Rupa Subramanya: Trudeau is a left-wing populist who may have bought himself the next election – National Post

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On Aug. 6, 2019, 55 per cent of those polled by Morning Consult disapproved of Trudeau and only 39 per cent approved. The gap began to close after the Liberals narrow re-election victory in October 2019, but Trudeaus net approval still remained in negative territory.

The pattern shifted dramatically in March 2020, as the first wave of COVID-19 hit. On March 23, the two lines finally crossed and Trudeau has had positive net approval ratings ever since. Among other Western leaders, German Chancellor Angela Merkel saw a similar jump in her approval ratings around the same time as Trudeaus.

While COVID-19 has been, and continues to be, a curse for humanity, the truth is that it has salvaged the careers of numerous politicians who appeared to be in deep trouble less than a year ago. Merkel was seen as a lame duck and Trudeau was reeling from scandals that came to light during his first term, to say nothing of the Blackface controversy that tarnished his woke image.

Fast forward to today, and Merkel is being described as one of Germanys greatest post-war leaders, while the Liberals, according to the latest CBC poll tracker, have a 49 per cent chance of winning a majority if the election were held today.

Despite its various missteps including its failure to put meaningful restrictions on international travel, the time its taking to roll-out rapid testing and its cock-up of the vaccine roll-out the Trudeau government has managed to buy a lot of voters with its massive public spending.

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The Century of Populism 01/30/2021 World KSU | The Sentinel Newspaper – KSU | The Sentinel Newspaper

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Populism is a global socio-political phenomenon and its emotional and debilitating nature of liberal democracy is one of its hallmarks. Personalist leaders around the world have attempted to weaken counter-majority institutions in order to exercise unhindered political power. Will the 21st century be marked by the steady rise of populist governments or will they have some kind of limit?

Pierre Rosanvallons recent publication, The Century of Populism (Ediciones Manantial, 2020), helps us understand the different characteristics of populist leaders left and right in the 21st century around the world.

This, through the approach of an anatomy of populist political culture with the identification of five elements that constitute it: the conception of the people, the theory of democracy, the modality of representation, the politics and the philosophy of economy and a regime of passions and emotions.

In the case of the United States, the political behavior and discursive recurrence of Donald Trump embodied some of these elements and, although he is no longer in office, left an imprint in the history of the country that will be difficult to understand. to erase.

The emotionality embodied in Trumps political speeches, structured in the us versus them logic, and the ongoing torpedoing of democratic institutions, has been a constant that peaked on January 6.

According to Nancy Pelosi, Speaker of the House of Representatives, the objective of the presidents supporters was to end our democracy, after sending a political message to his supporters with a withering phrase that says a lot about his philosophy of life : fight like hell.

It is a discursive strategy that had fake news, conspiracy theories and the deep state as fertile ground, a supposed network of public officials who act secretly, like the de facto power that is out of sight of the public. audience, controlling them manipulating things.

A perfect cocktail to maintain a regime of passions and emotions, the main connotation of populist political culture in which, as Rosanvallon says, objects are magnified in the midst of darkness. In the shade, everything seems hostile and gigantic.

This problem has only worsened in a world where disinformation, revelations and scandals arise every moment, while suspicions against the powerful are constantly renewed and confidence in institutions crumbles.

Another notable element of the populist universe is the polarization and destruction of the political center, a place where it is possible to deliberate, reach consensus and play by the rules of the game. In Bolivia, Evo Morales ran for the fourth consecutive time for the presidency in 2019, when he lost a constitutional referendum with which he was trying to renew his candidacy.

This weakened the democratic institutionality of the state, generated civic unrest, social polarization and civic rebellion which led to the resignation of the former president. According to Carlos de la Torre, although Latin American populisms from Pern to Chvez included the poor and the destitute, their practices in power were authoritarian.

In fact, the Constitutional Court acted as a puppet of the executive power administered by Evo for the benefit of its postulation, but to the detriment of the popular vote and the legal and legitimate result of a constitutional referendum which was unfavorable to it. From the point of view of political democracy and contrary to populist political culture, the Constitutional Court implies restrictions on independent authorities and a reduction of its area of intervention.

The consequences of this political event were the progressive weakening of the counter-majority institutions. According to famous political scientist Adam Przeworski, the function of constitutional courts is to protect rights against the whims of temporary majorities. But in Bolivia, the opposite happened: the Constitutional Court gave in to the whim of a temporary majorities leader who lost under the rules of democracy.

In perspective, it is an event that has undermined the political democracy of the country. But, more than that, it has made citizens distrust of public institutions and turned the constant violation of norms of social and political coexistence into habitual and almost natural behavior.

Without a doubt, Pierre Rosanvallon allows us to gain a broader and deeper understanding of populism as a political phenomenon. With its conceptual tools, it is possible to distinguish and interpret certain political events carried out by political leaders who break the rules of the game by identifying an enemy to attack and destroy, seeing themselves as the unique embodiment of collective interests.

However, the advancement of populist political culture seems to have no limits in the 21st century, the followers of messianic rulers continue to grow and lie in different spaces of the ideological spectrum. His political arguments are polarizing and based on fake news. Worse yet, they dilute the sanity of the political center, where democratic institutions must serve as regulators of passions and emotions.

* Translation by Maria Isabel Santos Lima

http://www.latinoamerica21.com, a pluralist media engaged in the dissemination of critical and true information about Latin America.

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Robinhood fiasco shows that populist movement was right all along Robinhood fiasco and the populist movement – Invezz

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The past decade has been defined by a populist movement all over the world. From the Arab Spring to Brexit to mass protests on both sides of the American political aisle, millions of everyday citizens around the world have watched the rich getting richer while they get poorer, and decided theyve had enough.

Set aside the specific reactions that populists have had for a moment, and consider whats driven all that anger: skyrocketing income equality, and as weve seen this week, rigged markets.

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If youre just catching up, read Invezz author Charlie Hancoxs excellent breakdown of the Robinhood fiasco that saw the trading platform stop accepting buy orders on graveyard-to-penthouse stocks such as AMC (AMC) and GameStop (GME). The short version of the story is that waves of retail investors started making a killing by trading beaten-down stocks on Robinhood that were being shorted in droves by hedge funds. So Robinhood responded Thursday by restricting trading on AMC, GameStop, and other heavily traded former laggards to closing positions only. The result was that hedge funds caught a huge break, while retail investors got demolished as these graveyard stocks tanked.

Its possible that the massive spike in Robinhood trading activity risked causing some huge catastrophe that we dont know about. But if you want to know whats triggered global outrage and a populist movement, consider whats happened to the world economy during the COVID-19 crisis, and also what happened in the years leading up to it.

Forget average salaries. If you want to measure peoples ability to live and provide for their families, real wages is a better metric. Real wages refer to wages adjusted for inflation, i.e. the goods and services that can be bought with the money that you make. It turns out that real wages have stagnated in many of the largest economies of the world for more than 40 years.

That already bleak picture only begins to tell the full story. If you break down average real wages in the past 40-plus years, when gains have occurred theyve overwhelmingly and disproportionately flowed to the highest tier of earners. As Pew Research explained in a 2018 report:

Meanwhile, wage gains have gone largely to the highest earners. Since 2000, usual weekly wages have risen 3% (in real terms) among workers in the lowest tenth of the earnings distribution and 4.3% among the lowest quarter. But among people in the top tenth of the distribution, real wages have risen a cumulative 15.7%, to $2,112 a week nearly five times the usual weekly earnings of the bottom tenth ($426).

Macro studies like these also miss some of the finer points and bigger challenges facing folks who are just trying to get by. For instance, the average price of a home in the U.S. more than doubled from 2000 to 2020, blocking millions of families from attaining housing stability while making one of the most effective methods of wealth accumulation available only to those who can afford the rising price of admission.

The wealth gap becomes far more shocking when you consider whats happened in the past year alone. Of the many forms of harm that the pandemic has caused, one of the most devastating has been massive spikes in global hunger. The rising death tools that we see on the news everyday dont take into account the hundreds of millions of people around the world facing mounting food insecurity, and the fast-growing number of deaths caused by hunger related to COVID-19.

So how are the worlds billionaires doing while all this is going on? The super-rich have collected added trillions to their collective wealth since global lockdowns started popping up less than a year ago. Its not hard to draw line from Point A to Point B too: While mom-and-pop businesses around the world have gone under during the pandemic, megacompanies like Amazon have seen massive growth in revenue and market share.

Stagnant wages. Declining rights for labourers. Mass job losses. Millions dying from a deadly virus and the poverty and hunger that have come with it. All coupled with skyrocketing housing prices, billionaires becoming multi-billionaires, bailouts for corporations while individuals go broke, and a political class that so far has done almost nothing to solve any of these problems, other than voicing their supposed outrage on Twitter.

Given all of those toxic factors smashed together, you can see why people would look at Robinhoods breakdown and conclude that the game of life is rigged. You can also see why the populist movement is raging, and why people around the world are beginning to revolt.

WallStreetBets, we salute you.

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Robinhood fiasco shows that populist movement was right all along Robinhood fiasco and the populist movement - Invezz

The media must not give African leaders platforms to spout homophobia it only helps their populism – Open Democracy

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In a recent interview with the UKs Channel 4 News, for example, Museveni claimed that Wine was being encouraged by Western homosexuals. The interviewer, Lindsey Hilsum, pushed back, asking what have the homosexuals got to do with it? and Museveni struggled to give a coherent answer, live on television.

Some local media has also withstood Musevenis attempts to make the political conversation about homosexuality. When Wines supporters, urban youth, took to the streets in protest and eventually riots after his arrest by state security, Museveni claimed the mayhem was an insurrection sponsored by homosexuals. Police said they arrested Wine for gathering a campaign crowd of more than 200 supporters, contrary to coronavirus restrictions.

The Kuchu Times responded by foregrounding voices that criticised Musevenis populist tactics and evasion of accountability, writing: These [homophobic] sentiments are usually heightened during campaign season and like clockwork, this same tired card is now being played to distract the citizenry.

Other shifts in the political landscape also made Musevenis homophobia less potent this election season. While he has been the default candidate for Christian moralists in the past, this time the Catholic Church threw its weight behind Wine and the evangelical church fielded three presidential candidates of their own.

Museveni has never had much traction with young, urban, middle-class Ugandans who watch international news shows like Amanpours. They love to hate him. For weeks now, #WeAreRemovingADictator, has been trending online.

His election campaign created a fake social media network to counter such online rejection. But his team was caught in the act, first by investigative journalists, and then by Facebook for coordinated inauthentic behavior. The social media giant closed numerous associated accounts, including those owned by Musevenis own press secretary.

This election season has been Musevenis hardest and in this context, Amanpour giving him a platform for his homophobia gave him a ray of light, and a rare opportunity for him to connect with voters on terms that he enjoys.

Some people who may otherwise see him as a dictator have actually rallied around him because of this interview. They see an African leader dismissing one of the Wests most famous journalists, in a way that allows them to feel self-righteous. They seem to have heard: Take that, world! We are independent people too!

Journalism has the potential to advance and add nuance to public debate about sexual rights and politics without inflaming outrage and without doing PR for populists.

I think Amanpour got it wrong on this occasion but she is an exception. Journalists around the world can learn from how the majority of their colleagues have covered the Ugandan leaders homophobia. These lessons include: talk about the people on the ground, not the political debates. Also, hot seat interviews are probably not the best way to hold politicians accountable. Do investigative journalism on these issues instead.

On 16 January 2020, two days after the controversial and disputed election, Museveni was declared the winner with 58% of the vote. It is the lowest majority he has ever got at the polls. On this occasion, every vote for him helped him stay in power.

