This is a continuing profile series on the directors of the Department of Energy (DOE) Office of Science user facilities. These scientists lead a variety of research institutions that provide researchers with the most advanced tools of modern science including accelerators, colliders, supercomputers, light sources and neutron sources, as well as facilities for studying the nano world, the environment, and the atmosphere.

The production of formate from CO2 is considered an attractive strategy for the long-term storage of solar renewable energy in chemical form.

Examining the factors that affect the number of females being harvested during the bear hunting season will help Pennsylvania wildlife officials manage population.

Owlet has decided that violin lessons are interesting, and so she’s doing a couple of private ones with her violin teacher from camp in the afternoons. From what I saw yesterday, she works better one on one than in a group setting, which doesn’t surprise me at all, really. The fingerboard popped off her violin […]

There are a few days left to put in a submission on the Electoral (Registration of Sentences Prisoners) Amendment Bill.
The bill would allow prisoners serving sentence of imprisonment under three years to vote, essentially restoring the status quo ante that existed before the members bill advanced by then National MP Paul Quinn was passed by a slim majority
For anyone interested in my views, they're published below. I've been sufficiently organised this time to publish them here a few days before submissions close, so if there are any errors, please let me know. 
The Justice Committee
Electoral (Registration of…

I got my sweet Jess for my birthday 14 years ago. Little did I know at the time that she would become my everything, the love of my life. She died 5 weeks

Maggie, it has been five days since you've passed from this life to the next. I miss you so terribly much! My heart aches every day. I listen for your

I had to say goodbye to my happy waggy boy Baron May 1st. Before me he had a hard life, he'd been a research dog, heavily hw infested, resulting in CHF,

My brother owned a Chinese Crested named Phantom for almost 15 years. Their relationship was far beyond owner and pet, it was 100% family. Old age left

We got Storm when he was 13 weeks old as a companion for our Border Collie, Shadow. We decided on a Labrador because they were the opposite of BC's. Storm

I had a Himalayan Chocolate Point named Mooshie. I had her since she was 6 months old. We grew very close in the coming years. When she was a kitten she

Our Beloved Denver, Thank you for teaching us the true meaning of what love was always meant to be. You were a beautiful dog with a beautiful soul that

Since I was little we had a lovely golden working Cocker Spaniel. She was a lovely little dog and everyone in my family loved her. I grew up with her,

On Friday my vet and I took the decision to put my beloved Springer, Max to sleep. He was my constant companion, loyal friend for 12 years. Because he

I lost my beloved cat Gemma, seven months ago and when I think about her, I can smile a little. I can now think of the happy times and not that dreadful

The first time we saw Buddy he was walking across the grave of one of our beloved cats, Harley, who had just passed away while we were on vacation. This

She passed away just not too long ago, 6-12-13. It was very hard for me to put her down. I had her for 21 years, going on 22 years. I know I feel her presence

Now, before I start this, I want to reassure you all that this is a true story. I'm not making this up. This really happened, and I thank God every night

13 years ago I found out that I had breast cancer. I asked my husband if I could get a dog for comfort. No he said. I started praying for comfort.

Ivy came into my life on December 22, 2012. She was the most beautiful little creature I had ever seen and I knew instantly that she was supposed to be

I lost my Taz April 20th. He was my best friend and companion. He looked at me with so much love. My children and grandchildren live so far away. He

Pepper was not my dog at first, she was given to me when she was a year old. She suffered horrible abuse for the first year of her life, when I got her

My 19 year old cat had to be euthanized a couple of days before Christmas. I must admit the guilt was horrible and all I could do is wonder where my dear

In the past year I had to put one dog to sleep. I adopted her when she was only 4. When we first got her she had a lot of health problems which got taken

  So I wrote an op-ed about the recent Macmillan/ebooks kerfuffle for CNN. Here’s how that all worked…. I got...

For years, the Orleans Parish District Attorney's Office in Louisiana issued fake subpoenas to witnesses and crime victims. Unlike subpoenas used in ongoing prosecutions, these were used during the investigation process to compel targets to talk to law enforcement. They weren't signed by judges or issued by court clerks but they did state in bold letters across the top that "A FINE AND IMPRISONMENT MAY BE OPPOSED FOR FAILURE TO OBEY THIS NOTICE."

