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Have you heard of Heath Freeman? He's a thirty-something hedge fund boss, who runs "Alden Global Capital," which owns a company misleadingly called "Digital First Media." His business has been to buy up local newspapers around the country and basically cut everything down to the bone, and just milk the assets for whatever cash they still produce, minus all the important journalism stuff. He's been called "the hedge fund asshole", "the hedge fund vampire that bleeds newspapers dry", "a small worthless footnote", the "Gordon Gecko" of newspapers and a variety of other fun things.

Reading through some of those links above, you find a standard playbook for Freeman's managing of newspapers:

These are the assholes who a few years ago bought the Denver Post, once one of the best regional newspapers in the country, and hollowed it out into a shell of its former self, then laid off some more people. Things got so bad that the Post’s own editorial board rebelled, demanding that if “Alden isn’t willing to do good journalism here, it should sell the Post to owners who will.”

And here's one of the other links from above telling a similar story:

The Denver newsroom was hardly alone in its misery. In Northern California, a combined editorial staff of 16 regional newspapers had reportedly been slashed from 1,000 to a mere 150. Farther down the coast in Orange County, there were according to industry analyst Ken Doctor, complained of rats, mildew, fallen ceilings, and filthy bathrooms. In her Washington Post column, media critic Margaret Sullivan called Alden “one of the most ruthless of the corporate strip-miners seemingly intent on destroying local journalism.”

And, yes, I think it's fair to say that many newspapers did get a bit fat and happy with their old school monopolistic hold on the news market pre-internet. And many of them failed to adapt. And so, restructuring and re-prioritizing is not a bad idea. But that's not really what's happening here. Alden appears to be taking profitable (not just struggling) newspapers, and squeezing as much money out of them directly into Freeman's pockets, rather than plowing it back into actual journalism. And Alden/DFM appears to be ridiculously profitable for Freeman, even as the journalism it produces becomes weaker and weaker. Jim Brady called it "combover journalism." Basically using skeleton staff to pretend to really be covering the news, when it's clear to everyone that it's not really doing the job.

All of that is prelude to the latest news that Freeman, who basically refuses to ever talk to the media, has sent a letter to other newspaper bosses suggesting they collude to force Google and Facebook to make him even richer.

You can see the full letter here:

Let's go through this nonsense bit by bit, because it is almost 100% nonsense.

These are immensely challenging times for all of us in the newspaper industry as we balance the two equally important goals of keeping the communities we serve fully informed, while also striving to safeguard the viability of our news organizations today and well into the future.

Let's be clear: the "viability" of your newsrooms was decimated when you fired a huge percentage of the local reporters and stuffed the profits into your pockets, rather than investing in the actual product.

Since Facebook was founded in 2004, nearly 2,000 (one in five) newspapers have closed and with them many thousands of newspaper jobs have been lost. In that same time period, Google has become the world's primary news aggregation service, Apple launched a news app with a subsription-based tier and Twitter has become a household name by serving as a distribution service for the content our staffs create.

Correlation is not causation, of course. But even if that were the case, the focus of a well-managed business would be to adapt to the changing market place to take advantage of, say, new distribution channels, new advertising and subscription products, and new ways of building a loyal community around your product. You know, the things that Google, Facebook and Twitter did... which your newspaper didn't do, perhaps because you fired a huge percentage of their staff and re-directed the money flow away from product and into your pocket.

Recent developments internationally, which will finally require online platforms to compensate the news industry are encouraging. I hope we can collaborate to move this issue forward in the United States in a fair and productive way. Just this month, April 2020, French antitrust regulators ordered Google to pay news publishers for displaying snippets of articles after years of helping itself to excerpts for its news service. As regulators in France said, "Google's practices caused a serious and immediate harm to the press sector, while the economic situation of publishers and news agencies is otherwise fragile." The Australian government also recently said that Facebook and Google would have to pay media outlets in the country for news content. The country's Treasurer, Josh Frydenberg noted "We can't deny the importance of creating a level playing field, ensuring a fair go for companies and the appropriate compensation for content."