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The media must not give African leaders platforms to spout homophobia it only helps their populism - Open Democracy

The AltFi view on Gamestonk: Populism is coming to fintech – AltFi

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Alternative LendingDigital BankingSavings and Investment

Stock market mania isnt new or innovative but, nonetheless, the future of investing for both retail and institutional money is set for rapid change as more and more participants come online.

Weekly Leading Article

Its a strange situation that unites Alexandria Ocasio-Cortez, Ted Cruz and Donald Trump Jnr. to a common cause.

Just one month in, irony looks set to be the best performing asset class in 2021, surpassing puppies' 500 per cent bull-run in 2020 when demand for pedigree pooches skyrocketed under lockdown.

Last week Robinhood, not exactly true to its folkloric namesake, shut off market access to retail investors in favour, according to six million Reddit users, of Wall Street's evil hedge funds.

What transpired? Was it collusion? What does it mean for the future of investing in the stock market? Was it all just a tad overblown?

No doubt, much of the activities on Wall Street last week, that saw an army of Reddit users push the price of a battered analogue business heavily shorted by professionals sky-high, were due to a combination of lockdown boredom, speculative greed and vitriolic desire to stick it to The Man. But, something more profound was at work too.

The power of the crowd, helped by lower barriers to entry to invest in the stock market and the giddying power of social media brought about a huge rise in the price of GameStop as well as a number of other stonks (stocks). It also pushed some formerly powerful hedge funds to hurry out of short positions in these companies and away with a bloody nose. It would be short-sighted to expect this to be the end of the story.

Robinhood, the biggest, most deep-pocketed and most well-known name in the digital wealth sub-sector of fintech, acted for unknown reasons when irritating its users, half of whom had piled into GameStop, but no doubt it did so because it had to.

The contagion was not just felt in the US. Freetrade in the UK, which provides a similar level of market access for UK-based investors had to put in a weekend of hard graft to work to off-set issues it had with providing US market access to its customers owing to its FX partner bank.

If there is a long term trend of greater and greater dominance of the retail investor in markets underway this is both a good thing in terms of fulfilling fintechs promise to democratise financial services but also carries the risk of uncharted populism that might well end in Trumpian catastrophe, not least for those investors bidding up the share price of a failing company that will ultimately crash.

Principally this is the kind of un-checked animal spirits that encourages people to bet using money they cant afford to lose. Decades of regulation have been driven by a belief in theneed to protect the retail market and encourage sensible practices. But in the age of the Reddit forum, much of it clearly needs updating.

More retail investors could spell long-lasting positive change, however. Shareholders also hold sway over companies values, future direction and executive compensation via voting rights. Traditionally, fund managers have voted on behalf of their retail and institutional clients at company AGMs but if the last week has shown us anything, its thatsocial medias populist power can quickly galvanise behind a cause. This could lead to meaningful positive change in areas such as climate change and persecution of minoritiesbut as the politics of the past five years or so have shown, populismcan also lead to chaos.

The AltFi Leader is a new weekly view for 2021 from our editorial team. Wed love to hear your ideas, thoughts, feedback and constructive criticism.editorial@altfi.com

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The AltFi view on Gamestonk: Populism is coming to fintech - AltFi

Researchers identify rare genetic syndrome caused by gene mutations – Health Europa

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Advances in DNA sequencing have uncovered three classes of mutations within the gene SATB1, which result in three variations of a neurodevelopmental disorder with varying symptoms ranging from epilepsy to muscle tone abnormalities.

The study, co-authored by academics from Oxford Brookes University, University of Lausanne, Radboud University, University of Oxford, University of Manchester, and led by Max Planck Institute for Psycholinguistics (The Netherlands), identified 42 patients with mutations in the gene SATB1 who were all displaying a range of similar symptoms, with varying severity.

The newly identified SATB1-syndrome is characterised by neurodevelopmental delay, intellectual disability, muscle tone abnormalities, epilepsy, behavioural problems, facial dysmorphism, and dental abnormalities.

Dr Dianne Newbury, Senior Lecturer in Medical Genetics and Genomics at Oxford Brookes University said: Previously, just one or two cases of patients with SATB1 variations had been described but it was not recognised as a specific syndrome. Patients displaying these characteristics and their families, will have known that they had an undefined neurological condition, but they wouldnt have known any specific detail about the condition, or why they had it.

We hope that the recognition of this new disorder, and the information about the molecular pathways contributing to it, will help the families and individuals affected understand more about the condition and achieve a diagnosis they would not have had previously.

The mutations were found to belong to three different classes with the first mutation class causing a loss of function of the SATB1 gene and halving the production of the encoded protein, leading to a less severe syndrome characterised by diminished cognitive function, visual problems, and facial dysmorphism.

The second class of mutations encode shorter proteins that are less efficient, ad shows as an intermediary syndrome, characterised as more severe than the first, but less severe than the third.

The third class modify the encoded protein, making it more active. This altered protein is sticky and binds better to DNA, diminishing the expression of genes it regulates and causing a more severe type of disorder, characterised by severe intellectual disability, epilepsy, a motor speech disorder (dysarthria) and specific facial features.

Dr Alexandre Reymond, Director of the Center for Integrative Genomics at the University of Lausanne in Switzerland said: These results demonstrate that each mutation is different and that is essential to understand their mode of action in order to explain the origin of genetic diseases. We must go beyond sequencing, which is only a first step.

The paper, Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction, has been published in The American Journal of Human Genetics.

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Human Genetics of Life-Threatening Infections | Events – Imperial College London

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Please join us for the latest instalment of the Wright-Fleming Institute,Infection and Immunity Seminar Series

Vanessa Sancho-Shimizus research is focused on identifying inborn errors of immunity underlying life-threatening infections of childhood ranging from invasive bacterial diseases to severe viral infections including herpes simplex encephalitis (HSE), severe COVID-19 disease, and invasive meningococcal disease (IMD).

She obtained her PhD at McGill University in Montreal, Canada on the genetics of host resistance to Salmonella infection. She moved to the laboratory of Human Genetics of Infectious Disease at Necker Enfants Malades Hospital/University Paris Descartes for her postdoc developing an expertise in investigating Mendelian predisposition to childhood HSE, and TLR3-antiviral IFN pathways.

She came to Imperial College in 2012 as a Marie Curie Research Fellow continuing her work on understanding childhood HSE but has also extended the search for Mendelian defects to other infectious phenotypes including severe childhood viral infections and IMD. She has particular interests in the type I IFN signalling pathway and autophagy. She started her own group in 2014, and is a UKRI Future Leaders Fellow and Lecturer in the Department of Infectious Diseases at Imperial College London St Marys Campus.

A recording will be available for college users. Event recording will be available via Teams/WFI seminar series listing page by the following day.https://www.imperial.ac.uk/infectious-disease/research/virology/wright-fleming-seminars/

Click here to join the meetingJoin on your computer or mobile app

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Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them – Gwinnettdailypost.com

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It's an ancient disease that may have evolved to confer protection against the plague -- but until 20 years ago, it had scientists and doctors flummoxed.

They couldn't explain why those afflicted, often in the same family, had recurring fevers, abdominal pain, troublesome rashes and muscle aches. Known as familial Mediterranean fever, the disease often went undiagnosed for years, and it was sometimes fatal.

Stacker ranked the 50 most physical jobs in America using data from the Occupational Information Network (O*NET), a system developed by the U.S. Department of Labor providing information for 965 occupations within the United States economy. Click for more.

A similar, but unrelated, mystery fever was initially thought to affect families with Scottish and Irish heritage.

"The pain I felt back then, it moved around. One week the pain was in my leg, and the next week my arm would hurt instead," said Victoria Marklund, 47, a Swedish woman who suffered from TRAPS, or tumor necrosis factor receptor-associated periodic syndrome, a disease first identified in a family of Irish and Scottish descent living in the UK city of Nottingham in 1982.

Her father and grandfather died prematurely from kidney complications, which were likely a consequence of the undiagnosed disorder.

Marklund has now received an effective treatment and lives symptom-free -- largely thanks to the work of one US physician and health researcher, Dr. Dan Kastner, a distinguished investigator at the National Institutes of Health who serves as scientific director of the National Human Genome Research Institute.

The Royal Swedish Academy of Sciences on Monday awarded Kastner the prestigious Crafoord Prize, considered a complement -- and for some winners, a precursor to -- a Nobel prize.

"What Dr. Kastner has accomplished is absolutely groundbreaking. The concept of autoinflammatory disorders didn't exist before he identified the cause behind a number of them," said Olle Kmpe, a professor of clinical endocrinology at Karolinska Institutet in Stockholm who is a member of The Royal Swedish Academy of Sciences and chair of the Prize Committee. The academy also selects Nobel laureates.

"His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of disease from which patients previously suffered enormously," Kmpe added.

Breakthrough

Kastner first came across familial Mediterranean fever in a patient with recurring arthritis and high fevers he treated as a rheumatology fellow just months into his first job at the NIH in Bethesda, Maryland, in 1985. That chance diagnosis set him on a 12-year journey to find the gene -- or genes -- responsible for the disease.

"It was known that familial Mediterranean fever was a genetic disease. It was known that it was recessively inherited, but no one knew what the gene was, or even the chromosome," he said.

He traveled to Israel, where he took blood samples from 50 families with familial Mediterranean fever.

It took Kastner seven years to locate the mutation to chromosome 16. It took another five years -- in 1997 -- for Kastner and his team to find the mutated gene itself -- one misprint in a genetic code comprised of 3 billion letters.

After this breakthrough, he stayed at NIH, where he studied undiagnosed patients with similar symptoms. He identified 16 autoinflammatory genetic disorders and found effective treatments for at least 12 of them, establishing a whole new field of medicine.

Now that the full human genome has been mapped, the process of detecting the genetic root of such disorders is quicker, and greater numbers of patients with these rare, unexplained diseases are being helped as a result of Kastner's work.

All-nighters

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There are few images in science more iconic than the DNA double helix structure, discovered in 1953 by James Watson and Francis Crick, two years after Kastner was born. As a seventh grader, he once created a version of the twisted ladder shape using jelly beans and pipe cleaners for a science fair.

Fast-forward to Kastner's medical career, which started in the early heyday of genetic research. He was inspired by the international race in the late '80s to identify the cystic fibrosis gene -- an achievement that at the time was called "one of the most important in human genetics."

His work to identify the gene that caused familial Mediterranean fever had its own element of competition. In the summer of 1997, to beat a rival team led by French researchers, Kastner took a last-minute flight from Bethesda, Maryland, where the NIH is based, to Boston to submit his manuscript detailing the gene mutation that caused familial Mediterranean fever by hand to the journal Cell on a Friday afternoon.

These were the days before papers could be submitted with the click of a mouse. He hoped to publish his work first. Ultimately, the two teams published their papers simultaneously in different journals -- both fortunately arriving at the same finding.

"I love that type of thing," he said. "We still have races to the finish, and there's nothing like a good week of all-nighters."

Kastner had discovered that the gene involved in familial Mediterranean fever produces a protein called pyrin. Normally this helps to activate our innate immune system -- our first line of defense to fight bacteria and viruses.

In this case, however, pyrin made the innate immune system become overactive, resulting in fever, pain and joint inflammation. He went on to study patients with similar and more devastating symptoms -- identifying TRAPS and many more rare diseases.

The family of diseases identified by Kastner are distinct from autoimmune diseases like rheumatoid arthritis and lupus, in which a different branch of the immune system malfunctions.

Transforming lives

What has motivated Kastner for five decades is how his work decoding the genetics of inflammation can inform new treatments and ultimately transform patients' lives.

