There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have...

Bread for toasties, milk and toilet rolls were also best sellers

Mount & Blade II: Bannerlord is currently $37.50 on cdkeys.com. Yesterday it was $41. 

https://www.cdkeys.com/pc/games/mount-and-blade-ii-2-bannerlord-pc

On Steam its MSRP is $50 with a limited time sale going on now for $45. The game just came out to Early Access 3/31.

The question now is: jump now on the good price, or will the price continue to fall?

Note: It's in Early Access and has been in development for like 8 years. Expect some clunk.

https://www.cdkeys.com/playstation-network-psn/playstation-plus/1-year-playstation-plus-membership-ps3-ps4-ps-vita-digital-code

These has been in the 35-40s recently

Former Tottenham manager Harry Redknapp believes Manchester United would not represent a step-up for in-demand striker Harry Kane.

In vitro and mouse studies suggest THZ1, a covalent CDK7 inhibitor, could help treat neuroblastoma and other cancers driven by MYCN and other c-MYC (MYC)-family oncoproteins.

BJP President Nitin Gadkari will be our guest at Idea Exchange on Monday. Send us your questions for him.

For most people, there's something particularly sad and gory about seeing wildlife killed on the side of the road--but for one British clothing designer, such critter-carnage is fodder for fashion. In an upcoming fashion show,

One British designer's fashionable collection of hats, coats and jewelry is made using all parts of animals that have died naturally or accidentally on the road.

Millions of animals are accidentally killed on US roads every year. Here's how one company is turning these sad statistics into something useful, beautiful and respectful.

It might cost $125 a bottle, but it tells a cool story about sustainability.

High Fashion from roadkill? We also have an art installation that sent Estonians into the trees, egg nog pancakes, the year in gingerbread design, and more.

New Amsterdam Vodka presents "It's Your Town"

New Amsterdam Vodka presents "It's Your Town"

Revised GSTR-3B for UT of J&K and Ladakh...

Fast bowler Jaydev Unadkat said that he feels fortunate to have played with former Australian captain Steve Smith and even played under the star batsman early on in his career. Smith was captain of Rising Pune Supergiant when Unadkat had his breakthrough season in the 2017 Indian Premier League (IPL).

"Ever since I have played under him, or for that matter since he has known me, he has backed me to the fullest," said Unadkat in a video interview with his Rajasthan Royals teammate Ish Sodhi on the IPL side's Facebook page.

"I am grateful that this happened to me at that time of my career when I was still trying to make a name for myself. I had confidence in myself but you know how important it is to have the captain's confidence. That happened in the 2017 season. I have been a big fan of his captaincy and obviously of him as a player."

The 28-year-old rejoined Smith at the Rajasthan Royals in the 2018 season where he also shares the dressing room with England trio Ben Stokes, Jos Buttler and Jofra Archer. Unadkat said that he tries to learn from all of them and spoke about how Stokes tried to motivate him when he was feeling low on confidence.

"These guys are not just good on the field, they are pretty lively even in the dressing room," said Unadkat.

"I have been speaking to Jos and Smithy when he was captain. I've had Ben coming to me and giving a nice piece of advice when I have not been confident about my own game and that has boosted me. Jofra was also of equal help, talking about what his mindset is when I asked him in the nets."

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Actress Anushka Sharma gave Instagram's viral 'Guess The Gibberish' filter a shot, but she failed to come up with the right word.

Guess The Gibberish filter works by showing you seemingly meaningless words until you can crack it and arrive at the correct phrase. A user gets 10 seconds to figure out the right words. The filer was created by a user named @gu_christopher, and has caught on.

Anushka posted a video on Instagram story, where she is seen participating in the guessing game.

Her Gibberish filter read: "Stir Range Earth Inks".

In the video, she is seen repeating the sentence and finally decides the correct answer to be "Strange Things", but the reply is actually "Stranger Things".

Seeing her guess is wrong, Anushka calls herself "Bewakoof ladki".