Recipients of these bogus subpoenas sued the DA's office. In early 2019, a federal court refused to grant absolute immunity to the DA's office for its use of fake subpoenas to compel cooperation from witnesses. The court pointed out that issuing its own subpoenas containing threats of imprisonment bypassed an entire branch of the government to give the DA's office power it was never supposed to have.

Allegations that the Individual Defendants purported to subpoena witnesses without court approval, therefore, describe more than a mere procedural error or expansion of authority. Rather, they describe the usurpation of the power of another branch of government.

The court stated that extending immunity would be a judicial blessing of this practice, rather than a deterrent against continued abuse by the DA's office.

The DA's office appealed. The Fifth Circuit Appeals Court took the case, but it seemed very unimpressed by the office's assertions. Here's how it responded during oral arguments earlier this year:

“Threat of incarceration with no valid premise?” Judge Jennifer Elrod said at one point during arguments. She later drew laughter from some in the audience when she said, “This argument is fascinating.”

“These are pretty serious assertions of authority they did not have,” said Judge Leslie Southwick, who heard arguments with Elrod and Judge Catharina Haynes.

The Appeals Court has released its ruling [PDF] and it will allow the lawsuit to proceed. The DA's office has now been denied immunity twice. Absolute immunity shields almost every action taken by prosecutors during court proceedings. But these fake subpoenas were sent to witnesses whom prosecutors seemingly had no interest in ever having testify in court. This key difference means prosecutors will have to face the state law claims brought by the plaintiffs.

Based upon the pleadings before us at this time, it could be concluded that Defendants’ creation and use of the fake subpoenas was not “intimately associated with the judicial phase of the criminal process,” but rather fell into the category of “those investigatory functions that do not relate to an advocate’s preparation for the initiation of a prosecution or for judicial proceedings.” See Hoog-Watson v. Guadalupe Cty., 591 F.3d 431, 438 (5th Cir. 2009)

[...]

Defendants were not attempting to control witness testimony during a break in judicial proceedings. Instead, they allegedly used fake subpoenas in an attempt to pressure crime victims and witnesses to meet with them privately at the Office and share information outside of court. Defendants never used the fake subpoenas to compel victims or witnesses to testify at trial. Such allegations are of investigative behavior that was not “intimately associated with the judicial phase of the criminal process.”

Falling further outside the judicial process was the DA's office itself, which apparently felt the judicial system didn't need to be included in its subpoena efforts.

In using the fake subpoenas, Individual Defendants also allegedly intentionally avoided the judicial process that Louisiana law requires for obtaining subpoenas.

The case returns to the lower court where the DA's office will continue to face the state law claims it hoped it would be immune from. The Appeals Court doesn't say the office won't ultimately find some way to re-erect its absolute immunity shield, but at this point, it sees nothing on the record that says prosecutors should be excused from being held responsible for bypassing the judicial system to threaten crime victims and witnesses with jail time.

One of the key points we've been making concerning Attorney General William Barr and his DOJ's eager support for the terrible EARN-IT Act, is that much of it really seems to be to cover up the DOJ's own failings in fighting child porn and child exploitation. The premise behind the EARN IT Act is that there's a lot of child exploitation/child abuse material found on social media... and that social media companies should do more to block that content. Of course, if you step back and think about it, you'd quickly realize that this is a form of sweeping the problem under the rug. Rather than actually tracking down and arresting those exploiting and abusing children, it's demanding private companies just hide the evidence of those horrific acts.

And why might the DOJ and others be so supportive of sweeping evidence under the rug and hiding it? Perhaps because the DOJ and Congress have literally failed to live up to their mandates under existing laws to actually fight child exploitation. Barr's DOJ has been required under law to produce reports showing data about internet crimes against children, and come up with goals to fight those crimes. It has produced only two out of the six reports that were mandated over a decade ago. At the same time, Congress has only allocated a very small budget to state and local law enforcement for fighting internet child abuse. While the laws Congress passed say that Congress should give $60 million to local law enforcement, it has actually allocated only about half of that. Oh, and Homeland Security took nearly half of its "cybercrimes" budget and diverted it to immigration enforcement, rather than fighting internet crimes such as child exploitation.

So... maybe we should recognize that the problem isn't social media platforms, but the fact that Congress and law enforcement -- from local and state up to the DOJ -- have literally failed to do their job.