"There's nothing more gratifying in life and nothing more satisfying scientifically," he said. He plans to step down from his role as scientific director at the NIH in the next few months and then focus his efforts on his clinic, where he has over 3,000 patients enrolled and "find yet more disease genes, understand how they work, and develop new treatments."

"Of course, one can never know how long that will last, but I love doing it, and will continue as long as I can."

In more recent work beginning in 2014, Kastner identified and pioneered treatment for a severely debilitating genetic disorder known as DADA2, short for deficiency of the enzyme ADA2 (adenosine deaminase 2), which can cause recurring fevers and strokes starting in childhood. His research has radically improved the life of the daughter of Dr. Chip Chambers.

"My daughter, who is 23, was sick from age 2. She got very sick late in her teen years. No one could figure it out. We didn't know what was wrong with her," said Chambers, an assistant clinical professor of surgery at Vanderbilt University Medical Center in Nashville, Tennessee, and founder of the DADA2 Foundation.

"She's now at college and the improvement in her quality of life has been dramatic."

Similarly, TRAPS survivor Marklund suffered for years before her diagnosis at the age of 38. Her nephews, who both have TRAPS but have been given medicine from an early age, don't feel the effects of the disease at all, she told The Royal Swedish Academy Of Sciences.

"I doubted many times that anyone would ever figure out what I was suffering from. So now it feels fantastic, to be told what it was, to understand the cause of the disease and that there is medicine that helps."

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Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them - Gwinnettdailypost.com

The risks and rewards of at-home genealogy testing – CBS News

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In 1953, James Watson and Francis Crick announced that the shape of DNA was a double helix. This monumental discovery of the structure of DNA empowered generations of scientists to unlock many mysteries of the human body.

In the nearly 70 years since that Nobel Prize-winning breakthrough, the Human Genome project sequenced the makeup of the entire human body, and a new at-home genealogy testing industry was born.

Companies including Ancestry.com and 23andMe have capitalized on new technology that allows customers to spit in a tube and mail in their saliva sample to labs to reveal information about their genetic make-up and ancestral origins.

This week on 60 Minutes, top intelligence officials from the United States government told correspondent Jon Wertheim about DNA data aggregation by foreign nations and the potential threat it poses to the United States.

"Sometimes Americans or people around the globe don't even know the value of their DNA, [or] that it even has value," said Bill Evanina, the former Director of the National Counterintelligence and Security Center. "But it's your single, sole identifier of everything about you as a human being."

Evanina served under Presidents Barack Obama and Donald Trump before he resigned from his senate-confirmed position earlier this month. He said each person has a fiduciary responsibility to safeguard their DNA.

When DNA samples are aggregated into large datasets, their value increases.

Law enforcement officials told 60 Minutes they are concerned about the lack of public awareness over who may eventually have access to an individual's DNA data after a sample is submitted through an at-home genealogy company. The U.S. lacks federal regulations specific to third party aggregation and the sale of genetic data.

"In the U.S., your HIPAA law allows you to have protection based upon what's called covered providers, your health care company or your health care provider, but not third-party aggregators or collectors of data like genetics [providers]," Evanina said.

Anne Wojcicki, the cofounder and CEO of direct-to-consumer DNA testing firm 23andMe, told 60 Minutes that she believes that her company adheres to stricter security measures than HIPAA requires.

"If I want to provide my customers with the best data security, there's all kinds of standards that are out there that do not involve HIPAA," Wojcicki said. "We have an incredibly sophisticated, nimble team that thinks all day long about data security, privacy, how do we make sure that we are doing everything reasonably possible to protect our customers' data."

In 2018, 23andMe began a partnership with the pharmaceutical company GlaxoSmithKline to develop medicines based on human genetic information. Wojcicki said that her company never defaults its customers into the database the firm uses for research, but that 80% of 23andMe's clients have opted in.

"If you talk to anyone who is sick, especially anyone with a terminal illness and you ask them what they want, what they're looking for is a treatment or something that's going to benefit their children," Wojcicki said to Wertheim. "And we learned the most important thing that 23andMe could do would be to put our own money into developing ways our customers are going to benefit from the human genome. But I should emphasize we are reinvesting all of our money into therapeutics development."

True to her promise of using the company's technology for the public good, last week, 23andMe launched an interactive tool that the company says, "allows people to see how certain non-genetic factors may impact the risk for hospitalization due to the [COVID-19] virus." On its website, the company says the tool was created using data from at least 10,000 people who enrolled in the study and provided saliva samples.

These samples may help advance scientific understanding of COVID-19, while also illustrating the potential that lies in large troves of DNA data, built on a foundation laid by scientists Watson and Crick nearly seven decades ago.

The videos above were produced by Keith Zubrow and Sarah Shafer Prediger. They were edited by Sarah Shafer Prediger.

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The risks and rewards of at-home genealogy testing - CBS News

Light-activated genes illuminate the role of gut microbes in longevity – Baylor College of Medicine News

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Getting old is a complex matter. Research has shown that gut microbes are one of the factors that can influence several aspects of human life, including aging. Elucidating how a specific microbial species contributes to longevity is quite challenging given the complexity and heterogeneity of the human gut environment.

To explore the influence of bacterial products on the aging process, researchers at Baylor College of Medicine and Rice University developed a method that uses light to directly control specific gene expression and metabolite production from bacteria residing in the gut of the laboratory worm Caenorhabditis elegans.

We used optogenetics, a method that combines light and genetically engineered light-sensitive proteins to regulate molecular events in a targeted manner in living cells or organisms, said co-corresponding author Dr. Meng Wang, Robert C. Fyfe Endowed Chair on Aging and professor of molecular and human genetics and the Huffington Center on Aging at Baylor.

In the current work, the team engineered E. coli bacteria to produce the pro-longevity compound colanic acid in response to green light and switch off its production in red light. They discovered that shining the green light on the transparent worms carrying the modified E. coli induced the bacteria to produce colanic acid, which protected the worms gut cells against stress-induced mitochondrial fragmentation. Mitochondria have been increasingly recognized as important players in the aging process.

When exposed to green light, worms carrying this E. coli strain also lived longer. The stronger the light, the longer the lifespan, said Wang, an investigator at Howard Hughes Medical Institute and member of Baylors Dan L Duncan Comprehensive Cancer Center. Optogenetics offers a direct way to manipulate gut bacterial metabolism in a temporally, quantitatively and spatially controlled manner and enhance host fitness.

For instance, this work suggests that we could engineer gut bacteria to secrete more colanic acid to combat age-related health issues, said co-corresponding author Dr. Jeffrey Tabor, associate professor of bioengineering and biosciences at Rice University. Researchers also can use this optogenetic method to unravel other mechanisms by which microbial metabolism drives host physiological changes and influences health and disease.

Read the complete report in the journal eLife.

Other contributors to this work include first author Lucas A. Hartsough, Mooncheol Park, Matthew V. Kotlajich, John Tyler Lazar, Bing Han, Chih-Chun J. Lin, Elena Musteata and Lauren Gambill. The authors are affiliated with one of more of the following institutions: Baylor College of Medicine, Rice University and Howard Hughes Medical Institute.

Funding for this project was provided by Human Health Services and National Institutes of Health grants (1R21NS099870-01, DP1DK113644 and R01AT009050), National Aeronautics and Space Administration (grant NSTRF NNX11AN39H), the John S. Dunn Foundation and the Welch Foundation.

By Ana Mara Rodrguez, Ph.D.

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Light-activated genes illuminate the role of gut microbes in longevity - Baylor College of Medicine News

Dogs likely migrated to the Americas with humans over 15,000 years ago, study says – WAAY

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Dogs have been following humans for thousands of years.

Archaeological and genetic data has revealed that dogs accompanied humans when they were migrating to the Americas from East Asia, according to a study published Monday in the Proceedings of the National Academy of Sciences.

Dogs were likely domesticated over 23,000 years ago in Siberia, said lead study author and archaeologist Angela Perri, a research fellow at Durham University's department of archaeology in the United Kingdom. Her team analyzed the genetic makeup of ancient dog remains to estimate when the domestication from wolves to dogs happened.

Archaeological evidence showed that the humans migrated over 15,000 years ago from Northeast Asia across the Bering Land Bridge, a piece of land that connected modern-day Russia to Alaska. The land crossing no longer exists due to rising sea levels.

Perri studied the lineage of American dogs outside the Arctic, which come from a different genetic ancestor than Arctic dogs, and traced it back to ancient Siberian dogs. This lineage has shown that humans brought their dogs with them when they migrated to the Americas, according to the study.

Many people have dogs as pets today and some wonder, "What is this animal and how did it go from a wild predator to curled up next to my bed?" Perri noted.

While there is no definitive answer on why dogs became domesticated, the freezing climactic conditions during this time likely brought wolves and humans closer together for survival, she said.

"Wolves likely learned that scavenging from humans regularly was an easy free meal, while humans allowed this to happen so long as wolves were not aggressive or threatening," Perri said.

The dogs could have also helped humans transport items faster, she said. There is also evidence in the Pacific Northwest of humans using furry creatures as emergency sources of food and fur.

The study is a fascinating example of how canine and human DNA and archaeology can be used to find out more about our past, said Jeffrey Kidd, associate professor of human genetics at the University of Michigan Medical School, who was not involved in the study.

Modern dogs are similar to domesticated dogs from 15,000 years ago, he said, but today there are different furs and colors as a result of breeding.

Kidd is not surprised that humans brought their dogs with them when they migrated to the Americas because of how intertwined dogs are in our society.

"If you and your entire community was going on a journey across the land, wouldn't you bring along your dog?" Kidd said.

The earliest confirmed dog bones were found in Germany over 100 years ago and are about 15,000 years old, Perri said, so her next project is to search for older dog bones in Siberia to aid in her research. She's hoping to gather more evidence to discover how dogs became man's best friend.

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Neurophth Therapeutics Further Expands Ocular Gene Therapy Expertise with Appointment of Qiutang Li, Ph.D., as Chief Scientific Officer – PRNewswire

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Dr. Li has over 30 years of experience in basic and applied biomedical research. She joins Neurophth from the University of Louisville School of Medicine, where she was a professor in the department of Ophthalmology and Visual Sciences for over 14 years. Her research focuses on the role of Hippo/YAP1 signaling pathway on different stages of ocular development, NF-kB/IKK2 inhibition of neovascularization, and gene discovery screening for eye diseases using mouse models.

Throughout her career, Dr. Li has contributed to more than 45 publications in journals including Investigative Ophthalmology & Visual Science (IOVS), Proceedings of the National Academy of Sciences of the United States of America(PNAS), Nature Review Immunology, and Science. She is currently the editorial board member of Scientific Reportsand Source Journal of Ophthalmology. Dr. Li holds a Ph.D. in cell biology from the Washington University in St. Louis and obtained both her Bachelor's and Master of Science degrees in Genetics from Beijing University.

"We are thrilled to have Dr. Li on our team, bringing over 3 decades of her diverse experience in basic and applied biomedical research," said Bin Li, M.D., Ph.D., Founder and Chairman of the Board of Neurophth. "Given her prior experience at Baylor College of Medicine mentored by Dr. Savio Woo, an internationally recognized expert in molecular human genetics and gene therapy, and Dr. Mark Kay, a leading researcher in the fields of AAV gene therapy and the current Head of Division of Human Gene Therapy at the Stanford University School of Medicine, Dr. Li has extensive knowledge in gene therapy for hepatic deficiencies, ocular diseases, and viral vector reconstruction."

