Last year, defense was the calling card of the Jazz. That's not the case this season.

• Facebook is taking a harder line on misinformation related to coronavirus than it has on other health topics in the past.
• This decision may increase the pressure on the company to act more decisively against other forms of harmful falsehoods that spread on its social networks.
• Facebook is banning events that promote flouting lockdown protests, and is removing the conspiracy theory video "Plandemic."
• But false claims that vaccines are dangerous still proliferate on Facebook — even though they contribute to the deaths of children.

Amid the pandemic, Facebook is taking a harder line on misinformation than it has in the past. That decision may come back to haunt it.

As coronavirus has wreaked havoc across the globe, forcing lockdowns and disrupting economies, false information and hoaxes have spread like wildfire on social media. Miracle cures, intentional disinformation about government policies, and wild claims that Bill Gates orchestrated the entire health crisis abound.

In the past, Facebook has been heavily criticised for failing to take action to stop its platform being used to facilitate the spread of misinformation. To be sure, coronavirus falsehoods are still easily found on Facebook — but the company has taken more decisive action than in previous years:

• For starters, Facebook is now displaying warning messages to people who have shared false information about COVID-19. They're imperfect — Stat reported that they may be too vague in their wording to have a major impact — but it's a step further than Facebook has taken on misinformation in the past.
• The company is also taking down event pages for events that reject mainstream science on coronavirus by calling on people to flout lockdown rules.
• And it is banning "Plandemic," a conspiratorial video about coronavirus that has been going viral on social media and contains numerous falsehoods.

But Facebook's actions to combat COVID-19 misinformation may backfire — in the sense that it has the potential to dramatically increase pressure on the company to take stronger action against other forms of misinformation.

The company has long struggled with how to handle fake news and hoaxes; historically, its approach is not to delete them, but to try to artificially stifle their reach via algorithmic tweaks. Despite this, pseudoscience, anti-government conspiracy theories, and other falsehoods still abound on the social network.

Facebook has now demonstrated that it is willing to take more decisive action on misinformation, when the stakes are high enough. Its critics may subsequently ask why it is so reticent to combat the issue when it causes harm in other areas — particularly around other medical misinformation.

One expected defence for Facebook? That it is focused on taking down content that causes "imminent harm," and while COVID-19 misinformation falls into that category, lots of other sorts of falsehoods don't.

However, using "imminence" as the barometer of acceptability is dubious: Vaccine denialism directly results in the deaths of babies and children. That this harm isn't "imminent" doesn't make it any less dangerous — but, for now, such material is freely posted on Facebook.

Far-right conspiracy theories like Pizzagate, and more recent, Qanon, have also spread on Facebook — stoking baseless fears of shadowy cabals secretly controlling the government. These theories don't intrinsically incite harm, but have been linked to multiple acts of violence, from a Pizzagate believer firing his weapon in a pizza parlour to the Qanon-linked killing of a Gambino crime boss. (Earlier this week, Facebook did take down some popular QAnon pages — but for breaking its rules on fake profiles, rather than disinformation.)

And Facebook is still full of groups rallying against 5G technology, making evidence-free claims about its health effects (and now, sometimes linking it to coronavirus in a messy web). These posts exist on a continuum, with believers at the extreme end attempting to burn down radio towers and assault technicians; Facebook does take down such incitements to violence, but the more general fearmongering that can act as a gateway to more extreme action remains.

This week, Facebook announced the first 20 members of its Oversight Board — a "Supreme Court"-style entity that will review reports from users make rulings as to what objectionable content is and isn't allowed on Facebook and Instagram, with — in theory — the power to overrule the company. It remains to be seen whether its decisions may affect the company's approach for misinformation, and it still needs to appoint the rest of its members and get up and running.

For now, limits remain in place as to what Facebook will countenance in its fight against coronavirus-specific misinformation.

CEO Mark Zuckerberg said the company would immediately take down posts advertising dangerous false cures to COVID-19, like drinking bleach. It is "obviously going to create imminent harm," he said in March. "That is just in a completely different class of content than the back-and-forth accusations a candidate might make in an election."

But in April, President Donald Trump suggested that people might try injecting a "disinfectant" as a cure, which both has the potential to be extremely harmful, and will not cure coronavirus.