At least some elected officials have decided to call the DOJ's bluff on why we need the EARN IT Act. Led by Senator Ron Wyden (of course), Senators Kirsten Gillbrand, Bob Casey, Sherrod Brown and Rep. Anna Eshoo have introduced a new bill to actually fight child sex abuse online. Called the Invest in Child Safety Act, it would basically make law enforcement do its job regarding this stuff.

The Invest in Child Safety Act would direct $5 billion in mandatory funding to investigate and target the pedophiles and abusers who create and share child sexual abuse material online. And it would create a new White House office to coordinate efforts across federal agencies, after DOJ refused to comply with a 2008 law requiring coordination and reporting of those efforts. It also directs substantial new funding for community-based efforts to prevent children from becoming victims in the first place.

Basically, the bill would do a bunch of things to make sure that law enforcement is actually dealing with the very real problem of child exploitation, rather than demanding that internet companies (1) sweep evidence under the rug, and (2) break encryption:

• Quadruple the number of prosecutors and agents in DOJ’s Child Exploitation and Obscenity Section from 30 FTEs to 120 FTEs;
• Add 100 new agents and investigators for the Federal Bureau of Investigation’s Innocent Images National Initiative, Crimes Against Children Unit, Child Abduction Rapid Deployment Teams, and Child Exploitation and Human Trafficking Task Forces;
• Fund 65 new NCMEC analysts, engineers, and mental health counselors, as well as a major upgrade to NCMEC’s technology platform to enable the organization to more effectively evaluate and process CSAM reports from tech companies;
• Double funding for the state Internet Crimes Against Children (ICAC) Task Forces;
• Double funding for the National Criminal Justice Training Center, to administer crucial Internet Crimes Against Children and Missing and Exploited Children training programs;
• Increase funding for evidence-based programs, local governments and non-federal entities to detect, prevent and support victims of child sexual abuse, including school-based mental health services and prevention programs like the Children’s Advocacy Centers and the HHS’ Street Outreach Program;
• Require tech companies to increase the time that they hold evidence of CSAM, in a secure database, to enable law enforcement agencies to prosecute older cases;
• Establish an Office to Enforce and Protect Against Child Sexual Exploitation, within the Executive Office of the President, to direct and streamline the federal government’s efforts to prevent, investigate and prosecute the scourge of child exploitation;
• Require the Office to develop an enforcement and protection strategy, in coordination with HHS and GAO; and
• Require the Office to submit annual monitoring reports, subject to mandatory Congressional testimony to ensure timely execution.

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A couple of months ago, a records request revealed a private surveillance contractor had access to nearly every piece of surveillance equipment owned and operated by the state of Utah. Banjo was the company with its pens in all of the state's ink. Banjo's algorithm ran on top of Utah's surveillance gear: CCTV systems, 911 services, location data for government vehicles, and thousands of traffic cameras.

All of this was run through Banjo's servers, which are conveniently located in Utah government buildings. Banjo's offering is of the predictive policing variety. The CEO claims its software can "find crime" without any collateral damage to privacy. This claim is based on the "anonymization" of harvested data -- a term that is essentially meaningless once enough data is collected.

This partnership is now on the rocks, thanks to an investigation by Matt Stroud and OneZero. Banjo's CEO, Damien Patton, apparently spent a lot of his formative years hanging around with white supremacists while committing crimes.

In grand jury testimony that ultimately led to the conviction of two of his associates, Patton revealed that, as a 17-year-old, he was involved with the Dixie Knights of the Ku Klux Klan. On the evening of June 9, 1990 — a month before Patton turned 18 — Patton and a Klan leader took a semi-automatic TEC-9 pistol and drove to a synagogue in a Nashville suburb. With Patton at the wheel, the Ku Klux Klan member fired onto the synagogue, destroying a street-facing window and spraying bullets and shattered glass near the building’s administrative offices, which were next to that of the congregation’s rabbi. No one was struck or killed in the shooting. Afterward, Patton hid on the grounds of a white supremacist paramilitary training camp under construction before fleeing the state with the help of a second Klan member.

If you're wondering where the state of Utah's due diligence is in all of this, there's a partial explanation for this lapse: the feds, who brought Patton in, screwed up on their paperwork.

Because Patton’s name was misspelled in the initial affidavit of probable cause filed in Brown’s case — an FBI agent apparently spelled Damien with an “o” rather than an “e” — any search of a federal criminal court database for “Damien Patton” would not have surfaced the affidavit.