"We are excited to have Qiutang join and expand our exceptional research and development team. She brings a wealth of experience in gene therapies for ocular diseases to Neurophth," said Alvin Luk, Ph.D., M.B.A., C.C.R.A., Chief Executive Officer at Neurophth. "Her deep understanding of viral vector design and animal models in the inhibition of neovascularization for ocular diseases, such as age-related macular degeneration and diabetic retinopathy, further bolsters our ability to deliver on our growing pipeline of clinical programs and platform capabilities."

"It has been captivating to watch the scale, scope, and speed with which Neurophth has successfully transformed itself into an innovative and diversified gene therapy company," said Dr. Li. "I look forward to being a part of Neurophth team as the company executes the next stage of its growth strategy and expands its pipeline of gene therapy candidates focused on ocular and non-ocular diseases, building a brighter future for patients worldwide."

About Neurophth

Neurophth is China's first gene therapy company in ophthalmic diseases.Headquartered in Wuhan with subsidiaries in Shanghai, Suzhou, and the U.S., Neurophth, a fully integrated company, is striving to discover and develop gene therapies for patients suffering from blindness and other eye diseases globally. Our AAV validated platform which has been published in Nature - Scientific Reports, Ophthalmology, and EBioMedicine, successfully delivered proof-of-concept data with investigational gene therapies in the retina. Our most advanced investigational candidate, NR082 (rAAV2-ND4), in development for the treatment ofND4-mutated LHON, has received orphan drug designations in theU.S. The pipeline also includesND1-mutated LHON, autosomal dominant optic atrophy, glaucoma, wAMD/DME, and other preclinical candidates. Neurophth has initiated the scaling up in-house process in single-use manufacturing technologies to support future commercial demand at the Suzhou facility. To learn more about us and our growing pipeline, visitwww.neurophth.com.

SOURCE Neurophth Therapeutics, Inc.

http://www.neurophth.com

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Simplifying the Study of Gene-Environment Interactions – Technology Networks

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Researchers at Weill Cornell Medicine and Cornell Universitys Ithaca campus have developed a new computational method for studying genetic and environmental interactions and how they influence disease risk.

Theresearch, in The American Journal of Human Genetics, makes the process of finding these interactions much less difficult and demonstrates their importance in determining body mass index and diabetes risk.

Our study demonstrates that your genes matter and the environment matters and that the interaction of the two can increase risk for disease, said co-senior author,Dr. Olivier Elemento, who is professor of computational genomics in computational biomedicine, professor of physiology and biophysics, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, and director of the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine.

Typically, studying gene-environment interactions creates a huge computational challenge, said lead author Andrew Marderstein, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences whose research was conducted both in Dr. Elementos lab in New York City andDr. Andrew Clarkslab in Ithaca, enabling him to have immediate access to computational biology and population health expertise.

Genotype-environment interaction can be thought of as the situation where some genotypes are much more sensitive to environmental insults than others, said Dr. Clark, co-senior author and Jacob Gould Schurman Professor of Population Genetics in the Department of Molecular Biology and Genetics in the College of Arts & Sciences and a Nancy and Peter Meinig Family Investigator at Cornell University. These are exactly the cases where changes in the diet or other exposures might have the biggest improvement in health, but only for a subset of individuals.

The millions of genetic variants, or inherited genetic differences found between individuals in a population, and different lifestyle and environmental factors, such as smoking, exercise, different eating habits, can be analyzed for combined effects in numerous ways. When researchers test for gene-environment interactions, they typically analyze millions of data points in a pairwise fashion, meaning they assess one genetic variant and its interaction with one environmental factor at a time. This type of analysis can become quite labor intensive, said Marderstein.

The new computational method prioritizes and assesses a smaller number ofvariantsin the genomeor the complete set of genetic material found in the bodyfor gene-environment interactions.We condensed a problem withanalyzing10 million different geneticvariantsto essentiallyanalyzing only tens ofvariants indifferent regions of the genome, Marderstein said.

While a standard genetic association study might look at whether asinglegeneticvariantcould lead to an average change in body mass index (BMI), this study assessed which geneticvariantswere associated with individuals being more likely to have a higher BMI or lower BMI. The researchers found that looking for sections of DNA associated with the variance in a human characteristic, called a variance quantitative trait locusor vQTL, enabled them to more readily identify gene-environment interactions. Notably, thevQTLs associated with body mass index were also more likely to be associated with diseases that have large environmental influences.

Another area of study where the new computational method might useful is determining how an individual might respond to a specific drug based on gene-environment interactions, said Marderstein. Analysis of social determinants of health, meaning a persons environmental and social conditions, such as poverty level and educational attainment, is a third area that the researchers are interesting in pursuing, according to Dr. Elemento.

Overall, scientists in the precision medicine field are realizing they can sequence a persons DNA, in addition to assessing environmental factors such air quality and physical activity, to better understand whether the individual is at risk of developing a specific disease. The idea down the line is to use these concepts in the clinic, said Dr. Elemento. This is part of the evolution of precision medicine, where we can now sequence somebody's genome very easily and then potentially analyze all of the variants in the genetic landscape that correlate with the risk of developing particular conditions.

Reference: Marderstein AR, Davenport ER, Kulm S, Van Hout CV, Elemento O, Clark AG. Leveraging phenotypic variability to identify genetic interactions in human phenotypes. AJHG. 2021;108(1):49-67. doi:10.1016/j.ajhg.2020.11.016.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Amgen Announces Webcast Of 2020 Fourth Quarter And Full Year Financial Results – BioSpace

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THOUSAND OAKS, Calif., Jan. 28, 2021 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that it will report its fourth quarter and full year 2020 financial results on Tuesday, Feb. 2, 2021, after the close of the U.S. financial markets. The announcement will be followed by a conference call with the investment community at 5 p.m. EST. Participating in the call from Amgen will be Robert A. Bradway, chairman and chief executive officer, and other members of Amgen's senior management team.

Live audio of the conference call will be simultaneously broadcast over the internet and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen's business given by management at certain investor and medical conferences, can be found on Amgen's website, http://www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen's Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About AmgenAmgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to beone ofthe world'sleadingindependent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visitwww.amgen.comand follow us onwww.twitter.com/amgen.

CONTACT: Amgen, Thousand OaksMegan Fox, 805-447-1423 (media)Trish Rowland, 805-447-5631(media)Arvind Sood, 805-447-1060 (investors)

View original content to download multimedia:http://www.prnewswire.com/news-releases/amgen-announces-webcast-of-2020-fourth-quarter-and-full-year-financial-results-301217691.html

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Turn 23andMe Raw Data Into Meaningful Results With These Websites and Tools – MakeUseOf

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There are so many different companies that offer genetic analysis to any interested client. One such company, 23andMe, offers some interesting features for those who use itsservices.

It provides insight into a users ethnic history and even breaks down parts of their genetic codes to explain how DNA influenced their appearance or senses. In addition to these easy-to-understand hereditary summaries, it also gives clients a copy of their "raw data."

Here, we'llgo over whattools you can use to interpret your 23andMe raw data, and we'll define what exactly raw data is.

To understand raw data, you need to know a little bit about how DNA works. DNA is something we inherit from both of our parents and, subsequentially, all previous ancestors. Unless you have an identical twin, your genetic code is unique to you. Understanding what your "genetic code" is can help you learn about raw data.

Deoxyribonucleic Acid (DNA) is a molecule that dictates everything that makes us, us. It contains codes for everything from our basic biology to personalized features. While all humans share a majority of the sequence, humans experience small differences in base pairs, which may influence everything, such as our appearance, behavior, and predisposition to diseases.

Base pairs are the "building blocks" of our genetic makeup. When looking at a model of a DNA double helix, they are those little "steps" of the ladder. Each step is comprised of one of four bases: adenine (A), cytosine (C), guanine (G), or thymine (T), and its complementary base pair (A and T or G and C).

When you send your tissue sample over to 23andMe facilities, scientists perform a process called genotyping. As opposed to sequencing, where technicians attempt to calculate the exact sequence of a given length of DNA, genotyping offers an accurate (and cost-effective) shortcut.

Our genetic code is very long, and there are huge chunks of information we cant do anything with yet. Genotyping is a far more effective process for getting useful data for clients.

The process scans genetic code to look for specific gene variants that are very popular or ones that we already know about. 23andMe takes these datasets and transforms them into an easy-to-understand infographic.

What you'll see is a neat little printout letting you know where your ancestors originated from. What the scientists behind the scenes see is a printout containing various locations and a whole bunch of As, Gs, Ts, and Cs. This printout is your raw data that 23andMe sends you with your results.

Related:The Best Ancestry Tracing Sites

Your raw data may seem like a jumbled mess of characters, but its incredibly useful information. Although 23andMe offers some insight into the genetic information it analyzes, it doesn'texplain everything.

The raw data offers tons of surprise information that you can use. This information isnt just interesting from ahistoricalperspective; the information also offers insight into your health and can be a useful genealogy tool for you and your loved ones.

To access this information, you need to find how to "read" this information. Luckily, you dont need to be a renowned geneticist to take that raw data and do something with it.

While you could theoretically search through journals and try to analyze your raw data yourself, there are a couple hundred thousand markers to sift through. The best way to make the most out of your raw data is to utilize one of the many available tools online.

With countless platforms to chose from, it may be challenging to pick out the best one for you. Consider what information you want to learn from your raw data before you choose an analysis tool.

Xcode Life offers a variety of packages, so you can order exactly what you want. With many different reports to chose from, you can customize the information you want, as well as find options to fit your budget. It displays its findings in an easy-to-read format for everyone to enjoy.

There are over 15 options to choose from, including Gene Sleep, Traits and Personality,Gene Allergy, and more.There are also different bundles available so you can save money. Its packages start at $20.

If you are interested in finding extended ancestry information and basic health information, DNA Land offers free assessment packages.

Although it doesn'tgo into as much detail as some of the paid contenders, it offers great added insight at no extra charge. DNA Land will even use your anonymous submissions to further scientific research.

Nutrahacker takes gene analysis one step further. It designs your reports so that you can "empower yourself" with the newfound information.

Its specialized assessments determine an optimized list of supplements and fitness information for you, in addition to general health data. While its packages start at $25, it also offers some free basic assessments.

If you are on a tighter budget, Promethease offers more inexpensive health reports. It anonymously cross-references your raw data with SNPedia, a human genetics wiki. While it gives you a lot of information for the price, the process is not as straightforward as other options.

You dont need to be an expert, but many find the platform a bit more technical. However, having a super basic background in statistics should suffice. Health reports start at $12.

Research continues to advance every day, and Genomelink makes a point to keep its dynamic options updated by the week. It offers over 200 analysis options to investigate everything from your personality and career strengths to your health vulnerabilities and longevity.

If you're on a budget, Genomelink also has over 20 free analyses. These come with the option to order premium reports delivered via straightforward infographics.

There is so much information to learn from your genetic makeup. With so many easy and accessible tools to further explore the data you already paid for, why not make the most of what you have? It only takes a few clicks of a button to receive a comprehensive health report that is both interesting and informative.

Considering online DNA testing? Several options are available, but 23andMe and ancestryDNA are the top dogs.

Brittni is a neuroscience graduate student who writes for MakeUseOf on the side of her studies. Shes a seasoned writer who began her freelance writing career back in 2012. While shes mainly focused on technology and medicine shes also spent time writing about animals, pop culture, video game recommendations, and comic book reviews.

