Daily Archives: June 18, 2023

Montgomery County school district sues Big Tech over youth mental … – Washington Times

Posted: June 18, 2023 at 1:05 pm

Montgomery County Public Schools, Marylands largest school district, is suing big tech companies in federal court, joining hundreds of other school systems in a legal battle over youth mental health, accusing the social media companies of profiting from vulnerable children, causing them to be depressed, commit violence or harm themselves.

James Frantz of Frantz Law Group is filing on behalf of dozens of districts anticipating that within the next month there will be more than 1,000 school districts involved in the litigation from at least 35 states.

The cases are being consolidated in the Northern District of California under Judge Yvonne Gonzalez Rogers, an Obama appointee. The litigation aims to hold big tech liable for using algorithms that target youth, which the lawsuit says are intentionally and deliberately designed to exploit and cause minors to become addicted, which has caused the harm.

It is a travesty what has happened and these social media companies wont take it upon themselves to regulate themselves, Mr. Frantz told The Washington Times.

The 107-page complaint filed Wednesday on behalf of Montgomery County Public Schools, which has more than 160,000 students, charges that Meta; Instagram; Snap Inc.; TikTok; Bytedance; Alphabet; Google; YouTube and WhatsApp should be held accountable under federal law for negligence and conspiracy to cause minors harm.

It also charges that Section 230 of the Communications Decency Act, which shields internet companies from legal liability for content posted by third parties, shouldnt be an escape from accountability for the tech giants because the companies know of the harm and do not censor the damaging content.

Defendants have successfully exploited the vulnerable brains of minors, causing millions of students across the United States, including in plaintiffs district, to become addicted to and excessively using defendants social media platforms. Furthermore, the content defendants direct to minors is many times harmful and [exploitative] (e.g., instigating vandalism, eating disorders, or encouraging self-harm), the lawsuit stated.

Defendants misconduct is a substantial factor resulting in a youth mental health crisis, which has been marked by increasingly higher proportions of minors struggling with anxiety, depression, thoughts of self-harm and suicidal ideation.

The Supreme Court had two cases this term challenging the liability of tech companies including an opportunity to chip away at Section 230 but the court left the protections intact for now.

Lawsuits from school districts against the tech companies began earlier this year and have been piling up, so the federal cases are being consolidated under one judge.

A spokesperson from Meta, the named plaintiff in the Montgomery County case, did not immediately respond to a request for comment. Meta owns Facebook, Instagram and WhatsApp, among other products.

Mark Zuckerberg, CEO of Meta, said in a Facebook post in 2021 that his company doesnt push content on users to induce a response.

The argument that we deliberately push content that makes people angry for profit is deeply illogical, he wrote at the time.

A report this year from the Centers for Disease Control and Prevention found that teen girls are experiencing increased sadness and violence.

In 2021, 16% of high school students were electronically bullied, including through texting, Instagram, Facebook, or other social media, during the past year. Female students were more likely than male students to be electronically bullied, the report read.

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Big Tech knows most Brits don’t know how to protect their online … – TechRadar

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With online services increasingly becoming the center of people's lives, the amount of personal data we share on the web is growing exponentially.

When data handling scandals occur, such as Meta's latest $1.3 billion blunder, we all get reminded of what's at stake for our right to privacy. However, the reality is that Big Tech companies have built their business model on exploiting information collected onlineand all too often they're found guilty of misconduct.

But, are citizens really aware of the risks of their digital lives? And, do they care about their privacy online? One of the best VPN services around, Proton VPN, asked these and other questions to people in the UK. What it found is that most Brits are "concerned about online surveillance but lack the knowledge and tools to protect themselves."

As mentioned, companies of the likes of Google and Meta are infamous for engaging in massive data collection. While we all know they can monitor basically anything their users do online, we are all still keen to use their services.

"If Big Tech sent actual spies into our homes, we would never stand for such an intrusion into our lives. But for some reason we put up with it online," said Andy Yen, Founder and CEO at Proton.

The discrepancy between people's attitude towards privacy in the offline and online world is known as the privacy paradox.

In March Proton, the company behind one of the best free VPN services and homonymous secure email app, decided to try to better understand why this happens and teamed up with YouGov to survey 2083 adults in the United Kingdom.

It turned out that more than three quarters of respondents (77%) are concerned about their online privacy, with two thirds of people preferring to lose their passport than access to their email account.