We have, of course, written about both the plans in France as well as those in Australia (not to mention a similar push in Canada that Freeman apparently missed). Of course, what he's missing is... well, nearly everything. First, the idea that it's Google that's causing problems for the news industry is laughable on multiple fronts.

If newspapers feel that Google is causing them harm by linking to them and sending them traffic, then they can easily block Google, which respects robots.txt restrictions. I don't see Freeman's newspaper doing that. Second, in most of the world, Google does not monetize its Google News aggregation service, so the idea that it's someone making money off of "their" news, is not supported by reality. Third, the idea that "the news" is "owned" by the news organizations is not just laughable, but silly. After all, the news orgs are not making the news. If Freeman is going to claim that news orgs should be compensated for "their" news, then, uh, shouldn't his news orgs be paying the actual people who make the news that they're reporting on? Or is he saying that journalism is somehow special?

Finally, and most importantly, he says all of this as if we haven't seen how these efforts play out in practice. When Germany passed a similar law, Google ended up removing snippets only to be told they had to pay anyway. Google, correctly, said that if it had to license snippets, it would offer a price of $0, or it would stop linking to the sites -- and the news orgs agreed. In Spain, where Google was told it couldn't do this, the company shut down Google News and tons of smaller publications were harmed, not helped, but this policy.

This surely sounds familiar to all of us. It's been more than a decade since Rupert Murdoch instinctively observerd: "There are those who think they have a right to take our news content and use it for their own purposes without contributing a penny to its production... Their almost wholesale misappropriation of our stories is not fair use. To be impolite, it's theft."

First off, it's not theft. As we pointed out at the time, Rupert Murdoch, himself, at the very time he was making these claims, owned a whole bunch of news aggregators himself. The problem was never news aggregators. The problem has always been that other companies are successful on the internet and Rupert Murdoch was not. And, again, the whole "misappropriation" thing is nonsense: any news site is free to block Google's scrapers and if it's "misappropriation" to send you traffic, why do all of these news organizations employ "search engine optimizers" who work to get their sites higher in the rankings? And, yet again, are they paying the people who make the actual news? If not, then it seems like they're full of shit.

With Facebook and Google recently showing some contrition by launching token programs that provide a modest amount of funding, it's heartening to see that the tech giants are beginning to understand their moral and social responsibility to support and safeguard local journalism.

Spare me the "moral and social responsibility to support and safeguard local journalism," Heath. You're the one who cut 1,000 journalism jobs down to 150. Not Google. You're the one who took profitable newspapers that were investing in local journalism, fired a huge number of their reporters and staff, and redirected the even larger profits into your pockets instead of local journalism.

Even if someone wants to argue this fallacy, it should not be you, Heath.

Facebook created the Facebook Journalism Project in 2017 "to forge stronger ties with the news industry and work with journalists and publishers." If Facebook and the other tech behemoths are serious about wanting to "forge stronger ties with the news industry," that will start with properly remunerating the original producers of content.

Remunerating the "original producers"? So that means that Heath is now agreeing to compensate the people who create the news that his remaining reporters write up? Oh, no? He just means himself -- the middleman -- being remunerated directly into his pocket while he continues to cut jobs from his newsroom while raking in record profits? That seems... less compelling.

Facebook, Google, Twitter, Apple News and other online aggregators make billions of dollars annually from original, compelling content that our reporters, photographers and editors create day after day, hour after hour. We all know the numbers, and this one underscores the value of our intellectual property: The New York Times reported that in 2018, Google alone conservatively made $4.7 billion from the work of news publishers. Clearly, content-usage fees are an appropriate and reasonable way to help ensure newspapers exist to provide communities across the country with robust high-quality local journalism.