On the work front, Anushka is all set to come up with a new web series as a producer on Amazon Prime Video web series, bankrolled by her production house Clean Slate Company.

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Bollywood actress and Congress candidate from Mumbai North Urmila Matondkar on Sunday played cricket with the youngsters of Sahyadri Nagar, Charkop in Kandivli. She tweeted a video of her playing cricket and wrote, "Since there is no time to watch the IPL anymore...in a league of my own with the youngsters of Sahyadri Nagar, Charkop Kandivali (W) #AapliMumbaichiMulagi." (sic)

Also Read: Elections 2019: Urmila Matondkar races for Lok Sabha polls with rally in Kandivli. See photos

Clad in simple salwar kameez, Matondkar tried her hand at cricket among cheering crowd. Watch video here...

Since there is no time to watch the IPL anymore...in a league of my own with the youngsters of Sahyadri Nagar, Charkop Kandivali (W) #AapliMumbaichiMulagi 😇 pic.twitter.com/JrRZmTNRNx

— Urmila Matondkar (@OfficialUrmila) April 14, 2019

Urmila Matondkar has declared assets worth around Rs 68.28 crore and a clean legal record. As per her affidavit filed with the Election Commission, Matondkar's income was Rs 1.27 crore in 2013-14, which more than doubled to Rs 2.85 crore in 2017-18. Her movable and immovable assets are totally worth Rs 40,93,46,474 and Rs 27,34,81,000, respectively.

Her husband M.A. Mir owns movable and immovable assets worth Rs 32,35,752.53 and Rs 30,00,000, respectively, totally around RS 62.35 lakh. Besides, Matondkar has declared an outstanding loan of Rs 32 lakh. Her assets include bank deposits, cash in hand, vehicles, and investments in land and properties.

Also Read: Watch video: Urmila Matondkar enjoys vada pav during election campaign in Mumbai

Urmila Matondkar was born in a small rural hospital in her (maternal) native region of Sindhudurg, to Shrikant and Sunita. Her father Shrikant is a retired officer of the erstwhile Grindlays Bank and her mother Sunita is a retired state government employee.

She was educated at the prestigious century-old King George High Shool, Dadar, which is now renamed as Raje Shivaji Vidyalaya, and then joined the Ruparel College, but couldn't complete her graduation as she got a big break in Bollywood.

With a successful film career behind her, Urmila married a Kashmiri businessman, M.A. Mir and regularly visits her inlaws in the Valley. While her sister is a former actresss-turned-lawyer Mamata A. Bhalekar who lives in Mumbai, her eldest brother, the Pune-based Kedar Matondkar is a retired Indian Air Force officer who saw action during the Kargil War of 1999.

"She loves social issues, reading, and has read all major literary works, especially the pennings of Sane Guruji who has influenced her deeply. Urmila is always dediated and committed in any venture she undertakes, whether acting or social work or politics," her proud father Shrikant said

Mumbai's six Lok Sabha constituencies go to polls in the fourth phase on April 29.

Also Read: Elections 2019: Urmila Matondkar, Priya Dutt, Sanjay Nirupam woo youth

Catch up on all the latest Crime, National, International and Hatke news here. Also download the new mid-day Android and iOS apps to get latest updates

Reacting sharply to a scuffle between Congress workers and BJP sympathisers earlier on Monday, actor-turned-politician Urmila Matondkar claimed that there is a threat to her life and she requires protection from the police.

Speaking to ANI after the scuffle that took place during her roadshow at Boriwali, Matondkar said, "It is being done to create fear. It is just beginning, it will take a violent turn. I have asked for police protection. There's a threat to my life, I have filed a complaint."

Talking about the scuffle that happened earlier in the day, Matondkar said, "We were peacefully addressing people and from nowhere 15-20 people came and started raising slogans in favour of Prime Minister Narendra Modi. Initially, I didn't react to it and thought these kinds of things keep happening. But they all started making vulgar actions and started dancing. They were trying to intimidate women at the back. They were moving forward towards the direction where my vehicle was standing. Because of this, our people had to intervene and asked them to stop doing this. A clash then broke out between them and they even hit some women."