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Turn 23andMe Raw Data Into Meaningful Results With These Websites and Tools - MakeUseOf

Profile of T Cells, Broadly Neutralizing Antibodies, Anti-Viral Targets: COVID-19 Updates – Bio-IT World

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January 29, 2021 I COVID-19 may become seasonal, severe infection associated with myeloid immune cells, potential Achilles heel of coronaviruses identified, melatonin synthesized in lungs could have protective effect, and plitidepsin outperforms remdesivir in preclinical trials. Plus: NSAID use during COVID-19 is time-dependent on its harm or benefit and NAU to test Allarity drug against Coronavirus Variant B117.

Research News

COVID-19 may be seasonal, like the flu, suggests a new paper published in Evolutionary Bioinformatics. Authors of the paper show that COVID-19 cases and mortality rates, among other epidemiological metrics, are significantly correlated with temperature and latitude across 221 countries. They also explain that our own immune systems could be partially responsible for the pattern of seasonality. For example, our immune response to the flu can be influenced by temperature and nutritional status, including vitamin D, a critical nutrient to our immune defenses. The researchers add that it is, however, too soon to say how seasonality and our immune systems interact in the case of COVID-19. DOI:10.1177/1176934321989695

SARS-CoV-2 independently entered Russia at least 67 times, primarily at the end of February and beginning of March 2020, according to a new study published in Nature Communications. Researchers of the study used 211 virus genomes, which were sequenced at Smorodintsev Research Institute of Influenza, and all genomes had been obtained from patients from 25 Russian regions during mid-March to April 2020. They determined that the vast majority of introductions came from European countries, and no cases of introduction from China were registered, which they attribute to the timely closure of borders with the country. Currently, nine local virus lineages are circulating in Russia, which are not present elsewhere in the world. DOI:10.1038/s41467-020-20880-z

Research led at Vanderbilt University Medical Center has discovered a proofreading exoribonuclease, called nsp14-ExoN, which can correct errors in the RNA sequence that occur during replication, when copies of a virus are generated. They believe that this may be the Achilles heel of the coronavirus, a finding that could help close the door on COVID-19 and possibly head off future pandemics. Using cutting-edge technologies and novel bioinformatics approaches, the researchers discovered that this ExoN also regulates the rate of recombination, which is the ability of the coronavirus to shuffle parts of its genome and even pull genetic material from other viral strains while it replicates in order to gain evolutionary advantage. These patterns of recombination are conserved across multiple coronaviruses, including SARS-CoV-2. They believe that the coronavirus ExoN is therefore a conserved, important target for inhibition and attenuation in the ongoing pandemic. This research is published in PLOS Pathogens. DOI:10.1371/journal.ppat.1009226

Also at Vanderbilt University Medical Center (VUMC), researchers have identified genetic factors that increase the risk for developing pneumonia to help identify patients with COVID-19 at greatest risk for this life-threatening complication. The researchers conducted genome-wide association studies (GWAS) of more than 85,000 patients whose genetic information is stored in VUMCs BioVU biobank. They identified nearly 9,000 cases of pneumonia in patients of European ancestry and 1,710 cases in patients of African ancestry. After further analysis, the research team linked the gene that causes cystic fibrosis (CF) and European ancestry and the mutation that causes sickle cell disease (SCD) in patients of African ancestry as the strongest pneumonia associations. After removing patients with CF and SCD, they then pinpointed a pneumonia-associated variation in a gene called R3HCC1L in patients of European ancestry, and one near a gene called UQCRFS1 in patients of African ancestry. They believe these findings could be applied to identifying patients with high risk of severe pneumonia to enable early interventions. They have published this work in the American Journal of Human Genetics. DOI:10.1016/j.ajhg.2020.12.010

Melatonin produced in the lungs acts as a barrier against SARS-CoV-2, blocking the expression of genes that encode proteins in cells serving as viral entry points, finds researchers at the University of So Paulo (USP). The hormone, therefore, prevents infection of these cells by the virus and inhibits the immune response so that the virus remains in the respiratory tract for a few days and then leaves the host, say the researchers. They used RNA sequencing data to quantify the level of expression of 212 COVID-19 signature genes in 288 samples from healthy human lungs. The researchers correlated these gene expression levels with a gene index that estimated the capacity of the lungs to synthesize melatonin (MEL-index). They then were able to determine that when the MEL-index was high, the entry points for the virus in the lungs were closed, and vice-versa. The research team suggests the potential for nasal administration of melatonin to prevent disease from developing in pre-symptomatic COVID-19 patients. This study is published in Melatonin Research. DOI:10.32794/mr11250090

In a new study, published in Cell Reports Medicine, La Jolla Institute for Immunology (LJI) researchers suggest that T cells can mount attacks against many SARS-CoV-2 targets, beyond the key sites on the viruss spike protein. They believe that by attacking the virus from many angles, the body is equipped to potentially recognize different SARS-CoV-2 variants. The researchers examined T cells from 100 people who had recovered from COVID-19 to take a closer look at the genetic sequence of the virus to separate the potential epitopes from the epitopes that these T cells would recognize. Their analysis revealed that not all parts of the virus induce the same strong immune response in everyone, and T cells can recognize dozens of epitopes on SARS-CoV-2 that vary from person to person. They determined that each study participant had the ability to recognize about 17 CD8+ T cell epitopes and 19 CD4+ T cell epitopes. DOI:10.1016/j.xcrm/2021/100202

John Hopkins Medicine researchers, in collaboration with Immunoscape, have published a complete profile of the response of T cells in people who have recovered from SARS-CoV-2 infection. The paper, published in The Journal of Clinical Investigation, better defines which T cells interact with which specific portion of the SARS-CoV-2 virus and how those interactions can provide long-lasting immunity against COVID-19. The researchers collected blood samples from 30 convalescent patients who had recovered from mild cases of COVID-19 and the Immunoscape team, a U.S.-Singapore biotechnology company, used its highly sensitive human leukocyte antigen (HLA)-SARS-CoV-2 tetramers to tag and identify the types of virus-recognizing CD8+ T cells. The researchers found that as levels of neutralizing antibodies increased in the convalescent plasma, so did the number of memory CD8+ T cells that recognized SARS-CoV-2 epitopes. They believe this means lasting protection against reinfection, and this knowledge will guide COVID-19 vaccine design to produce a strong immune response that could provide years of protection. DOI:10.1172/JCI145476

Severe COVID-19 patients have significantly elevated levels of a certain type of immune cell in their blood, call monocytic myeloid-derived suppressor cells (M-MDSC), according to a new study published in the Journal of Clinical Investigation. Karolinska Institutet researchers studied 147 patients with mild to fatal COVID-19 who were sampled repeatedly from blood and respiratory tract. These samples were then compared with patients who had influenza and healthy individuals. They found that the patients with severe COVID-19 had significantly higher levels of M-MDSCs in their blood when compared to milder cases and healthy participants. COVID-19 patients also had fewer T cells in their blood than healthy individuals that showed signs of impaired function. Additionally, their analysis revealed that the levels of M-MDSCs early in the course of infection seemed to reflect subsequent disease severity. DOI:10.1172/JCI44734

Researchers have engineered an antibody that effectively neutralizes SARS-CoV-2 and that also acts against multiple SARS-like viruses. Their antibody, ADG-2, was studied in mice. To engineer this broadly neutralizing antibody (bnAb), the researchers started with antibodies from the memory B cells of a 2003 SARS survivor that cross-neutralized multiple SARS-related viruses with modest potency. They then selectively engineered the binding affinities of several of these bnAbs, creating improvements in their abilities to bind the virus. The researchers then studied the engineered antibodies for SARS-CoV-2 neutralizing activity in mouse cell lines. ADG-2 was particularly effective. It showed broad binding activity to more than a dozen SARS-related coronaviruses. This research is published in Science. DOI:10.1126/science.abf4830

Plitidepsin has shown a potent efficacy against SARS-CoV-2 in preclinical trials, outperforming the antiviral remdesivir. These results, published in Science, show that in studies in human cells, plitidepsin demonstrated potent anti-SARS-CoV-2 activity: 27.5-fold more so than remdesivir as tested in the same cell line. In a model of human lung cells, plitidepsin greatly reduced viral replication. In further experiments involving both plitidepsin and remdesivir in vitro, the researchers suggest that plitidepsin has an additive effect with the approved drug and would be a potential candidate for a combined therapy. Authors of the research article believe that this promising treatment, which has limited clinical approval for the treatment of multiple myeloma, should be strongly considered for expanded clinical trials for the treatment of COVID-19. DOI:10.1126/science.abf4058

Oregon Health & Science University (OHSU) researchers have demonstrated that antibodies generated by the SARS-CoV-2 virus react to other strains of coronavirus and vice-versa. They determined, however, that antibodies generated by the 2003 SARS outbreak had only limited effectiveness in neutralizing SARS-CoV-2. The researchers believe that these findings have implications on both vaccine effectiveness and diagnosis of COVID-19. They believe that more work needs to be done to determine the lasting effectiveness of COVID-19 vaccine, given the speed of mutations. The team believes their study also suggests that efforts to accurately discern a previous COVID-19 infection, by analyzing antibodies in the blood, may be complicated by the presence of antibodies reacting to other strains of coronavirus including the common cold. This study is published in Cell Reports. DOI:10.1016/j.celrep.2021.108737

A new method to mapping viral mutations that escape leading clinical antibodies against COVID-19 has revealed mutations in the SARS-CoV-2 virus that allow it to evade treatments, including a single amino-acid mutation that fully escapes Regenerons antibody cocktail. University of Washington researchers and colleagues developed this scanning method to map how mutations to the receptor-binding domain (RBD) affect its recognition by antibodies. Their maps identified mutations that escape antibody binding, including a single mutation that escapes both antibodies in the Regeneron antibody cocktail. To further investigate, the team examined deep sequencing data from a persistently infected patient who was treated with the antibody cocktail at day 145 after diagnosis with COVID-19, and their analysis identified resistance mutations that arose in the patient. Furthermore, after they examined all human-derived SARS-CoV-2 sequences available as of mid-January 2021, the researchers report a substantial number of RBD mutations that escaped one or more of the antibodies that are in circulation. This paper is published in Science. DOI:10.1126/science.abf9302

Monash University researchers have discovered two new molecules that provide profound protection in experimental models of asthma, as well as protection from acute respiratory distress syndrome (ARDS) that is seen in some patients with severe COVID-19. In their study, originally designed to investigate how the immune system impacts gut bacteria, the researchers found that p-cresol sulfate (PCS), a gut bacteria by-product, led to a striking protection against asthma. They then determined that PCS was produced by enhanced bacterial metabolism of L-tyrosine, a well-known amino acid found in dietary supplements. The researchers saw significant protection against lung inflammation in mice given either L-tyrosine or PCS, as well as protection from ARDS. The researchers now aim to test one of the molecules in a clinical trial in asthmatics this year. These new findings are published in Nature Immunology. DOI:10.1038/s41590-020-00856-3

Non-steroidal anti-inflammatory drugs (NSAIDs) reduced both antibody and inflammatory responses to SARS-CoV-2 infection in mice, a new study finds that is published in the Journal of Virology. The authors of the study highlight that the timing of NSAID use during COVID-19 is important. They explain that NSAIDs anti-inflammatory activity could be detrimental early in SARS-CoV-2 infection because inflammation is usually helpful during this stage. This changes at later stages of COVID-19, particularly if the patient experiences intense inflammation known as cytokine storm. The researchers also note that a reduction in neutralizing antibodies caused by NSAIDs could be benign, or it might hinder the immune systems ability to fight the infection in its early stages. It could also reduce the magnitude or duration of protection from either natural infection or vaccination. DOI:10.1128/JVI.00014-21