Facebook is not taking down video of his comments.

Do you work at Facebook? Contact Business Insider reporter Rob Price via encrypted messaging app Signal (+1 650-636-6268), encrypted email (robaeprice@protonmail.com), standard email (rprice@businessinsider.com), Telegram/Wickr/WeChat (robaeprice), or Twitter DM (@robaeprice). We can keep sources anonymous. Use a non-work device to reach out. PR pitches by standard email only, please.

SEE ALSO: Facebook announced the first 20 members of its oversight board that will decide what controversial content is allowed on Facebook and Instagram

Join the conversation about this story »

NOW WATCH: A cleaning expert reveals her 3-step method for cleaning your entire home quickly

• Oracle's bid to become a bigger player in the cloud has become more aggressive in the COVID-19 crisis, highlighted by a new partnership with Zoom.
• The tech giant is up against stronger rivals led by Amazon, Microsoft and Google, but the need for more cloud capacity sparked by the sudden pivot to remote work has created opportunities for the Silicon Valley behemoth.
• Here are the 10 Oracle executives who are playing key roles in CEO Safra Catz and founder Larry Ellison bold cloud offensive.
• Click here for more BI Prime stories.

Oracle has been through some jarring changes in the last seven months. 

The tech giant lost a well-regarded and experienced co-CEO when Mark Hurd died in October after taking leave for health reasons, leaving Safra Catz as the solo CEO. Now, like other major tech companies, Oracle is grappling with the impact of the coronavirus crisis.

But Oracle has been through tough times in its 43-year history. In fact, the Silicon Valley giant has been known to seize opportunities during rough spots. It's already seen some success during this crisis, too: Oracle just scored a big win when videoconferencing company Zoom — suddenly facing a surge in demand — chose to expand on Oracle Cloud, instead of other platforms like top cloud provider Amazon. Oracle is generally considered a smaller player in the cloud wars, behind giants Amazon, Microsoft, Google, and Alibaba.

Yes, Oracle still has a long way to go to match its rivals' reach, but its strategy of expanding its capacity by building more data centers seems to be paying off, IDC President Crawford Del Prete told Business Insider.

That increased capacity and Oracle's "world class" applications are key in the cloud words, Del Prete said: "Oracle is one of the few companies able to deliver both at scale in order to compete."

While Catz and founder, executive chairman, and chief technology officer Larry Ellison the lead company, they're also relying on key top executives, including cloud veterans from rival Amazon, to advance Oracle's cloud strategy. 

Nearly all are white men, something Oracle has criticized for in the past: Over 30 members of Congress slammed the company late last year about the lack of diversity in its leadership team and on its board.

Meet the 10 top executives playing important roles in Oracle's cloud offensive:

SEE ALSO: Oracle is known for making bold M&A moves in a recession and it's sitting on a fresh $20 billion. Here are the 7 companies experts think it could acquire as the coronavirus crisis drives down valuations

SEE ALSO: Experts lay out five moves that Oracle founder Larry Ellison, one of tech's best tacticians, might take in a coronavirus-driven downturn

Don Johnson left Amazon to focus on Oracle's cloud infrastructure.

Title: Executive vice president, cloud infrastructure

Reports to: Larry Ellison

Johnson  played a key role in Amazon's dramatic expansion in the cloud before joining Oracle in 2014.

He was instrumental in setting up Oracle's cloud engineering development center in Seattle and in the tech giant's expanding data center footprint.  Johnson has also led another major Oracle initiative: forming a cloud partnership with Microsoft.

Oracle's chief corporate architect Edward Screven has been with the company since 1986.

Title: Chief corporate architect

Reports to: Larry Ellison

Screven is an Oracle veteran who helped lead the company through all of the major industry changes of the past 30 years.

He admits that cloud market-leader Amazon had a head start, but says that there are benefits to following it. 

"We definitely started after Amazon: The bad news is they have market share, the good news is we get to learn a lot," he told Business Insider in an interview in May 2019. "Mindshare, that may be their biggest asset. But there is no technology they have that is concerning to me at all."

As one of Oracle's top technologists, he's focused on making Oracle's cloud infrastructure more secure, with more sophisticated and efficient ways to manage data. 