She also said that she has filed a police complaint on today's incident.

Matondkar has been fielded by Congress from Mumbai (North) constituency.

Earlier in the day, when Matondkar was holding a roadshow near a railway station, some onlookers started raising pro-Modi slogans. The sloganeering was countered by 'Chowkidar Chor hai' slogans by Congress supporters.

A scuffle subsequently broke out between the two groups. In a video of the incident, Congress supporters can be seen running towards people raising pro-Modi slogans and roughing up a few of them.

Catch up on all the latest Crime, National, International and Hatke news here. Also download the new mid-day Android and iOS apps to get latest updates

Ek Ladki Ko Dekha Toh Aisa Laga
U/A: Drama, Comedy, Romance
Director: Shelly Chopra Dhar
Cast: Sonam Kapoor, Anil Kapoor, Juhi Chawla, Rajkummar Rao
Rating: 

Towards the film’s climax, Rajkummar Rao, who plays playwright Saahil Mirza in the film, tells those watching his play to do so ‘from the heart’. It’s imperative that we follow this instruction, because, like with every Bollywood film, it’s easy to dismiss this one on many technical frailties. But, what you can’t fault, is its intention to depict a love story for what it truly is — a love story. Why does it matter if it is about a woman falling in love with another woman?

Written beautifully by the prolific Gazal Dhaliwal, Ek Ladki Ko Dekha Toh Aisa Laga breaks perceptions to introduce to us what normal truly implies — being compassionate about one another’s uniqueness. The point, in this case, isn’t to merely celebrate homosexuality and treat it as the regular. It attempts to reiterate that even personal choices, like those of marriage, career, or love, must be respected. Being rendered claustrophobic shouldn’t be the outcome of accepting an emotion that goes against the tide of societal norms. The narrative’s tapestry is woven with care and compassion; it evidently comes from a personal space, for Dhaliwal.

Watch the trailer here...

The film kicks off with a play about love in the age of Tinder. Leading lady Sonam K Ahuja’s Sweety brutally criticises this as “upar-upar ki love story”. Sweety is forced to live a life of shame. A closeted lesbian, she struggles to come to terms with her own orientation. Her family’s unwillingness to acknowledge it, a brother who pressurises her to ‘fix’ herself, and persistent loneliness, makes her journey cumbersome.

Sonam plays Sweety with charm and earnestness, and is yet uninhibited when she must be fierce. It takes courage to back a script of this nature, and she gets full marks for doing so. Rao’s Saahil shows compassion in his scenes with Sweety. Another cast-member, Anil Kapoor is affable. Given that he is as closeted as his daughter in the film — Anil’s character is a chef at heart who is stuck in a business of garment — the final scene of acceptance seems to come from a place of empathy.

What doesn’t work, however, is director Shelly Chopra Dhar’s constant ploy to whip up mystery around Sweety’s orientation. Her big revelation comes with orchestrated music, a futile attempt given that the title and trailer are revealing of the plot. There is also a latent desire to underplay the theme. Sweety’s partner, Kuhu (played beautifully by Regina Cassandra) gets a mere 15 minutes of screen time. Yet, it doesn’t particularly take away from the final product.

Commendably, Dhar manages to keep the film from becoming preachy. But, what she achieves with this feat, she instantly loses when Sweety says Saahil must be a saviour for others like her. It is offensive, given that it treats heterosexuals as the all-powerful, while the unique as those who need rescuing. Despite the faltering and the flaws, this one is a hit for every romantic. It’s never too late to celebrate love without labels, right?

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Every year, April 14 is observed as Ambedkar Jayanti, to celebrate the birth of one of most exceptional leaders in Indian history, who rallied a revolution and became a voice to reckon with – Dr. B.R. Ambedkar. Reverently called 'Babasaheb', his life and legacy have been an inspiration for many. This Ambedkar Jayanti, &TV launches the Ek Desh Ek Awaaz initiative, to pay a special tribute to Babasaheb and his vision of a unified India. As a part of this initiative, the channel urges everyone to come together for Bheem Vandana and pay special homage to Babasaheb on April 14 at 8:00 pm only on &TV.