Rhesus macaque monkeys infected with SARS-CoV-2 developed protective immune responses that could be reproduced with a vaccine, according to University of California, Davis (UC Davis) researchers. The team infected eight rhesus macaques at the California National Primate Research Center (CNPRC) with SARS-CoV-2 virus isolated from the first human patient treated at UC Davis, and they followed the immune responses in the monkeys over two weeks. The animals showed signs of lasting immunity and, most importantly, structures called germinal centers developed in the lymph nodes near the lungs. These germinal centers contained cells call T follicular helper (Tfh) cells. Germinal centers and Tfh cells are associated with generating plasma cells that remain in the body for many years to produce antibodies against pathogens the immune system has seen before, the researchers explain. They believe these results suggest that vaccines that induce this response will support immunity against COVID-19. This study is published in Nature Communications. DOI:10.1038/s41467-020-20642-x

Patients who have recovered from severe COVID-19 infection could be left with more protective T cells needed to fight reinfection, finds a team of researchers led at La Jolla Institute for Immunology (LJI). For their study, published in Science Immunology, the team analyzed CD8+ T cells from 39 COVID-19 patients and 10 individuals who had never been exposed to the virus. Of the COVID-19 patients, 17 had a mild case that did not require hospitalization, 13 had been hospitalized, and nine needed intensive care support. Surprisingly, the researchers saw weaker CD8+ T cell responses in patients with milder COVID-19 cases and saw the strongest CD8+ T cell responses in the patients who required hospitalization or intensive care. The team now hopes to study how T cells in tissues hit hardest by SARS-CoV-2, such as the lungs, react to the virus. They explain the importance of this as the memory T cells that provide long-term immunity need to live in the tissues. DOI:10.11260/sciimmunol.abe4782

In a new study published in Science Signaling, scientists discovered that SARS-CoV-2 may enter and replicate in human cells by exploiting newly identified sequences within cell receptors. They also suggest that these sequences could potentially serve as targets for new therapies against COVID-19. After analyzing the Eukaryotic Linear Motif database, the team of scientists discovered that ACE2 and various receptors contained several short linear motifs (SLiMs), or small amino acid sequences, that they predict plays a role in endocytosis and autophagy, or the entering of human cells and cellular housekeeping. The team determined that two SLiMs in ACE2 bound to endocytosis-related proteins, and one SLiM in the integrin beta-3 (3) bound to two proteins involved in autophagy. They believe that their prediction models could help identify similar SLiMs that assist with the replication of not only SARS-CoV-2, but other viruses that cause disease. DOI:10.1126/scisignal.abd0334

Ohio University researchers have published the first structural biology analysis of a section of the COVID-19 viral RNA called the stem-loop II motif, which they believe could be a potential target for anti-viral drugs to combat the virus. The research team identified this non-coding section of the RNA that is likely key to SARS-CoV-2 replication. Interestingly, they determined that the structural flexibility of this noncoding RNA motif differs by only a single nucleotide when compared to that in the early 2000s SARS-CoV outbreak, and the team also identified FDA-approved drugs that bind to the RNA motif and alter its flexibility. Since the structure and flexibility of noncoding RNA affects its function, the researchers suggest that it may be possible to develop antiviral drugs that specifically target this RNA motif to battle the virus. This research is published in Biochemical and Biophysical Research Communications. DOI:10.1016/j.bbrc.2021.01.013

Innate immunity may play a larger role in controlling SARS-CoV-2 viral load than adaptive immunity, according to a new study published in ACS Pharmacology & Translational Science. Researchers of the study developed a mathematical model that predicts viral load over time in organs that express the ACE2 receptor, which allows SARS-CoV-2 entry into human cells. They then used this model to simulate different conditions to determine this key role for innate immunity in controlling viral load. The researchers suggest the importance of starting antiviral or interferon therapy as soon as possible after the onset of COVID-19 symptoms. DOI:10.1021/acsptsci.0c00183

Industry News

Allarity Therapeutics in Denmark plans to further test the antiviral activity of stenoparib, its Poly ADP-Ribose Polymerase (PARP) inhibitor, against the B.1.1.7 variant of SARS-CoV-2. Stenoparib is a small molecule, targeting inhibitor of PARP, a key DNA damage repair enzyme active in tumors, which was originally developed by the pharmaceutical company Eisai. Results of previous pre-clinical studies for SARS-CoV-2 demonstrated that stenoparib inhibits SARS-CoV-2 as a single agent, and stenoparib in combination with remdesivir was active in inhibiting coronavirus in vitro. Allarity will now work with scientists at Northern Arizona Universitys Pathogen and Microbiome Institute (PMI) to test the similar ability of stenoparib to block the infection and replication of Coronavirus Variant B117. Press Release

Clear Labs announced the availability of the Clear Dx Whole Genome Sequencing (WGS), the first automated WGS solution that determines the complete RNA sequence of the SARS-CoV-2 genome in less than 24-hours with only minutes of hands-on time. The Clear Dx platform is powered by next generation sequencing (NGS), robotics and cloud-based analytics, and as a result, their WGS can more easily determine the nature of virus transmission by differentiating virus strains and monitoring mutations that lead to variants. In addition to WGS, the platform also features the Clear Dx SARS-CoV-2 Diagnostic Assay, which has received EUA, that allows labs to perform diagnostic screening and genomic surveillance simultaneously. Press Release

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Profile of T Cells, Broadly Neutralizing Antibodies, Anti-Viral Targets: COVID-19 Updates - Bio-IT World

[Full text] Association of CYP3A5 Gene Polymorphisms and Amlodipine-Induced Periph | PGPM – Dove Medical Press

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Introduction

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. In addition to their antihypertensive effects, CCBs may also lead to many adverse reactions, including peripheral edema, dizziness, flushing, fatigue, headache, palpitations, and gingival enlargement.14 Peripheral edema, particularly of lower limbs, is the most common side effect of CCBs. CCBs-induced peripheral edema is more common in women and is related to age, upright posture and duration of CCBs therapy.2,5 Although it has been known for decades that CCBs could cause peripheral edema, there are still very few genetic markers that could be used in clinical treatment.

Amlodipine is a first-line antihypertensive drug and a long-acting 1,4-dihydropyridine calcium channel blocker.6 It became the fifth most prescribed medication in the United States in 2018.7 However, therapy trials report that the incidence of amlodipine-induced peripheral edema is about 19%, which also probably serves as the main reason behind the limited use of this drug.8,9 To our knowledge, factors that increase the serum concentration of drugs may also increase the risk of side effect. Accordingly, genetic factors affecting the metabolism of amlodipine will consequently influence its clearance, thus possibly resulting in peripheral edema. In recent years, numerous studies have focused on identifying genetic factors determining the responses to amlodipine therapy, including aspects of efficacy and safety.1012 Nevertheless, the genetic predisposition to amlodipine-induced peripheral edema remains unclear. However, some studies shine light on CYP genes, which are involved in the metabolism of amlodipine.13,14

CYP3A is a subfamily of cytochrome P450 and is involved in the metabolism of many compounds.10,1517 CYP3A4 and CYP3A5 are the two major enzymes of CYP3A family and play important roles in the dehydrogenation of amlodipine.18 However, it has been reported that CYP3A4, rather than CYP3A5, plays a more important role in amlodipine clearance in vivo.16 However, according to our observations, almost all SNPs of CYP3A4 are very rare in Chinese Han or East Asian.1921 A recent study evaluated the influence of CYP3A polymorphisms on the pharmacokinetic (PK) parameters of 10 CYP3A substrates including amlodipine, and it turned out CYP3A4 polymorphisms did not show a pronounced influence on PK of amlodipine.22 So, as far as we know, CYP3A4 does not suffice as an explanation towards the incidence of amlodipine-induced adverse responses. Additionally, the contribution of CYP3A5 in amlodipine metabolism is still controversial. CYP3A5 expression varies among individuals due to gene polymorphisms that result in non-productive mRNA splicing and lower or undetectable expression of the protein.14,23,24 Pharmacogenomics studies have found that CYP3A5 gene polymorphisms have significant impact on drug metabolism, efficacy, and toxicity.25,26 Recent studies have reported a possible relationship between CYP3A5 and amlodipine. CYP3A5*3/*3 genotypes might be associated with blood pressure response to amlodipine,27 and CYP3A5*3 may affect the disposition of amlodipine.13 In Chinese hypertensive patients who underwent renal transplantation, researchers have demonstrated that CYP3A5*3 polymorphism affects the antihypertensive efficacy of amlodipine. In such patients with CYP3A5*3/*3, the reduction in diastolic blood pressure (DBP) was significantly higher than those with other genotypes.28 Additionally, compared with CYP3A5*1/*1, CYP3A5*1/*3 patients exhibit a lower metabolic ratio of amlodipine in vivo and hypertensive patients with CYP3A5*1/*3 genotypes show a higher decrease in blood pressure.14 These findings suggest that CYP3A5 genetic variants are really involved in amlodipine response, having an impact on treatment effectivity of amlodipine.

Although studies have identified that CYP3A5 polymorphisms do play a role in blood pressure control and treatment responses of amlodipine, the effect of a particular genotype in amlodipine-induced peripheral edema remains unclear. Here, we aim to test whether any genetic variants associate with amlodipine-induced peripheral edema. For this, we used the targeted region sequencing method to genotype the SNPs in all known haplotypes of CYP3A5, and evaluated their effect on amlodipine-induced peripheral edema in Chinese Han hypertensive patients.

We recruited a total of 240 patients with essential hypertension who have ever been treated with amlodipine or L-amlodipine for more than 4 weeks. The participants were outpatients from Beijing Chaoyang Hospital of Capital Medical University and the Second Hospital of Jilin University. The demographic characteristics and baseline data were collected, including gender, age, body mass index (BMI), smoking and drinking status, blood pressure, heart rate and use of medications. Participants were also questioned about peripheral edema symptoms (leg or ankle edema). Two trained physicians evaluated the adverse drug reactions caused by the amlodipine or L-amlodipine based on the WHO-UMC scale.29 We classified the participant as a peripheral edema case if WHO-UMC causality categories were certain, probable, or possible. The others were grouped as controls.

The DNA Sampling Swabs (Taitong Gene Testing Equipments Co., Ltd., Suzhou, China) were used for collecting oral buccal mucosa cells. Genomic DNA was isolated from the swabs, using Hi-Swab DNA kit (TIANGEN, Beijing, China) according to the manufacturers instructions. Quantification of the DNA concentration was performed using the manufacturers protocol with the Qubit dsDNA HS Assay Kit (Yeasen, Shanghai, China). Methods for targeted region capture and NGS have been reported previously.30 Illumina HiSeq X was used to sequence the captured DNA with paired-end reads of 150 bp length. Table S1 lists the targeted regions of sequencing and the 24 SNPs of CYP3A5.

High-quality sequencing reads were obtained from the raw data by removing reads that contained adapters, were with unknown bases, or had a low-quality using the Trimmomatic (v0.36)31 program. The high-quality reads were aligned to human reference genome hg19 using the Burrows-Wheeler Aligner (BWA, v0.7.15)32 using the default parameters. The Genome Analysis ToolKit (GATK, v3.8)33 was used for indels realignment, quality score recalibration, variant calling, and genotyping (using Haplotype Caller).

Demographic and clinical characteristics of different groups were compared by t-test or Chi-square (2) test according to the data category. The associations between gene polymorphisms and the risk of peripheral edema were assessed by codominant model, dominant model, recessive model and allele model by calculating the odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression with or without adjustment by gender and alcohol status. Stratification was done by gender. Analyses above were carried out on R-4.03. PLINK 1.934 was used to calculate the minor allele frequency and assess HardyWeinberg equilibrium (HWE) for each SNP. Additionally, linkage disequilibrium (LD) block and haplotype were assessed by Haploview35 software. The D and r2 values for all pairs of SNPs were calculated. P value<0.05 was considered as the significant level.

