrin, BSc
Marketing Manager at REPROCELL
Zara is a GCU graduate based at our Glasgow office. She loves minimalism, marketing and molecular biology. You can contact her on LinkedIn.
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J Nat Prod. 2015 Dec 24;78(12):2867-79. doi: 10.1021/acs.jnatprod.5b00700. Epub 2015 Nov 20.
Can Small Chemical Modifications of Natural Pan-inhibitors Modulate the Biological Selectivity? The Case of Curcumin Prenylated Derivatives Acting as HDAC or mPGES-1 Inhibitors.
Iranshahi M1, Chini MG2, Masullo M2, Sahebkar A1, Javidnia A3, Chitsazian Yazdi M1, Pergola C4, Koeberle A4, Werz O4, Pizza C2, Terracciano S2, Piacente S2, Bifulco G2.
Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences , Vakil Abad Boulevard, Opposite Mellat Park, 91775-1365 Mashhad, Iran.
Department of Pharmacy, University of Salerno , Via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences , Enghlab Street, 14155-6559 Tehran, Iran.
Institute of Pharmacy, Friedrich Schiller University Jena , Philosophenweg 14, 07743 Jena, Germany.
Curcumin, or diferuloylmethane, a polyphenolic molecule isolated from the rhizome of Curcuma longa, is reported to modulate multiple molecular targets involved in cancer and inflammatory processes. On the basis of its pan-inhibitory characteristics, here we show that simple chemical modifications of the curcumin scaffold can regulate its biological selectivity. In particular, the curcumin scaffold was modified with three types of substituents at positions C-1, C-8, and/or C-8' [C5 (isopentenyl, 5-8), C10 (geranyl, 9-12), and C15 (farnesyl, 13, 14)] in order to make these molecules more selective than the parent compound toward two specific targets: histone deacetylase (HDAC) and microsomal prostaglandin E2 synthase-1 (mPGES-1). From combined in silico and in vitro analyses, three selective inhibitors by proper substitution at position 8 were revealed. Compound 13 has improved HDAC inhibitory activity and selectivity with respect to the parent compound, while 5 and 9 block the mPGES-1 enzyme. We hypothesize about the covalent interaction of curcumin, 5, and 9 with the mPGES-1 binding site.