"We have hundreds of thousands of customers that store their most important data in Oracle databases," Screven said. "We could do a far better job for them than any other cloud provider. We are doing a far better job for them."

Clay Magouyrk leads cloud infrastructure engineering and played a key role in forging Oracle's new alliance with Zoom.

Title: Executive vice president, cloud infrastructure engineering

Reports to: Don Johnson

Magouyrk is another veteran of Amazon Web Services who joined the Oracle team in Seattle in 2014. 

He was Oracle's point-man in forging its new partnership with Zoom, which was seen as a major victory for Oracle.

"They needed capacity," Magouyrk told Business Insider last month "They reached out to us and we were like, 'Awesome, we can work with you.' Within a day, we had their application up and running."

Magouyrk was a founding team member of Oracle's cloud engineering development center in Seattle, which is spearheading the company's cloud infrastructure efforts.

Ariel Kelman left Amazon Web Services to become Oracle's chief marketing officer.

Title: Chief Marketing Officer

Reports to: Safra Catz

One of the biggest hurdles for Oracle is the public perception that it's a minor player in the cloud. In other words, it's a marketing problem.

This is where Kelman comes in. Before Oracle brought him on board in January 2020, Kelman led rival Amazon's cloud marketing efforts, and served as a marketing executive at Salesforce for six years before that.

"Ariel is a super smart hire for Oracle," analyst Ray Wang of Constellation Research told Business Insider. "He brings the cred in the market and understands how to counter all of Amazon's tactics and long-term strategy. He has the ear of Larry and Safra and is making progress with some great hires on his team."

Juergen Lindner left SAP to lead Oracle's software-as-a-service marketing strategy.

Title: Senior vice president, software-as-a-service marketing

Reports to: Ariel Kelman, chief marketing officer

Lindner spent most of his career helping SAP outsell Oracle in the traditional business software market: both dominated teh market for software installed in private data centers. 

He switched sides and roles four years ago to support Oracle's bid to become a stronger player in cloud software, also referred to as software-as-a-service, where businesses access applications through cloud platforms and pay via a subscription, usually based on the number of users granted access. 

Lindner has said it became clear to him that Oracle had a better strategy for the cloud-software era.

"Oracle has architected a very sustainable cloud infrastructure and applications strategy," he told Business Insider last year.

Steve Daheb left Citrix to lead Oracle's cloud marketing strategy.

Title: Senior vice president, cloud go-to-market

Reports to: Ashley Hart, senior vice president, global marketing cloud platform and database

Daheb joined Oracle in 2015 after serving as the chief marketing officer of Citrix, a cloud pioneer that first let businesses set up computing networks on web-based platforms instead of on-premise data centers, leading to dramatic IT cost savings.

Daheb witnessed the unexpected rise of Amazon in cloud computing, which began in the early : 2000s when the online retail giant realized it could make some extra money by giving businesses access to its massive but underutilized computing infrastructure, hosted from its data centers.

"Amazon had spare computing resources to rent out," he told Business Insider last year. "It's like, 'Hey, man, I got an extra room in the house during the summer when it's not spike retail time. There's nobody in there, so why don't I put this thing on Airbnb and see if anybody wants it?'"

Amazon Web Services has led the industry ever since. 

Like others on the Oracle team, Daheb thinks the software giant's technology and track record of working with major players across industries will eventually propel it to the front of the cloud pack.

"There's a level of understanding we have and a level of empathy we have for enterprise users: We serve the major banks, we serve transportation, we serve healthcare," he said. "We brought this enterprise mentality to it."

Juan Loaiza, who has been with Oracle since 1988, is in charge of mission-critical database technologies.

Title: Executive vice president, mission-critical database technologies

Reports to: Larry Ellison

Loaiza is another Oracle veteran who has been with the company for more than 30 years and is currently focused on its bid to expand the reach of its flagship database product.

The tech giant's cloud-based automated data-management platform Autonomous Database uses machine learning to quickly repair and update itself.Loaiza has compared the status of this fairly new initiative to the development of the self-driving car:

"It took a long time to get to a point where we are now and say, 'The next step is a self-driving car,'" he told Business Insider last year. "It's got to be safe. It has to have seatbelts and airbags and a navigation system. All that stuff was necessary before you take it to the next stage." 