First of all, the $4.7 billion is likely nonsense, but even if it were accurate, Google is making that money by sending all those news sites a shit ton of traffic. Why aren't they doing anything reasonable to monetize it? And, of course, Digital First Media has bragged about its profitability, and leaked documents suggest its news business brought in close to a billion dollars in 2017 with a 17% operating margin, significantly higher than all other large newspaper chains.

This is nothing more than "Google has money, we want more money, Google needs to give us the money." There is no "clearly" here and "usage fees" are nonsense. If you don't want Google's traffic, put up robots.txt. Google will survive, but your papers might not.

One model to consider is how broadcast television stations, which provide valuable local news, successfully secured sizable retransmission fees for their programming from cable companies, satellite providers and telcos.

There are certain problems with retransmission fees in the first place (given that broadcast television was, by law, freely transmitted over the air in exchange for control over large swaths of spectrum), and the value they got was in having a large audience to advertise too. But, more importantly, retransmission involved taking an entire broadcast channel and piping it through cable and satellite to make things easier for TV watchers who didn't want to switch between an antenna and a cable (or satellite receiver). An aggregator is not -- contrary to what one might think reading Freeman's nonsense -- retransmitting anything. It's linking to your content and sending you traffic on your own site. The only things it shows are a headline and (sometimes) a snippet to attract more traffic.

There are certainly other potential options worth of our consideration -- among them whether to ask Congress about revisiting thoughtful limitations on "Fair Use" of copyrighted material, or seeking judicial review of how our trusted content is misused by others for their profit. By beginning a collective dialogue on these topics we can bring clarity around the best ways to proceed as an industry.

Ah, yes, let's throw fair use -- the very thing that news orgs regularly rely on to not get sued into the ground -- out the window in an effort to get Google to funnel extra money into Heath Freeman's pockets. That sounds smart. Or the other thing. Not smart.

And "a collective dialogue" in this sense appears to be collusion. As in an antitrust violation. Someone should have maybe mentioned that to Freeman.

Our newspaper brands and operations are the engines that power trust local news in communities across the United States.

Note that it's the brands and operations -- not journalists -- that he mentions here. That's a tell.

Fees from those who use and profit from our content can help continually optimize our product as well as ensure our newsrooms have the resources they need.

Again, Digital First Media, is perhaps the most profitable newspaper chain around. And it just keeps laying off reporters.

My hope is that we are able to work together towards the shared goal of protecting and enhancing local journalism.

You first, Heath, you first.

So, basically, Heath Freeman, who has spent decade or so buying up profitable newspapers, laying off a huge percentage of their newsrooms, leaving a shell of a husk in their place, then redirecting the continued profits (often that exist solely because of the legacy brand) into his own pockets rather than in journalism... wants the other newspapers to collude with him to force successful internet companies who send their newspapers a ton of free traffic to pay him money for the privilege of sending them traffic.

Sounds credible.

This seems to be something of a thing. Our last "Tales From the Quarantine" post focused on how television celebrities had taken to offering people help on Twitter with their virtual home decor in the latest Animal Crossing game. This post also involves Animal Crossing, but in a much more direct way. Due to the COVID-19 pandemic, there are enormous numbers of people who have suddenly found themselves without jobs or regular income. And, so, they've turned to irregular sources of income instead.

Ars Technica has an interesting interview with one of many people who have taken to the internet to indirectly sell Animal Crossing's "bells", the currency of the game.

In the midst of COVID-19, some New Horizons players are turning to World of Warcraft-style gold farming methods to make ends meet. In early April, Lexy, a 23-year-old recent college grad, created a Twitter account offering up bells (Animal Crossing’s in-game currency) for real-world cash (she requested we refer to her by a nickname to avoid potential reprisal from Nintendo). “I got laid off due to COVID so I'm farming bells in ACNH,” she wrote. “I really need to make rent this month so I'm selling 2 mil bells per $5, please message me if interested, I'll give you a discount the more you buy.”