Considered as the architect of the Indian constitution, Dr. B.R. Ambedkar was a leader par excellence and whose legacy is unparalleled. He believed that the only way India could foster national unity and stability was through instating a unified code of One Nation One Constitution.

Here's what television artists had to say about the great man who charted the course of the country, to become a nation unified by one constitution.

Prasad Jawade says "Dr B.R. Ambedkar laid the foundation of a unified India by bringing millions of Indians under the ambit of one nation and one constitution. His teachings and philosophy still resonate with the Indians across the country, even today. As we celebrate the 129th birth anniversary of Babasaheb on April 14th, I urge everyone to come forward and join us in paying a special tribute to him at 8:00 pm on &TV.'

Neha Joshi says "Babasaheb truly was a visionary leader. Today, the way our nation has progressed, a lot of credit goes to him. He not only brought people together but also got them to take collective action towards all forms of suppression. On Ambedkar Jayanti, let us all come together to pay our respect to Babasaheb at 8:00 pm on April 14th on &TV."

Jagannath Nivangune says, "Dr Ambedkar was truly a leader par excellence. His work has touched and impacted the lives of all Indians. On Ambedkar Jayanti, I urge everyone to join us at &TV to pay a special tribute to Babasaheb at 8:00 pm."

Sneha Wagh says, "Babasaheb has been an inspiration to many. His ability to challenge and mobilize a revolution that redefined the democracy for the Indian soil made him one of the greatest leaders of our times. Let us collectively come together to pay a special homage to him - Dr B.R. Ambedkar at 8:00 pm on &TV on Ambedkar Jayanti on April 14th."

Rohitashv Gour says, "Dr B. R. Ambedkar was a great visionary leader. His only dream was to make our country as one unified nation through various social and economic reforms and of course through the writing of the Indian constitution. On Ambedkar Jayanti, I urge all the citizens to come together at 8:00 pm on April 14th on &TV to pay a special tribute to this prolific leader and social reformer – Dr B.R. Ambedkar."

Aasif Sheikh says, "I have grown up reading stories of Dr B.R. Ambedkar, and his fight for equality has had a great influence on me. Dr Ambedkar has been the most powerful advocate of equality and fraternity in modern India. On Babasaheb's birth anniversary, I request all my fans and viewers to join us at 8:00 pm on &TV to pay a special tribute to Babasaheb for his immense contribution to this nation."

Gracy Singh says, "Babasaheb is one of the most prominent voices in Indian history. Be it his fight for equality, women empowerment, or his involvement in the reformation of education; he has impacted the lives of every Indian. As we honour Babasaheb through our special tribute at 8:00 pm on &TV, I urge everyone to join me in this initiative to celebrate Ambedkar Jayanti."

Yogesh Tripathi says, "Dr Ambedkar envisaged our society as one based on liberty, equality and fraternity. It takes great vision and belief to bring about social and economic reforms that touched so many lives. Few other leaders could unite the nation the way Babasaheb did. Let all of us collectively come together to pay a special tribute to this great leader at 8:00 pm on &TV on Ambedkar Jayanti."

So, let us unite to pay a special tribute to Dr. B.R. Ambedkar through Ek Desh Ek Awaaz initiative at 8:00 pm to celebrate Ambedkar Jayanti only on &TV.

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Union minister Nitin Gadkari on Sunday said India should look at converting the world's "hatred" for China amid the coronavirus pandemic into an economic opportunity for itself by attracting large-scale foreign investments.

Interacting with overseas Indian students via video conferencing, the minister for MSME and Road Transport and Highways said across the world now, there is "hatred for China. Is it possible for us to convert it into an opportunity for India?" Referring to the economic package announced by Japan for its businesses exiting China, Gadkari said, "I feel that we should think on that and we will concentrate on it. We will open the Indian scenario for that. We will give the clearances and everything to them and attract foreign investment."