The database is ready for that next stage. 

Jason Williamson left Amazon to lead Oracle's outreach to startups.

Title: Vice president, Oracle for Startups

Reports to: Mamei Sun, Ellison's chief of staff

Startups have played an important role in the growth of cloud computing and Oracle has launched a big push to establish closer ties with these smaller companies, given that they could eventually become the biggest power players. 

Williamson has been the company's point-man in this effort, as he develops ways to make Oracle's products and services more accessible to startups.

Williamson is another veteran of Amazon Web Services where he led the cloud giant's private-equity team before joining Oracle in 2017.

Evan Goldberg cofounded NetSuite, which is now part of Oracle.

Title: Executive vice president, NetSuite

Reports to: Safra Catz

Goldberg is part of the elite club of Oracle alums who went on to launch successful enterprise-software companies. (Salesforce CEO Marc Benioff is perhaps the best-known.)

Goldberg left a long career at Oracle in the late 1990s to launch NetSuite, a cloud-based provider of financial- and accounting-management services. He was the chief technology officer alongside CEO Zach Nelson, another Oracle alum, and Ellison was actually one of their early backers.

Oracle acquired the company in 2016 and it now has more than 18,000 customers. 

Steve Miranda has been with Oracle since 1992 and leads cloud-applications development.

Title: Executive vice president, applications product development

Reports to: Ellison

Miranda is an Oracle veteran in charge of different aspects of the company's cloud-software business, including product development and strategy.

This covers applications used for major business operations, like supply-chain management, human resources, and enterprise performance management.

Bernie Sanders joined rapper Cardi B on her Instagram page to talk politics and nail care.

Review of 'She Said: Breaking the Sexual Harassment Story that Helped Ignite a Movement' by Jodi Kantor and Megan Twohey

The credibility of statistics apparently depends on whether they’re beneficial.

One of the biggest mistakes a business owner can make today is ignoring social media marketing or treating it as an afterthought. This is even more so in an increasingly competitive space like the web design niche where small businesses have to strive to leave the shadows of more established brands with years of history […]

The post How to Use Instagram To Grow Your Web Design Business appeared first on SpyreStudios.

oscon: RT @oreillyanimals Vote Instant Wild's Digital Eyes & Ears for Wildlife Protection to win Google Global Impact Award http://t.co/BM3qufX1PF

Recently, The Washington Post published an article about the latest hostilities in the “reading wars.” I noticed it because the columnist, Jay Matthews, quoted from this blog.

Recently, The Washington Post published an article about the latest hostilities in the “reading wars.” I noticed it because the columnist, Jay Matthews, quoted from this blog.

Instant Reaction: September Jobs Report

Instant reaction: NAR’s Lawrence Yun on Case-Shiller

velocityconf: RT @oreillyanimals Vote Instant Wild's Digital Eyes & Ears for Wildlife Protection to win Google Global Impact Award http://t.co/Z0EetiQshZ

After a month-long hiatus, additional instant offer firms are stepping back in to purchase homes, using contact-free processes.

If you’ve been holding on to the presumption that gun confiscation will never take place in the United States, it’s time for you to wake up. Gun confiscation is already here, and it’s not slowing down anytime soon. As a result of the passage of red flag laws, 412 guns have been confiscated in Broward…

The post Op-Ed: The Case Against Red Flag Laws appeared first on The Western Journal.

If you’ve read Shoshana Zuboff’s Surveillance Capitalism, you likely agree that the most important asset for a data-driven advertising platform is consumer engagement. That engagement throws off data, that data drives prediction models, those models inform algorithms, those algorithms drive advertising engines, and those engines drive revenue, which drives profit. And profit, of course, drives … Continue reading "Zoom Is YouTube, Instagram, and WhatsApp – All in Two Months."

Western powers are in a bind, analysts say, as ISIS is likely to continue pursuing attacks abroad in retaliation to the loss of territory in Iraq and Syria.

Striso is a digital instrument with pressure-sensitive buttons that plays a variety of acoustic-like sounds.  Read more...

Instant Reaction: Unemployment, May 8, 2020

Introducing Instapaper 4.0 for iPad and iPhone

The lede here is that my pal, Marco, has just released the stellar new 4.0 version of his Instapaper suite.