The results show that the data Brits are most worried about is financial information (78%), login details (74%), and other personal identification info (68%). Unsurprisingly, people who got hacked in the past were the ones expressing more concern over their sensitive data.

There was also a big generational discrepancy in the responses, as more than a quarter of respondents (26%) aged between 18 and 24 said not to be concerned about their privacy online at all.

Dr. Gus Hosein, Executive Director at UK-based charity Privacy International, said "People are concerned. People want agency. They want to be able to do something. Actually, perhaps, more often than not, they just want to be left alone. They don't want to be poked at, prodded and surveilled as they just go around their daily lives. People want to not have to be worried about these things."

The results also show that, (69%) don't understand how online services are using their data. Despite this, over half of them (52%) believe it's unethical for free services to make a profit on this information.

"For too long, people have gotten a raw deal from tech companies monetizing and abusing their data. And people are upset about their online privacy, but they dont know what to do about it," said Yen from Proton.

The survey depicts a quite grim picture when it comes user knowledge on how to secure their digital lives. The most popular measures were one-click solutions like refusing optional web trackers cookies or browsing the web in incognito mode. Sadly, these steps aren't enough to really escape digital surveillance.

The good news is that the majority of British people (83%) said to be willing to take additional steps to protect their privacy online in the next 12 months.

For those that want to take addtional steps, Proton advises users to introduce the following habits into their every day digital life:

As the so-called surveillance capitalism model becomes more prelevant, governments have been trying to regulate the wild world around the web. Legislations like the GDPR in the EU and UK are the current best attempts to minimize data collection. These are far away from perfect and many countries, most notably the US, are still lacking such a law.

Worryingly, commentators believe that simply fining the companies breaking privacy laws isn't enough to foster a real change. " When a companys market cap is the same size as a small country, the fines that are currently being issued are a drop in the ocean. Big Tech has calculated that the surveillance capitalism model is so profitable that fines are simply a cost of doing business," a Proton spokesperson told TechRadar.

Even if Big Tech change their ways, unethical commercial data abuses are just a side of the story. Government surveillance and cybercrime are other major risks that come from sharing too much of you online.

Proton is committed to keeping on with its mission by equipping users with a wide range of end-to-end encrypted products to help them protect themselves from Big Tech. The tools it currently provides are a VPN, secure email, password manager (Proton Pass), encrypted calendar, and drive. All are open-sourced too, and the company claims to collect no customer data.

Yen said: "Online business models where people come first and their data can never be seen, abused, or monetized need to become the norm. At Proton we firmly believe that surveillance-centric platforms arent the only way to operate online, and that the internet can work in the interests of people."

The Swiss-based security provider believes that "a carrot and stick approach" is what's really needed. This means that governments need to foster competition to help privacy-first alternatives to have a chance in the marketplace. That's partially what the EU Digital Market Act is trying to doacross the European Union at least.

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Meet the man calling out Big Techs climate hypocrisy – Corporate Knights Magazine

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Bill Weihl has lost his voice. In the last year, the San Franciscobased founder of ClimateVoice, a non-profit that is pushing the tech industry to support stronger climate policy, has developed an irreversible throat condition that has robbed him of speech.

But far greater than the irony of Weihls voicelessness is the symbolism of his determination to be heard. Possessed of the urgency of the climate crisis, Weihl is using all the means at his disposal to continue to broadcast his message: that Big Tech needs to step out of the shadows, take a decisive stance on the climate crisis and put its full financial and political weight behind climate policy and action.

Tech companies are viewed as forward looking, Weihl types into the chat function of our Zoom conversation. They have enormous influence. And theyre innovators. We need innovation at this point.

Weihl knows the tech industry from the inside. He spent the first decade of his career as a professor of computer science at the Massachusetts Institute of Technology before shifting into the tech sector to land the position of green energy czar at Google in 2006 and later acting as director of sustainability for Facebook. He acknowledges the significant efforts these companies were making to mitigate climate change: buying billions of dollars of clean energy to power their operations, maintaining venture investment funds for cleantech start-ups, investing heavily in the research and development of decarbonization technologies. And yet, as the climate clock ticked on, Weihl could also see that the sector wasnt doing enough.

We were winning, but we werent winning fast enough, and with climate, winning slowly is the same as losing, he said in a 2020 TED Talk. The same year, he founded ClimateVoice.