Before setting up this unorthodox income stream, Lexy had been working at a supermarket while developing her animation portfolio. She began exploring the idea of turning bells into cash after showing friends just how much in-game income she’d been making. “One of them asked to legitimately buy some for me,” she recalled in a Twitter interview. “I did some research and found some people selling bells on sites such as eBay, but for pretty ridiculous prices.” (Current prices on eBay seem more competitive, with some sellers offering rare gold tools and gold nuggets to sweeten the deal).

The threat from Nintendo is probably real. After all, unlike some other games where people do this sort of thing, Nintendo's game doesn't include any method for selling in-game resources for real currency. Nintendo is also notoriously prudish about things like this. And, finally, to make an effective go at this sort of thing, it takes some manipulation of the console in a way that is somewhat controversial with gamers generally.

Understandably, Lexy adjusts the clock on her Nintendo Switch to speed up the game’s slow, “natural” money-making cycle of harvesting daily fruit, digging up bells from the ground, and planting a daily “money tree” that can yield big profits. This kind of in-game “time traveling” is controversial practice among casual Animal Crossing players, but it's a practical necessity to maximize real-world bell-farming profits.

As for how much money people like Lexy are bringing in, it's in the four figures, but she wasn't any more specific than that. Payments are made through digital apps like PayPal, after which she visits the game islands of others and deposits the bells.

That all of this is going on during a global pandemic that has some folks farming bells to make ends meet and others with apparently enough disposable income to be buyers is all, of course, deeply strange. But it's also just yet another way technology is having an impact on our lives during the COVID-19 pandemic.

Well, this one hits the sweet spot of topics I keep trying to demonstrate: both a Streisand Effect and Masnick's Impossibility Theorem. As you may have heard, a group of Republican political consultants and strategists, who very much dislike Donald Trump, put together an effort called The Lincoln Project, which is a PAC to campaign against Trump and Trumpian politics. They recently released an anti-Trump campaign ad about his terrible handling of the COVID-19 pandemic, called Mourning in America, which is a reference to Ronald Reagan's famous Morning in America campaign ad for the 1984 Presidential election. The new ad is, well, pretty powerful:

And while it's unlikely to convince Trump fans deep into their delusions, it certainly got under the President's skin. He went on one of his famous late night Twitter temper tantrums about the ad, and later lashed out at the Lincoln Project when talking to reporters. He was super, super mad.

And what did that do? Well, first it got the ad a ton of views. Earlier this week, one of the Lincoln Project's founders, Rick Wilson, noted that the ad had already received 15 million views across various platforms in the day or so since the ad had been released. Also, it resulted in the Lincoln Project getting a giant boost in funding:

The Lincoln Project, which is run by Republican operatives who oppose President Donald Trump, raised $1 million after the president ripped the group on Twitter this week – marking it the super PAC’s biggest day of fundraising yet.

Reed Galen, a member of the Lincoln Project’s advisory committee, told CNBC that the total came after the president’s Tuesday morning Twitter tirade in reaction to an ad titled “Mourning in America,” which unloads on Trump’s response to the coronavirus pandemic. It recently aired on Fox News, which Trump often watches and praises. Galen said it was the Lincoln Project’s best single-day fundraising haul

Not only that, but it has opened up more opportunity for the Lincoln Project team to get their word out. With so much interest in the ad, it opened up opportunities for the project members to get their message in various mainstream media sources. Reed Galen wrote a piece for NBC:

What we accomplished this week was not something to be celebrated. No commercial should have the power to derail the leader of the free world.

And another Lincoln Project founder, George Conway (who, of course, is the husband of Trump senior advisor Kellyanne Conway), wrote something similar for the Washington Post:

It may strike you as deranged that a sitting president facing a pandemic has busied himself attacking journalists, political opponents, television news hosts and late-night comedians — even deriding a former president who merely boasted that “the ‘Ratings’ of my News Conferences etc.” were driving “the Lamestream Media . . . CRAZY,” and floated bogus miracle cures, including suggesting that scientists consider injecting humans with household disinfectants such as Clorox.