Two hundred and forty enrolled patients were separated into 64 cases and 176 controls. The general characteristics of the study population are summarized in Table 1. In agreement with previous reports, a higher incidence of CCB-induced peripheral edema was observed in women. A significant difference was found in the sex ratio between cases and controls (P=0.00048). In addition, the frequency of drinkers was 29.69% in the case group and 46.02% in the control group (P=0.034). There was no significant difference between the two groups regarding other characteristics.

Table 1 Characteristics of the Study Population

All the observed SNPs and the minor allele frequencies (MAF) in two groups are listed in Table 2. Except rs15524, rs4646453 and rs776746, the other SNPs were rare or not detected in the studied population. Therefore, we focused on these three SNPs (MAF>0.05) for further studies. Distributions of genotype frequencies of the SNPs did not show any deviation in HardyWeinberg equilibrium (P>0.05).

Table 2 Observed CYP3A5 Variations and Frequencies

The genotype and allele allocations of the test polymorphisms differed considerably between cases and controls (Table 3). In more detail, the frequencies of alleles rs15524 G, rs4646453 A, and rs776746 T were significantly lower in cases than those in the control group (G vs A: OR=0.53, P=0.011; A vs C: OR=0.54, P=0.019; T vs C: OR=0.58, P=0.03; respectively). Furthermore, there was a statistically significant difference in genotype of the rs15524 and rs4646453 between the two groups in dominant model with or without adjustment by gender and alcohol status (GG+AA vs AA: OR=0.5, P=0.021; AA+AC vs CC: OR=0.54, P=0.04). As for rs776746, the presence of TT+CT genotype demonstrated a significantly lower risk after gender and alcohol status adjustment (TT+CT vs CC: OR=0.57, adjusted P=0.044).

Table 3 Genotype Frequencies of Study SNPs in Case and Control Groups

Stratified analyses were performed to access the differential effect of gender on the association between amlodipine-induced edema and the polymorphisms. No significant differences were identified, but the relevant genotypes still showed lower risk in all subgroups. The details are presented in Table 4.

Table 4 Stratified Analyses Between SNPs and Risk of Amlodipine-Induced Peripheral Edema

We employed Haploview program to assess the Linkage disequilibrium (LD) block and haplotype of the three SNPs of CYP3A5. The LD analysis indicated that these SNPs were in strong LD with each other (Figure 1, rs15524 and rs4646453 D=0.965, r2=0.821; rs15524 and rs776746 D=0.979, r2=0.919; rs776746 and rs4646453 D=0.989, r2=0.898). Frequencies of four haplotypes were found to be more than 1% in the haplotype analysis (Table 5). The most represented haplotype in the whole cohort of controls and cases was ACC, followed by GAT, GCC and GCT. Two haplotypes (ACC and GAT) were significantly associated with the risk of amlodipine-induced peripheral edema. The frequency of the ACC haplotype was higher in the cases than controls (79.7% vs 67.9%, P=0.012), whereas the frequency of the GAT haplotype was lower in the cases (17.2% vs 28.1%, P=0.015).

Figure 1 Linkage disequilibrium coefficients (|D|) and LD block among the three polymorphisms of CYP3A5.

Table 5 Haplotype Frequencies of CYP3A5 Gene and the Association with the Amlodipine-Induced Peripheral Edema Risk

Studies have demonstrated that genetic polymorphisms may influence the gene function, thus causing alterations in the pharmacokinetics (PK) and pharmacodynamics (PD) of the gene-associated drugs. Moreover, genetic variants have been confirmed for their association with appearance of adverse reactions to drugs, such as ACE inhibitors-induced cough36 and rosuvastatin-induced myotoxicity.37 To our knowledge, this is the first study to investigate the relationships of CYP3A5 polymorphisms and amlodipine-induced peripheral edema by using a casecontrol retrospective study in the Chinese population. Our study reveals that amlodipine-induced peripheral edema may associate with genetic polymorphisms in CYP3A5 gene. We find that the distribution of allele and genotype frequencies of the three SNPs are significantly different between cases and controls. Specifically, the alleles rs15524 G, rs4646453 A, and rs776746 T reduce the risk of amlodipine-induced peripheral edema. On the other hand, A, C, and C increase the risk and haplotype analysis also confirms this. These findings support the hypothesis that genetic variation in CYP3A5 is involved in the development of amlodipine-induced peripheral edema.

CYP3A5 is highly polymorphic with significant inter-individual variation in the enzyme activity contributing to the absorption, metabolism and tissue distribution of drugs.24,38 Genetic polymorphisms of CYP3A5 may potentially alter its proteins expression and function, and subsequently influence the clearance of any drugs metabolized by CYP3A5.38 The most studied SNP related to CYP3A5 functional variation is rs776746 (also known as CYP3A5*3 or CYP3A5*3C). Homozygous carriers of this SNP (*3/*3 or CC) lack functional CYP3A5 protein because of the frameshift mutation and truncation of the translated protein.39 Previous studies have confirmed that CYP3A5*3 is associated with drug metabolism, and CYP3A5*3/*3 carriers have decreased metabolism of nifedipine40 and tacrolimus,41 compared to CYP3A5*1/*1 and CYP3A5*1/*3 carriers. Patients with CYP3A5*3/*3 who are treated with tacrolimus may have an increased risk of nephrotoxicity as compared to patients without it.25,26 These findings suggest that the CYP3A5 *3/*3 carriers have low activity of CYP3A5 enzyme and decreased metabolism for certain drugs dependent on it, resulting in the appearance of an adverse reaction to the drug. Conforming to these findings, our study also indicates that there is an association between CYP3A5*3 and the occurrence of amlodipine-induced peripheral edema and that *3/*3 (CC) carriers have a higher risk of peripheral edema.

CYP3A5*1D (rs15524) is another frequently studied SNP in CYP3A5, which is in the 3-untranslated region (UTR). CYP3A5*1D is differentially distributed among populations ranging from 77.5% in Americans to 71.4% in East Asians, 40.6% in Africans, and even rarer in Europeans (less than 8%) (GnomAD).21 SNPs in UTRs may influence the stability of mRNA, thus affecting the expression and activity of the enzyme.42,43 According to a study identifying the potential SNPs related to miRNA, rs15524 may influence the hsa-miR-500a-5p that targets CYP3A5, affecting its expression.44 In addition, studies have found that CYP3A5*1D influences the pharmacokinetics of many drugs, including tacrolimus45 and carbamazepine.46 Therefore, rs15524 may act as a genetic marker and should be considered while studying or prescribing drugs metabolized by CYP3A5. Here, we find that the frequencies of rs15524 G allele and GA+GG genotypes in cases are lower than controls, which indicates that this SNP is associated with reduced risk of incidence of amlodipine-induced peripheral edema. In other words, CYP3A5*1D/*1D carriers may have an increased risk than others.

As for CYP3A5*1E (rs4646453), it is associated with a decreasing risk of amlodipine-induced peripheral edema. However, there is litter information about the function of the rs4646453. To some extent, this is possible because the SNP locates in the intron region. Studies have revealed that CYP3A5 rs4646453 is in LD with rs776746,47 and there is a strong LD between rs15524 and rs776746.39,46 Our findings are consistent with these studies and further promote that the presence of LDs with rs776746 may partly explain the role of rs15524 and rs4646453 in amlodipine-induced peripheral edema.

Given all these findings, there are some limitations in our present study that we would like to acknowledge. First, the population in our study is Chinese Han, and it is known that the frequency of mutations differs among ethnic groups. Hence, our results may apply well to Chinese population but are probably not suitable for populations of other ethnic groups. Second, we have performed a retrospective study and not a prospective one. The study is also limited by the smaller number of samples. The third limitation is not involving other genes contributing to amlodipine metabolism, such as CYP3A4. As we mentioned before, polymorphisms of CYP3A4 are rare in Chinese, and the evidence so far that CYP3A4 polymorphisms influence amlodipine metabolism is scarce. So, we took no account of them currently. But it would be better for future studies to include these related genes to better explain the connection between genetic factors and amlodipine-induced peripheral edema. Hence, more casecontrol studies with large number of polyethnic samples and involvement of diversified factors are necessary.

None the less, our study does investigate the novel relationship between the genetic variants and amlodipine-induced peripheral edema. In conclusion, we provide evidence that CYP3A5 polymorphisms are involved in the occurrence of amlodipine-induced peripheral edema, and the three genetic variants of CYP3A5 have the potential to serve as novel biomarkers for amlodipine-induced adverse reactions. Our findings thus provide new insights into amlodipine-induced peripheral edema and are of importance in developing and prescribing personalized and precise medicine for hypertension.

The raw data are available on reasonable request to the correspondence author Songnian Hu.

All the participants have signed the written informed consent, and approval was obtained from the Research Ethics Board of Beijing Chaoyang Hospital of Capital Medical University and the Research Ethics Board of the Second Hospital of Jilin University. This study has been conducted in accordance with the World Medical Association Declaration of Helsinki.

We thank all the participants included in this study.

All authors declare that they have no conflicts of interest for this work.

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With fertile land and water growing scarce, high-yield wheat and barley could help save millions from hunger – Genetic Literacy Project

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By the time I am 60 years old in 2050, our global population will have increased to 9.7 billionpeople. Thats an additional ~2 billion human beings that will need to be fed. With over275 million hectares(680 million acres) of irrigated land globally, researchers note that to grow enough food for our projected population increase, we will need crops to produce more output on existing land.

Experts estimate that to provide for the 2050 population forecast, annual cereal production will need to rise by 50% to about3 billion tonnes. To do this, we must implement plant breeding technologies as one part of a comprehensive solution for global hunger.

The big news, as reported in the journalNature, is that researchers have sequenced new variations of genomes in barley and wheat. The international team includes scientists from the University of Adelaides Waite Research Institute, along with the10+ Genome Project, spearheaded by Curtis Pozniak, a professor at the University of Saskatchewan, Canada. Pozniak is in collaboration with the International Barley Pan Genome Sequencing Consortium, led by Nils Stein, professor at theLeibniz Institute of Plant Genetics and Crop Plant Research.

What does that mean for society today? Because barley and wheat are staple crops on a global level, scientists may have found a way to produce the high yield necessary to feed more mouths within our lifetime. And its not just a boon to cereal production; these discoveries bring us one step closer to unlocking the entire gene set, otherwise known aspan-genome,in wheat and barley, which has ramifications for all future research in plant genomics and cereal farming.

Heres how the research unfolded: Scientists conducting field tests in Chile found a way to increase the amount of protein (expansin) in the plants, which controls growth rate.The result: grains that were up to 12% larger than usual with higher yields as well. In the past, there had always been a tradeoff between grain size and number.

This is especially good news because wheat provides about 20% of the calories consumed by humans, and the current yield is increasing at only about 1% annually a far cry from the 50% needed to supply the population by 2050. Field results were a critical component, as they helped prove the effectiveness of these variations, by showing that the plants could perform under typical agricultural conditions. The teams of researchers are now working to make this research available to farmers and the greater food industry to help inform their decisions on crop production.

Currently, more than 800 million peopleworldwideare chronically hungry, and about 2 billion are nutritionally deficient. This is ahugepublic health concern. Whats more, fertile land and water supply are becoming scarcer, and production increases are falling off amplifying the need for more productive land.