Inspiration for the project stemmed in part from what Weihl had observed in 2015/2016, as the American corporate world mobilized around LGBTQ2S+ rights. Companies like Apple, Walmart and the National Basketball Association threatened to pull out of states that were considering, or passing, regressive sexual- and gender-rights legislation. Weihl watched business affect social policy, and it got him thinking.

Most companies talk about how urgent climate is. And how committed they are to it. But when doing something on climate conflicts with or risks their core business, the profit concerns win.

He knew that the tech industry with its forward-looking leaders, focus on innovation and massive influence on culture and politics had a major role to play in climate action. But he also realized that despite the progress made the innovations and cost reductions in renewable technologies and investments in green energy the tech sector was failing to exploit its biggest lever: its potential to influence public policy.

Rather than stand up to the fossil fuel industry, as they were uniquely positioned to do, he saw tech companies playing at best a passive, and at worst an obstructive, role.

To illustrate this point, Weihl cites the fact that only one of the U.S.s five Big Tech companies Microsoft was prepared to endorse last years Inflation Reduction Act. Containing a US$369-billion investment in climate-related programs, the IRA represented the most significant single step the U.S. Congress has ever taken to tackle climate change. Only after it passed into law, in August 2022, did Google let out a quiet cheer in a tweet from its chief sustainability officer.

Most companies talk about how urgent climate is, Weihl types. And how committed they are to it. But when doing something on climate conflicts with or risks their core business, the profit concerns win. He says that tech companies are deeply compromised by their memberships in trade associations that consistently oppose climate bills, chief among them the U.S. Chamber of Commerce, which bristles at any mention of corporate tax hikes.

The tech sectors hypocrisy on climate plays out in many ways. Earlier this year, Amazon effectively killed a bill put forward in the Oregon legislature that would have impelled large data centres and crypto miners in the state to use only clean energy by 2040. Data centres are big business in Oregon, many of them owned by Seattle-based Amazon, and they require vast amounts of power equivalent to a small city to cool their armies of computers. The Oregon utility that serves Amazon has long since exhausted its renewable supply and been forced to buy fossil-fuel-backed electricity; its emissions per kilowatt hour have increased 543% since 2010.

Young employees want to see climate action. And recruitment and retention are big pain points, so companies have to pay attention to employee sentiment on this.

Amazon takes every opportunity to tout its Climate Pledge, a commitment to reach net-zero carbon emissions by 2040; the arena it built in 2021 for Seattles new NHL franchise is named Climate Pledge Arena and aspires to become the first net-zero-certified arena in the world. At the same time, Amazon was willing to lobby hard and successfully to ensure that that clean energy bill died on the floor this spring, claiming that Oregons transmission lines and energy infrastructure wouldnt support the switch.

Weihl says that this kind of duplicity doesnt wash well with the tech sector workforce and that ClimateVoice is working hard to harness its frustration. Young employees want to see climate action, he types. And recruitment and retention are big pain points, so companies have to pay attention to employee sentiment on this.

ClimateVoice engages with tech workers, informing them of what their employers are doing on the climate front both in and out of public view. Weihl says that when he launched his non-profit, most workers were oblivious to their companies lobbying activities and trade association involvement, but the more they learned, the more inclined they were to advocate. In the fall of 2021, he was pleased to see a loud chorus of tech workers speak out in support of the Build Back Better Act and again last summer in favour of the Inflation Reduction Act.

Weihl believes that this is how to foment change from below. In my experience, its very hard to persuade management on purely moral grounds, or on whats best for society, he types. But if the workforce is clamouring for something, that makes it a near-term operational issue.

In Weihls estimation, the tech industry has already developed some 80% of the technological solutions required to help mitigate the climate crisis. Now it has to deploy them faster, innovate further and, most importantly, speak louder and with one voice.

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The time for talk is over is time for action on data privacy – The Hill

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Members of Congress have spent an enormous amount of time recently talking about online data privacy, highlighted by the House’s five-hour grilling session of TikTok’s CEO in March and subsequent calls for banning the social media platform in the United States. But instead of generating headlines for themselves by talking tough to Big Tech companies, lawmakers should focus on actual solutions for protecting consumers, such as legislation that has languished in Congress that could rein in the biggest abusers of data privacy.