If so, you’re not alone. Tens of thousands of mental-health professionals, testing the bounds of professional ethics, have warned for years about Trump’s unfitness for office.

Some people listened; many, including myself, did not, until it was too late.

That's the kind of media exposure you can't buy, but which you get when you have a President who appears wholly unfamiliar with the Streisand Effect.

And that then takes us to the Impossibility Theorem, regarding the impossibility of doing content moderation at scale well. After Trump's ongoing tirade, Facebook slapped a "Partly False" warning label on the video when posted on Facebook. While the whole situation is ridiculous, it's at least mildly amusing, considering how frequently clueless Trumpkins insist that Facebook censors "conservative" (by which they mean Trumpian) viewpoints. Also, somewhat ironic in all of this: the only reason that Facebook now places such fact check labels on things is because anti-Trump people yelled at how Facebook needed to do more fact checking of political content on its site. So, now you get this.

Part of the issue is that Politifact judged one line in the ad as "false." That line was that Trump "bailed out Wall St. but not Main St." Politifact says that since the CARES Act Paycheck Protection Program has given potentially forgivable loans to some small businesses, and because the bill was done by Congress, not the President, that line is "false." And yet, because angry (usually anti-Trump) people demanded that Facebook do more useless fact checking, the end result is that the video now gets a "false" label.

Of course, this shows both the impossibility of doing content moderation well and the silliness of betting big on fact checking with a full "true or false" claim. One could argue that that line has misleading elements, but is true in most cases. Tons of small businesses are shuttering. Many businesses have been unable to get PPP loans, and under the current terms of the loans, they're useless for many (especially if they have no work for people to do, since the loans have to be mostly used on payroll over the next couple months). But does that make the entire ad "false"? Of course not.

And Rick Wilson is super mad about this. He's right to be mad about Politifact's designation, though it's really a condemnation of the religious focus on "true or false" in fact checking, rather than in focusing on what is misleading or not:

But the ad doesn’t actually claim that small businesses received zero help. Rather, it makes the point that Main Street America is still seriously struggling as the economic fallout from the coronavirus pandemic continues.

But Wilson is also mad at Facebook:

Speaking exclusively to Mediaite, Wilson called the decision “the typical fuckery we’ve come to expect from both the Trump camp and their tame Facebook allies.”

“Facebook is perfectly content to allow content from QAnon lunatics, anti-vaxxers, alt-righters, and every form of Trump/Russian — but I repeat myself — disinformation,” he pointed out. “This is a sign of just how powerfully ‘Mourning In America’ shook Donald Trump and his allies. Their attempt to censor our ad isn’t a setback for us; it’s a declaration of an information war we will win.”

Separately, the Lincoln Project also sent out an email to supporters, again blaming Facebook:

... it's no secret that Facebook has stood by and done little to nothing as lie after lie — from the Liar-In-Chief himself — runs wild on their platform.

(Oh, and let's also not forget the conspiracy theories, foreign disinformation campaigns and negligence that got Mark Zuckerberg questioned by the United States Congress.)

But, this? This is an entirely different and dangerous kind of collusion.

And what is Facebook's excuse for playing favorites with its recently-transferred former employees in the Trump campaign?

They say a "fact-checker" labeled our claim that "Donald Trump helped bailout Wall Street, not Main Street" was untrue.

....Really?

The email goes on to justify the "main street" line with a bunch of links, and then again argues that Facebook is "censoring the truth" to help Trump:

Is that "Partly False?" Of course not.

We told the truth about Donald Trump...

He lost his damn mind over it on Twitter...

Attacked us in front of Air Force One...

Then sent his spin machine to discredit us...

And now his allies at Facebook are doing his damage control by censoring the truth he doesn't like.