Now that his past has been exposed, the state of Utah has announced it won't be working with Banjo.

The Utah attorney general’s office will suspend use of a massive surveillance system after a news report showed that the founder of the company behind the effort was once an active participant in a white supremacist group and was involved in the shooting of a synagogue.

The AG's office can only shut down so much of Banjo's surveillance software. Other government agencies not directly controlled by the state AG are making their own judgment calls. The University of Utah is suspending its contract with Banjo, but the state's Department of Public Safety has only gone so far as to "launch a review" of its partnership with the company. City agencies and a number of police departments who have contracts with Banjo have yet to state whether they will be terminating theirs.

And the AG's reaction isn't a ban. The office appears to believe it might be able to work through this.

“While we believe Mr. Patton’s remorse is sincere and believe people can change, we feel it’s best to suspend use of Banjo technology by the Utah attorney general’s office while we implement a third-party audit and advisory committee to address issues like data privacy and possible bias,” Piatt said. “We recommend other state agencies do the same.”

It's refreshing to hear a prosecutor state that it's possible for former criminals to turn their lives around and become positive additions to their communities, but one gets the feeling this sort of forgiveness is only extended to ex-cons who have something to offer law enforcement agencies. Everyone else is just their rap sheet for forever, no matter how many years it's been since their last arrest.

The other problem here is the DA's office's tacit admission it did not take data privacy or possible bias into account before granting Banjo access to the state's surveillance equipment, allowing it to set up servers in government buildings, and giving it free rein to dust everything with its unaudited AI pixie dust.

These are all steps that should have taken place before any of this was implemented, even if the state had chosen to do business with a company with a less controversial CEO. This immediate reaction is the right step to take, but a little proactivity now and then would be a welcome change.

Kelly Loeffler is, by far, the wealthiest elected official in Congress, with an estimated net worth of half a billion dollars (the second wealthiest is Montana Rep. Greg Gianforte (famous for his body slamming a journalist for asking him a question and then lying to the police about it)). Loeffler may be used to getting away with tearing up the red tape in her previous life, but in Congress, that often looks pretty corrupt. In just the last few months since she was appointed, there were concerns about her stock sales and stock purchases, which seemed oddly matched to information she was getting during briefings regarding the impact of COVID-19. She has since agreed to convert all her stock holdings to managed funds outside of her control (something every elected official should do, frankly).

Now, the NY Times is noting another form of what we've referred to as "soft corruption" -- moves that might technically be legal, but which sure look sketchy as hell to any regular non-multimillionaire elected official. In this case, Senator Loeffler received what was, in effect, a gift worth $9 million from her former employer, Intercontinental Exchange (the company that runs the NY Stock Exchange, and where her husband is the CEO).

The key issue was that since she was leaving the job to go join the Senate, she had a bunch of unvested stock. For normal people, if you leave a job before your stock vests, too bad. That's the deal. The vesting period is there for a reason. But for powerful, rich people, apparently the rules change. Intercontinental Exchange changed the rules to grant her the compensation that she wasn't supposed to get, because why not?

Ms. Loeffler, who was appointed to the Senate in December and is now in a competitive race to hold her seat, appears to have received stock and other awards worth more than $9 million from the company, Intercontinental Exchange, according to a review of securities filings by The New York Times, Ms. Loeffler’s financial disclosure form and interviews with compensation and accounting experts. That was on top of her 2019 salary and bonus of about $3.5 million.

The additional compensation came in the form of shares, stock options and other instruments that Ms. Loeffler had previously been granted but was poised to forfeit by leaving the company. Intercontinental Exchange altered the terms of the awards, allowing her to keep them. The largest component — which the company had previously valued at about $7.8 million — was a stake in an Intercontinental Exchange subsidiary that Ms. Loeffler had been running.

The entitlement factor oozes out of the statement put out from her office in response to this:

“Kelly left millions in equity compensation behind to serve in public office to protect freedom, conservative values and economic opportunity for all Georgians,” said Stephen Lawson, a spokesman for Ms. Loeffler. “The obsession of the liberal media and career politicians with her success shows their bias against private sector opportunity in favor of big government.”