This is fantastic news, and–as if you needed one more of Marco’s beta testers to say so–I do sincerely hope you’ll mark the occasion (and support his hard work) by purchasing the Instapaper iOS app(s). I promise you’ll be treating yourself to a massive update to an already excellent product.

Now, it’s fortunate and appropriate that you’ll be hearing this advice at length from a lot of people this week. Because, if it’s not already obvious, Marco’s little app (and its associated services) enjoys a rabid fanbase of sundry paragraph cultists who are as eager as I am to spread the word; and, yes, we do want you to join the Reading Nerd cult.

But, I also want to mark the occasion by adding a few thoughts on exactly what Instapaper has done, and continues to do, for me. (As you may already know, I’m a big Marco fan.)

Thing is, I want to tell you how Marco has made a magical machine for people who have decided to read.

Long-Time Fan

For years, Instapaper has been one of the best made, most used, and most beloved apps in my iOS ecosystem. It’s always lived on my iPhone’s home page, and, as you can surmise, that’s because I use Instapaper a lot. Like, a lot a lot. Specifically, I use Instapaper a lot because it helps me do four things extremely well. Four things that work together to make my life a little better.

In that typically annoying mixed order I can’t seem to stop doing, here goes.

2. Deciding WHEN to read

Second, and most obviously, I use Instapaper maybe five to ten times a day to catch up on my reading. Which is great. This is what Instapaper is actually for, right? You read stuff.

Long articles, smaller features, short books, big piles of documentation, and really just anything that I would like to read…later. More saliently, these are things that I have decided to read. This decision part’s important, but more on that in a couple minutes.

But, how does all this “stuff” I’ve decided to read get in to Instapaper?

1. Deciding WHAT to read

See, this is the really important first part. Because as much as I use Instapaper for all manner of reading, its use as an ephemeral destination for mostly ephemeral content wouldn’t be nearly so useful if I didn’t have so many ways to collect all that stuff. So, that flexibility in collecting material is where I end up using some form of Instapaper dozens of times each day.

Examples?

I have a bookmarklet for adding items to Instapaper in 4 browsers on 7 devices. I have (and use the hell out of) the “Send to Instapaper” services that are built in to everything from Google Reader to Reeder to Flipboard to Instacast to Tweetbot to Zite to you name it. I can automate in or out of Instapaper with If This Then That, I can email items directly to Instapaper–hell, I can even just copy a URL from iOS Safari, and paste it directly into the motherscratching Instapaper app.

Suffice it to say, there are many ways to get “stuff” into Instapaper. E.g.:

But, that banner dump only tells part of the story.

Yes, a big part of this is about ubiquity and ease-of-use. But, the practical result is that all those little entrees to Instapaper are available to me everywhere I might need them, and they each represent a single little click that silently adds an item of “stuff” to my Instapaper pile.

Each button is one more simple opportunity for me to decide to read.

3. Deciding WHERE to read

Now, the third part of this magic is less immediately obvious, not least because the reading experience of the Instapaper iOS apps is, for my own purposes, perfect. But, there’s more.

Because, all that support for getting stuff into Instapaper is mirrored by an endless number of ways to get stuff back out. To, in fact, read. That thing I decided to read is now everywhere.

However I ended up deciding to read something, seconds after that *click*, the real magic starts happening, and–through whatever inscrutable black art and transmogrification is happening inside the fearsome celestial engine Marco has made–that decision to read is expressed in the most elegant of results and in a startlingly broad variety of convenient places.

It’s readable on a website; it’s readable on an iPhone, and 2 iPads; it’s readable on a Kindle 3; it’s readable on the crazy number of apps and services that display Instapaper items. And, it’s even preserved for posterity in my private Pinboard archive.

So, for practical purposes, this stuff that I’ve decided to read can now go whooshing through a network of customized tubes, and gently land practically anywhere that well-formed bits may reside.

4. Just…Deciding to Read

I know most of you know these things. I know you’re familiar with the many “Features and Benefits” of Instapaper. And, I even know that most of you reading this are probably already using Instapaper–perhaps even to read this very article.

So, the point here is not simply that Instapaper is flexible, idiot-proof, and sanity-savingly redundant. Although it is all those things and many more.