I get the frustration -- and I find it at least a bit ironic that the whole "fact checking" system was a response to anti-Trump folks mad at Facebook for allowing pro-Trump nonsense to spread -- but this is just another example of the Impossibility Theorem. There is no "good" solution here. We live in a time where everyone's trying to discredit everyone they disagree with, and many of these things depend on your perspective or your interpretation of a broad statement, like whether or not Trump is helping "main street."

We can agree that it's silly that Facebook has put this label on the video, but also recognize that it's not "Trump's allies at Facebook" working to "censor the truth he doesn't like." That's just absurd (especially given the reason the fact checking set up was put together in the first place).

But, hey, outrage and claims of censorship feed into the narrative (and feed into the Streisand Effect), so perhaps it all is just designed to work together.

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At Let Grow, a wise mom named Kate Sundquist admits that while her kids were already good at playing, they certainly weren’t good at filling hours and hours of free time, playing by themselves. (Read the piece here.) So she her and boys created a schedule. “While these routines might seem restrictive or even the […]

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Spiegel has a piece Inside the Desperate Battle against Sports Doping. Lots of athletes get away with it. Pretty unfair for the ones who do not cheat. I've made this argument many times: anti-doping efforts are a losing cause. Doping techniques will become harder to detect. They will also become more powerful. But there is hope of a sort on the horizon: In 10 years time we have orders of magnitude more understanding of how genetic variants cause differences in human performance. This is inevitable due to the plunging costs of DNA sequencing. As a result it will become possible to measure a person's genetic potential to perform in various sports. Test the genetic potential. Then report for each athlete...

Check out this qz article: The robot that takes your job should pay taxes, says Bill Gates. About 35-40 years ago secretary was the biggest job in most states. Those days are long past. As you can see by advancing the time bar for the USA states map on that page, by 2000 truck driver was the biggest job. So I have a question for Bill Gates: Do you want to tax word processors too? Also, autonomous vehicle technology will surely wipe out most truck driving jobs in the next 20 years. Do you want to tax autonomous truck technology to slow the rate of that transition? Keep in mind that thousands of lives will be saved each year once...

Contes de fées aux enfants - Frédéric la grenouille et Elias l'éléphant.

The post What’s Cooking: Why Bleeding your Fish is Important? appeared first on Ocean Blue Fishing Adventures.

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Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson’s disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) — not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances — not antagonizes — the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow–derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress–triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.

Organ shortage continues to limit the lives of patients who require liver transplantation. While extending criteria for liver organs provides a needed resource, tissue damage from prolonged ischemic injury can result in early allograft dysfunction and consequent rejection. In this issue of the JCI, Nakamura et al. used a mouse transplantation model with prolonged ex vivo cold storage to explore liver graft protection. The authors found that liver grafts with absent carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) exhibited increased ischemia-reperfusion injury inflammation and decreased function in wild-type recipients. The authors went on to correlate CEACAM1 levels with postreperfusion damage in human liver transplant recipients. Notably, this study identified a potential biomarker for liver transplant donor graft quality.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain–containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti–PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti–PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

BACKGROUND Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODS In this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day –2 (n = 3, group B) or day –7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTS MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSION MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATION EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220FUNDING Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.

Immunosuppression continues to be a necessary component of transplantation, despite its association with a multitude of adverse effects. Numerous efforts have been made to circumvent the need for immunosuppression by using various techniques to achieve donor hyporesponsiveness. In this issue of the JCI, Morath et al. take this endeavor forward. Prior to transplantation, the researchers infused recipients with donor-modified immune cells and achieved immunologic hyporesponsiveness. This successful phase I trial also provides a possible avenue for achieving transplantation without the requisite immunosuppression.

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.

BACKGROUND The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODS We performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTS All BPZE1 vaccinees showed robust B. pertussis–specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1–specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSION The breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATION ClinicalTrials.gov NCT02453048, NCT00870350.FUNDING ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.