No, Stephen, that's not the issue. The issue is that normal people who haven't vested yet, don't get to have the board change the vesting rules as you're leaving to go legislate in order to give you a $9 million windfall you didn't earn because it hadn't vested. If it had just been a question of compensation, no one would be complaining. If she had played by the rules that everyone else played by, lived up to her end of the contract and vested the equity, then no big deal. The problem is the last minute changing of the rules to get her a pretty massive payout (perhaps not by her standards, but by anyone else's).

Indeed, the details show that this wasn't just a timing thing, like a standard vesting deal, but that Loeffler was supposed to reach certain milestones to be able to get the equity. She didn't, but she still gets it. That's the part that has people concerned.

In February 2019, Intercontinental Exchange gave Ms. Loeffler a stake in a limited liability company that owned a stake in Bakkt, according to a March 2019 securities filing. The company at the time estimated the award was worth $15.6 million. But Ms. Loeffler would be able to cash in on the award only under certain circumstances, including if Bakkt’s value soared or if it became a publicly traded company.

When Ms. Loeffler stepped down from the company less than 10 months later, she was poised to forfeit much of that Bakkt stake. But Intercontinental Exchange sped up the vesting process so that she got half of it immediately.

The company, of course, puts a nice spin on it, saying "We admire Kelly’s decision to serve her country in the U.S. Senate and did not want to discourage that willingness to serve,” but what else are they going to say anyway?

Still waiting for that supposed swamp draining we keep hearing about.

The coronavirus pandemic and its associated lockdown in most countries has forced major changes in the way people live, work and study. Online learning is now routine for many, and is largely unproblematic, not least because it has been used for many years. However, online testing is more tricky, since there is a concern by many teachers that students might use their isolated situation to cheat during exams. One person's problem is another person's opportunity, and there are a number of proctoring services that claim to stop or at least minimize cheating during online tests. One thing they have in common is that they tend to be intrusive, and show little respect for the privacy of the people they monitor.

As an article in The Verge explains, some employ humans to watch over students using Zoom video calls. That's reasonably close to a traditional setup, where a teacher or proctor watches students in an exam hall. But there are also webcam-based automated approaches, as explored by Vox:

For instance, Examity also uses AI to verify students' identities, analyze their keystrokes, and, of course, ensure they're not cheating. Proctorio uses artificial intelligence to conduct gaze detection, which tracks whether a student is looking away from their screens.

It's not just in the US that these extreme surveillance methods are being adopted. In France, the University of Rennes 1 is using a system called Managexam, which adds a few extra features: the ability to detect "inappropriate" Internet searches by the student, the use of a second screen, or the presence of another person in the room (original in French). The Vox articles notes that even when these systems are deployed, students still try to cheat using new tricks, and the anti-cheating services try to stop them doing so:

it's easy to find online tips and tricks for duping remote proctoring services. Some suggest hiding notes underneath the view of the camera or setting up a secret laptop. It's also easy for these remote proctoring services to find out about these cheating methods, so they're constantly coming up with countermeasures. On its website, Proctorio even has a job listing for a "professional cheater" to test its system. The contract position pays between $10,000 and $20,000 a year.

As the arms race between students and proctoring services escalates, it's surely time to ask whether the problem isn't people cheating, but the use of old-style, analog testing formats in a world that has been forced by the coronavirus pandemic to move to a completely digital approach. Rather than spending so much time, effort and money on trying to stop students from cheating, maybe we need to come up with new ways of measuring what they have learnt and understood -- ones that are not immune to cheating, but where cheating has no meaning. Obvious options include "open book" exams, where students can use whatever resources they like, or even abolishing formal exams completely, and opting for continuous assessment. Since the lockdown has forced educational establishments to re-invent teaching, isn't it time they re-invented exams too?

Follow me @glynmoody on Twitter, Diaspora, or Mastodon.

Senator Richard Burr's potential insider trading issues, for which he's being investigated, may have gotten quite a bit worse this week. A new report notes that on the same day Burr sold off a "significant percentage" of his stock holdings (while also telling the public not to worry about COVID-19), it turns out his brother-in-law just coincidentally decided to dump a bunch of stock too. Amazing!

Sen. Richard Burr was not the only member of his family to sell off a significant portion of his stock holdings in February, ahead of the market crash spurred by coronavirus fears. On the same day Burr sold, his brother-in-law also dumped tens of thousands of dollars worth of shares. The market fell by more than 30% in the subsequent month.

Burr’s brother-in-law, Gerald Fauth, who has a post on the National Mediation Board, sold between $97,000 and $280,000 worth of shares in six companies — including several that have been hit particularly hard in the market swoon and economic downturn.