The point is that my life always gets better when I decide to read things–and then actually read those things I decided to read. This is not a trivial point.

We’re all busy, and we’re all bombarded with 10,000 potential calls on our attention every day. Some days, we handle that better than others. Some days, we don’t handle it all.

All I know, is that, throughout my life, deciding to read has made that life better.

It made my life better at 7 with Henry Huggins. It made my life better at 16 with Slaughterhouse-Five. It made my life better at 20 with Absalom, Absalom!. And, it made my life way better at 25 with A Confederacy of Dunces (cf.).

And, now, for the past few years–following over a decade during which I read way more href tags than actual prose paragraphs–my life has gotten better, in part, due to Instapaper. I’ve finally gotten my hands around this “too much stuff” issue, at least insofar as it relates to words of theoretical interest. Now, I know where it goes. It goes into Instapaper.

Because, now? Yeah. Twenty-some years after a college career sucking down over 1,000 pages a week, I am finally returning to reading a lot more. Because, I am deciding to read a lot more. Instapaper means there’s no excuse for not reading a lot more. Period.

How about you?

What Are YOU Deciding?

When you’re in line at the ATM or the professional sporting event, what do you do?

If you’re like a lot of people, you hit your mobile device like a pigeon on a goddamned pellet. Then, you decide what happens.

You can decide to throw birds at pigs. You can decide to check in on which strangers are pretending to like you today. You may even decide to see what you would look like if you were really fat.

Thing is, you could also decide to read. Just for a couple minutes. Maybe more. Maybe less. Who knows. It’s your decision.

A Nudge Towards “Better”

But, if you have followed the circuitous skeins of yarn comprising this little sweater you’ve been reading, it comes down to this:

If you’ve decided that you want to read, Marco’s app will really help you. He’s removed any phony barriers you’ve built about “not having time” or “not having it with you” or “not knowing where to put it.” There are no excuses, apart from the superficial animated ones you’ve constructed out of cartoon birds.

As for me? In the last week alone, I decided to read a lot of things in Instapaper. A small sampling:

I decided to read about an American family’s educational experiment in Russia.

I decided to read about what Heidegger means by Being-in-the-World.

I decided to read about why toasters are so bad.

I decided to read about responsive web design.

I decided to read about why Charlie Kaufman wrote Being John Malkovich.

I decided to read about how Open Data could make San Francisco Public Transportation better.

I decided to read about how John Siracusa remembers Steve Jobs.

I decided, and then I read. I read, and I read.

So, thanks, Marco. You’ve made my life better by making it easier to decide to read. Then, you made it way easier to do the actual reading.

And, to you–the kind readers-of-prose-paragraphs who were inexplicably patient enough to decide to read this long article–please consider supporting Marco’s work.

Please get an account at Instapaper and, if you have an iOS dingus, please do buy the Instapaper app.

In addition to having exquisite taste in app icons and a lovely speaking voice, Marco’s just a very good human. And, good humans more than deserve our support.

Buy Instapaper 4.0 by Marco Arment.

The following article, BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her, was first published on 100PercentFedUp.com.

Michigan was the first state to see protests against draconian lockdown measures by an overreaching governor. On April 15, the Michigan Conservative Coalition organized an in-vehicle protest in Lansing, MI that drew an estimated 15,000 vehicles. Since that time, several protests by Michigan workers who are being devastated by the one-size-fits-all shut down of the […]

Continue reading: BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her ...

The following article, Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn, was first published on 100PercentFedUp.com.

Yesterday, after 3 1/2 years of having his character and integrity called into question, President Trump's first NSA, General Michael Flynn was finally...

Continue reading: Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn ...

In Lakeshore, it may be a little while longer before a retail cannabis store opens.

Invitation Only Research Event

1 September 2016 , Volume 92, Number 5

8 January 2020 , Volume 96, Number 1

Corporate Members Event Webinar

Che Sidanius, Global Head of Regulation & Industry Affairs, Refinitiv

Patricia Sullivan, Global Co-Head, Financial Crime Compliance, Standard Chartered

Dame Sara Thornton, Independent Anti-Slavery Commissioner, UK

Chair: Tom Keatinge, Director, Centre for Financial Crime and Security Studies, RUSI

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

8 January 2020 , Volume 96, Number 1