Gene-editing technologies can only address global hunger and land and water availability if theyve gained consumer trust.GMOsand gene-editing are some of the most studied plant technologies. They also have the capacity to increase yield and lower chemical fertilizer and pesticide use, provide crops with better resilience to poor climate conditions, ward off pests, reduce post-harvest loss, and produce more nutrient-dense foods.

And yet, even with 30 years of research and countless commercial applications proving that gene-edited or GMO crops are as safe as conventionally grown crops, there is still hesitation from mainstream culture.

What if you were to wake up at 60, 70 or 80 years old, and instead of looking at flourishing families youre looking at 900 million people going hungry,landonce used for playgrounds now dedicated to growing food, and the population still multiplying? While this may seem like a stretch, if we dont accept plant breeding technology and realize its fundamental impact on food security, we may not meet increasing global food demands. More and more people will go hungry.

It seems like a luxury to even discuss consumer food production preference when people in developing countries are dying of starvation. With COVID running rampant, Africa is unable to make use of new plant technology, including GMOs, due to bottlenecks caused by the pandemic. This, asRuramiso Mashumba, an African smallholder farmer shared with us, is not a matter of preference but truly, a matter of life and death.

So, while our issue here in the United States remains a social challenge of widespread consumer adoption,developing countries are struggling with political barriers, preventing them from using lifesaving technology.

We hope to see more plant technologies such as this emerge and we hope that consumers do their research and come to understand the safety and vital nature of these developments.

What will 2050 look like? Your decisions today have an impact. Understanding the safety of new plant technologies, and the good they can do, is of chief importance to feeding generations to come.

Hayley N. Philip is a writer and researcher for Dirt to Dinner with a focus in health and nutrition.

A version of this article was originally posted at Dirt To Dinner and has been reposted here with permission. Dirt To Dinner can be found on Twitter @Dirt_To_Dinner

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With fertile land and water growing scarce, high-yield wheat and barley could help save millions from hunger - Genetic Literacy Project

Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder – Newswise

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Newswise PHILADELPHIAScientists in the Perelman School of Medicine at the University of Pennsylvania have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCM which affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failure is one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In the study, published this week in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cells but not two other cell types studied leading to the abnormal activation of non-heart muscle genes.

Were now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types, said study co-senior author Rajan Jain, MD, an assistant professor of Cardiovascular Medicine and Cell and Developmental Biology at the Perelman School of Medicine.

Further work along these lines should enable us to predict how LMNA mutations will manifest in individual patients, and ultimately we may be able to intervene with drugs to correct the genome disorganization that these mutations cause, said study co-senior author Kiran Musunuru, MD, PhD, a professor of Cardiovascular Medicine and Genetics, and Director of the Genetic and Epigenetic Origins of Disease Program at Penn Medicine.

Inherited LMNA mutations have long puzzled researchers. The LMNA gene encodes proteins that form a lacy structure on the inner wall of the cell nucleus, where chromosomes full of coiled DNA are housed. This lacy structure, known as the nuclear lamina, touches some parts of the genome, and these lamina-genome interactions help regulate gene activity, for example in the process of cell division. The puzzle is that the nuclear lamina is found in most cell types, yet the disruption of this important and near-ubiquitous cellular component by LMNA mutations causes only a handful of relatively specific clinical disorders, including a form of DCM, two forms of muscular dystrophy, and a form of progeria a syndrome that resembles rapid aging.

To better understand how LMNA mutations can cause DCM, Jain, Musunuru, and their colleagues took cells from a healthy human donor, and used the CRISPR gene-editing technique to create known DCM-causing LMNA mutations in each cell. They then used stem cell methods to turn these cells into heart muscle cells cardiomyocytes and, for comparison, liver and fat cells. Their goal was to discover what was happening in the mutation-containing cardiomyocytes that wasnt happening in the other cell types.

The researchers found that in the LMNA-mutant cardiomyocytes but hardly at all in the other two cell types the nuclear lamina had an altered appearance and did not connect to the genome in the usual way. This disruption of lamina-genome interactions led to a failure of normal gene regulation: many genes that should be switched off in heart muscle cells were active. The researchers examined cells taken from DCM patients with LMNA mutations and found similar abnormalities in gene activity.

A distinctive pattern of gene activity essentially defines what biologists call the identity of a cell. Thus the DCM-causing LMNA mutations had begun to alter the identity of cardiomyocytes, giving them features of other cell types.

The LMNA-mutant cardiomyocytes also had another defect seen in patients with LMNA-linked DCM: the heart muscle cells had lost much of the mechanical elasticity that normally allows them to contract and stretch as needed. The same deficiency was not seen in the LMNA-mutant liver and fat cells.

Research is ongoing to understand whether changes in elasticity in the heart cells with LMNA mutations occurs prior to changes in genome organization, or whether the genome interactions at the lamina help ensure proper elasticity. Their experiments did suggest an explanation for the differences between the lamina-genome connections being badly disrupted in LMNA-mutant cardiomyocytes but not so much in LMNA-mutant liver and fat cells: Every cell type uses a distinct pattern of chemical marks on its genome, called epigenetic marks, to program its patterns of gene activity, and this pattern in cardiomyocytes apparently results in lamina-genome interactions that are especially vulnerable to disruption in the presence of certain LMNA mutations.

The findings reveal the likely importance of the nuclear lamina in regulating cell identity and the physical organization of the genome, Jain said. This also opens up new avenues of research that could one day lead to the successful treatment or prevention of LMNA-mutations and related disorders.

Other co-authors of the study were co-first authors Parisha Shah and Wenjian Lv; and Joshua Rhoades, Andrey Poleshko, Deepti Abbey, Matthew Caporizzo, Ricardo Linares-Saldana, Julie Heffler, Nazish Sayed, Dilip Thomas, Qiaohong Wang, Liam Stanton, Kenneth Bedi, Michael Morley, Thomas Cappola, Anjali Owens, Kenneth Margulies, David Frank, Joseph Wu, Daniel Rader, Wenli Yang, and Benjamin Prosser.

Funding was provided by the Burroughs Wellcome Career Award for Medical Scientists, Gilead Research Scholars Award, Pennsylvania Department of Health, American Heart Association/Allen Initiative, the National Institutes of Health (DP2 HL147123, R35 HL145203, R01 HL149891, F31 HL147416, NSF15-48571, R01 GM137425), the Penn Institute of Regenerative Medicine, and the Winkelman Family Fund for Cardiac Innovation.

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Penn Medicineis one of the worlds leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nations first medical school) and theUniversity of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health Systems patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Centerwhich are recognized as one of the nations top Honor Roll hospitals byU.S. News & World ReportChester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nations first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder - Newswise

Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them – CNN

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They couldn't explain why those afflicted, often in the same family, had recurring fevers, abdominal pain, troublesome rashes and muscle aches. Known as familial Mediterranean fever, the disease often went undiagnosed for years, and it was sometimes fatal.

A similar, but unrelated, mystery fever was initially thought to affect families with Scottish and Irish heritage.

"The pain I felt back then, it moved around. One week the pain was in my leg, and the next week my arm would hurt instead," said Victoria Marklund, 47, a Swedish woman who suffered from TRAPS, or tumor necrosis factor receptor-associated periodic syndrome, a disease first identified in a family of Irish and Scottish descent living in the UK city of Nottingham in 1982.

Her father and grandfather died prematurely from kidney complications, which were likely a consequence of the undiagnosed disorder.

Marklund has now received an effective treatment and lives symptom-free -- largely thanks to the work of one US physician and health researcher, Dr. Dan Kastner, a distinguished investigator at the National Institutes of Health who serves as scientific director of the National Human Genome Research Institute.

"What Dr. Kastner has accomplished is absolutely groundbreaking. The concept of autoinflammatory disorders didn't exist before he identified the cause behind a number of them," said Olle Kmpe, a professor of clinical endocrinology at Karolinska Institutet in Stockholm who is a member of The Royal Swedish Academy of Sciences and chair of the Prize Committee. The academy also selects Nobel laureates.

"His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of disease from which patients previously suffered enormously," Kmpe added.

Breakthrough

Kastner first came across familial Mediterranean fever in a patient with recurring arthritis and high fevers he treated as a rheumatology fellow just months into his first job at the NIH in Bethesda, Maryland, in 1985. That chance diagnosis set him on a 12-year journey to find the gene -- or genes -- responsible for the disease.

"It was known that familial Mediterranean fever was a genetic disease. It was known that it was recessively inherited, but no one knew what the gene was, or even the chromosome," he said.

He traveled to Israel, where he took blood samples from 50 families with familial Mediterranean fever.

It took Kastner seven years to locate the mutation to chromosome 16. It took another five years -- in 1997 -- for Kastner and his team to find the mutated gene itself -- one misprint in a genetic code comprised of 3 billion letters.

After this breakthrough, he stayed at NIH, where he studied undiagnosed patients with similar symptoms. He identified 16 autoinflammatory genetic disorders and found effective treatments for at least 12 of them, establishing a whole new field of medicine.

Now that the full human genome has been mapped, the process of detecting the genetic root of such disorders is quicker, and greater numbers of patients with these rare, unexplained diseases are being helped as a result of Kastner's work.

All-nighters

There are few images in science more iconic than the DNA double helix structure, discovered in 1953 by James Watson and Francis Crick, two years after Kastner was born. As a seventh grader, he once created a version of the twisted ladder shape using jelly beans and pipe cleaners for a science fair.

His work to identify the gene that caused familial Mediterranean fever had its own element of competition. In the summer of 1997, to beat a rival team led by French researchers, Kastner took a last-minute flight from Bethesda, Maryland, where the NIH is based, to Boston to submit his manuscript detailing the gene mutation that caused familial Mediterranean fever by hand to the journal Cell on a Friday afternoon.

These were the days before papers could be submitted with the click of a mouse. He hoped to publish his work first. Ultimately, the two teams published their papers simultaneously in different journals -- both fortunately arriving at the same finding.

"I love that type of thing," he said. "We still have races to the finish, and there's nothing like a good week of all-nighters."

Kastner had discovered that the gene involved in familial Mediterranean fever produces a protein called pyrin. Normally this helps to activate our innate immune system -- our first line of defense to fight bacteria and viruses.

In this case, however, pyrin made the innate immune system become overactive, resulting in fever, pain and joint inflammation. He went on to study patients with similar and more devastating symptoms -- identifying TRAPS and many more rare diseases.

Transforming lives

What has motivated Kastner for five decades is how his work decoding the genetics of inflammation can inform new treatments and ultimately transform patients' lives.

"There's nothing more gratifying in life and nothing more satisfying scientifically," he said. He plans to step down from his role as scientific director at the NIH in the next few months and then focus his efforts on his clinic, where he has over 3,000 patients enrolled and "find yet more disease genes, understand how they work, and develop new treatments."

"Of course, one can never know how long that will last, but I love doing it, and will continue as long as I can."

In more recent work beginning in 2014, Kastner identified and pioneered treatment for a severely debilitating genetic disorder known as DADA2, short for deficiency of the enzyme ADA2 (adenosine deaminase 2), which can cause recurring fevers and strokes starting in childhood. His research has radically improved the life of the daughter of Dr. Chip Chambers.

"She's now at college and the improvement in her quality of life has been dramatic."

Similarly, TRAPS survivor Marklund suffered for years before her diagnosis at the age of 38. Her nephews, who both have TRAPS but have been given medicine from an early age, don't feel the effects of the disease at all, she told The Royal Swedish Academy Of Sciences.

"I doubted many times that anyone would ever figure out what I was suffering from. So now it feels fantastic, to be told what it was, to understand the cause of the disease and that there is medicine that helps."

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Mysterious untreatable fevers once devastated whole families. This doctor discovered what caused them - CNN