Could this actually be a coincidence? Sure. Maybe. But the timing (the very same day...) does seem notable. As the ProPublica report notes, Fauth "is not a frequent stock trader." Burr insists that his sales were based on public information, though it's difficult to see how he could simply ignore the classified briefings he got concerning the rising pandemic issues, and base decisions entirely on public information. Indeed, this is why government officials should be required to hand off any equities like this to a blind trust where they have no visibility into how it's traded.

Even if this is all legal (which is not certain either way yet...), it again reinforces the belief that the powerful live by different rules and are able to game the system for personal advantage, even as they're supposed to be serving the public interest.

I recently travelled to Pittsburgh, USA, to present the paper “From Playing Games to Committing Crimes: A Multi-Technique Approach to Predicting Key Actors on an Online Gaming Forum” at eCrime 2019, co-authored with Ben Collier and Alice Hutchings. The accepted version of the paper can be accessed here. The structure and content of various underground … Continue reading From Playing Games to Committing Crimes: A Multi-Technique Approach to Predicting Key Actors on an Online Gaming Forum →

In this reboot of the Three Paper Thursdays, back after a hiatus of almost eight years, I consider the many different ways in which programs can be sanitised to detect, or mitigated to prevent the use of, the many programmer errors that can introduce security vulerabilities in low-level languages such as C and C++. We … Continue reading Three Paper Thursday: Sanitisers and Mitigators →

'Seriously sometimes seems Google's moderators are only optimized to respond to social media outrage'

Three weeks after Google removed 49 Chrome extensions from its browser's software store for stealing crypto-wallet credentials, 11 more password-swiping add-ons have been spotted – and some are still available to download.…

Apparently. But we’re so incredulous, we’re gonna test those claims on live internet TV…

Webcast “The journey to cloud” echoes through all organisations. It’s a Bildungsroman – a story of empowerment and betterment. A shiny, towering cityscape of gleaming edifices and elegant spires. It’s like an ascension into the actual clouds. Like dying and waking up in heaven.…

There was an issue with the tracker where old torrents with an old announce URL were not working properly. This has been fixed now.

A review by Medio DeCritici (165). A 2020 Review - Aliens Versus Predator (PC, 1999)

A review by Medio DeCritici (165). A 2020 Review - Aliens vs. Predator (PC, 2010)

The incentive to automate will be enormous for $15 per hour minimum wage. Of America’s nearly 16 million retail workers, the biggest group — 4.6 million — are salespeople. Their average wage is $10.47 an hour. After that, the country has another 3.4 million cashiers, and their average wage is $9.28 an hour. Only a quarter of salespeople earn more than $14 — and only 10 percent earn more than $19. The figures are worse for cashiers. But in the race to automate there will be a clear winner: Amazon. Why: Amazon can automate more easily than can physical stores. It is analogous to why long haul trucking can be automated before taxis: Just as highways are simpler places than...

The bartender says “You can’t have that thing in here! Get out!” The guy says “It’s okay, this Alligator is highly trained. Just give me a few seconds and I’ll show you.” The bartender, intrigued, gives him the go-ahead. The man gingerly lifts the alligator up onto a table. By this point, everybody in the […]

The post A Man Walks Into A Bar With An Alligator On A Leash appeared first on Funny & Jokes.

Hearing loss caused by the death of sensory hair cells of the inner ear is an unfortunate side effect for many patients treated with aminoglycoside antibiotics or platinum-containing chemotherapy agents. In animal models, induction of heat shock confers substantial otoprotection against aminoglycoside- and cisplatin-induced hair cell death. In this issue of the JCI, Breglio et al. demonstrate that inner ear tissue released exosomes carrying heat shock protein 70 (HSP70) in response to heat stress. HSP70 acted by a paracrine mechanism that engaged the Toll-like receptor 4 (TLR4) on hair cells to protect them from death. Exosomes and the HSP70/TLR4 pathway could thus provide treatment targets for the protection of hair cells from chemically induced death or from other insults, such as noise.

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.

Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. As a result of globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY receptors represent a highly conserved, stress-activated system involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased expression of NPY5 receptor (Y5R) in HCC, which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peritumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R activation. TGF-β1 was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R activation and function in liver cancer. The TGF-β/NPY/Y5R axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.

Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.