Asked if India can take any action against China incase it is found to have deliberately "suppressed" information on coronavirus, the minister said this was a sensitive subject related with the Ministry of External Affairs and the prime minister, and therefore it will not be appropriate for him to comment on it. Gadkari said all government departments, particularly the finance ministry as well as the Reserve Bank of India (RBI), are formulating policies to win the "economic war" post the COVID-19 pandemic and fulfil the prime minister's dream of making India a USD 5 trillion economy. "At the same time, we can make infrastructure of Rs 100 lakh crore," he added.

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Rise in plaintiffs comes as German chemicals group reports 19% jump in sales

A number of popular apps including Spotify, GroupMe, Pinterest and TikTok were fielding user iOS crash reports Wednesday evening, the result of an apparent issues with Facebook’s SDK according to a lengthy GitHub thread on the topic. Downdetector logged tens of thousands of user crash reports on Spotify between 3:30 and 5:30 pm PT, the […]

The Borussia Dortmund star is United's top transfer target and the club are said to be convinced they have got their man after holding secret talks, according to recent reports.

On a Friday night it's more common to be sipping a vodka cocktail than to be applying one to your hair.

COMMENT: Perhaps, the one plus side to this summer's European Championship being moved to 2021 is that it offers Kane time. The team figurehead will not have to rush to get back.

Former Chicago Bulls star Dennis Rodman opened up on his unlikely friendship with the Supreme leader of North Korea Kim Jong-un ever since he visited the country in 2013.

Adrian Pearson, 48, smashed bottles, abused staff, attacked a taxi driver and hit a police officer during an alcohol-fuelled rampage in Chester-le-Street but was only given a suspended sentence.

A deal worth £300million from Saudi Arabia's Private Investment Fund, Amanda Staveley and the Reuben Brothers to take control of the club from current owner Mike Ashley is close to being finalised.

Celebrities including Simon Cowell were spotted looking rather bleary-eyed as they left The Grosvenor House Hotel in London on Monday night.

Ora was joined on stage by Iggy Azalea and actress Emmy Rossum, who both danced next to her as she continued singing.

British singer Rita Ora wore a zebra-print fur coat over a black and red plaid dress while American actress Victoria Justice looked elegant in monochrome black and white as they lent their support for designer Donna Karan at her fashion show Sunday.

It was confirmed on Wednesday that Gigi Hadid is expecting a baby girl with on-and-off boyfriend and former member of One Direction Zayn Malik, 27.

Australia's Eurovision star Kate Miller-Heidke has shared details of her experience with postnatal depression.

The world number one is currently inactive, with the golfing calendar suspended due to the coronavirus pandemic. But McIlroy spoke to Sportsmail's Redknapp about all things golf.

JAMIE REDKNAPP - Word is Jordan Henderson could be fit to face Atletico Madrid in Wednesday's second leg at Anfield and do not underestimate the impact that would have for this team. 

She's newly single after splitting from Chris Hughes - and Jesy Nelson showed off her incredible abs as she posed for an Instagram picture on Monday. 

Harry Redknapp believes a sure-fire way of Jose Mourinho getting the backing of Tottenham fans would be to sign Gareth Bale. Bale moved from Tottenham to Real Madrid six years ago.

The 40-year-old actress announced the launch of King St. Vodka today. It's named for the street she once live on in New York City.

Hudson, the daughter of Hollywood star Goldie Hawn, already has her own line of active wear called Fabletics and a clothing line called Happy X Nature.

JAMIE REDKNAPP: If Mourinho needs a striker, then he could do worse than look at Troy Parrott. He's been training with the first team, learning from the master Kane and has been capped by Ireland.

JAMIE REDKNAPP: We look at VAR as if it's the oracle but in reality it's one man, sat behind a bank of screens at Stockley Park, offering his opinion. It's not matter of fact - it's subjective.

JAMIE REDKNAPP: Watching Paul Pogba send his header into the back of Bournemouth’s net was like seeing LeBron James leap up to the hoop. The power, the pace, how high he gets.