Congress is certainly right: From TikTok to Amazon, Big Tech represents an imminent threat to Americans’ privacy — which is why it needs to get serious about taking action on bipartisan bills currently sitting on the table. There is, for example, the 2021 Social Media Privacy Protection and Consumer Rights Act, which would force websites to give users more control over their data and provide them the opportunity to reject data tracking and collection. Or there’s the 2022 American Data Privacy and Protection Act, which proposed a national standard for how companies can collect and use people’s data.

For each day these bills sit dormant, tech companies remain hard at work expanding their reach into our personal data. Take, for instance, Amazon’s recent acquisition of One Medical, which has raised fears among privacy experts that the tech behemoth will soon have unfettered access to millions of Americans’ medical records and other sensitive data. Or, the impending Federal Trade Commission case against the company for alleged privacy violations tied to the use of children’s data with the Alexa voice assistant.

Amazon’s lax approach to data security poses the greatest threat to Americans’ privacy. Today, the company has grown into a colossal data collector, allowing it to access troves of consumer and seller data. And while Google and Twitter may harvest the most consumer data, Amazon doesn’t fall far behind, and outpaces Facebook when it comes to intrusiveness.

The issue isn’t just whether Big Tech can simply mine personal data, but rather its ability to monetize said data. Even worse is if the data is left unguarded and falls into the wrong hands. The added convenience offered by these companies may seem alluring, but unwary consumers handing over their digital identities should be worried.

Amazon’s broad privacy policy allows the tech giant to collect information you provide, the data it already collects automatically, and information from other sources. Like other Big Tech companies, Amazon’s advertising network allows advertisers to use customer data for targeting. But Amazon’s data sharing processes across its various business units exist in a grey area, opening the door, for instance, for an Alexa user to see targeted advertisements on the company’s e-commerce site.

This may already be the reality. According to a recent study, Amazon harvests voice data from Echo devices to serve pointed ads on its own platforms and on the web, sharing your data with as many as 41 advertising partners. The company, which has a burgeoning advertising business and overshadows the $113 billion smart home market, is expected to emerge as a “winner” in the digital ads space due to its massive customer shopping database. Amazon hasn’t been forced to rely on tracking info provided by Apple’s mobile operating system, making it a more effective entity than other technology firms.

Additionally, consumers have expressed concern over the technology used in Amazon Go stores, where cameras and technology replace cashiers. A new lawsuit claims the stores in New York City illegally collect customer data, including a person’s size and shape, without their knowledge.

With Big Tech companies able to access our digital identities at any given moment, one would expect them to have robust data safeguards in place. But this is not the case. Amazon whistleblowers have warned about the company’s lax approach to data security, speaking out about how its security shortcomings may expose sensitive information in data breaches or theft.

Large tech companies are only going to continue exploiting our information for their gain — and never cared much about protecting this data to begin with. Rather than talking tough in hearings, Congress must take real action now by catalyzing the legislation already in motion to protect all American consumers.

José A. Marquez-Leon is national president and CEO of TechLatino: Latinos in Information Sciences and Technology Association (LISTA).

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Letter: UK watchdog’s tough stance on Big Tech should reassure MPs – Financial Times

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Peter Thiel on Big Tech: A Throwback Lecture – Walter Bradley Center for Natural and Artificial Intelligence

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News June 11, 2023 1 Technology Peter Thiel opens up about how artificial intelligence, 5G wireless, and blockchain security are converging in a new era News June 11, 2023 1 Technology

We’ve been sharing and promoting several videos from the 2022 COSM conference, but there’s also a wealth of material to be found in the YouTube archives. Today, we’d like to share a lecture from the 2019 conference featuring prominent venture capitalist and technology innovator Peter Thiel.

Peter Thiel opens up about how artificial intelligence, 5G wireless, and blockchain security are converging in a new era. In a substantive and wide-ranging discussion with tech guru George Gilder, Thiel outlines how new Internet and monetary systems can remedy the currently torturous relations between the U.S. and China, and how understanding money as time overthrows the prevailing economic and technological models and opens the way to a cornucopian future.

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Partial convergence of the human vaginal and rectal maternal … – Nature.com

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Tiny device mimics human vision and memory abilities – Science Daily

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Researchers have created a small device that 'sees' and creates memories in a similar way to humans, in a promising step towards one day having applications that can make rapid, complex decisions such as in self-driving cars.

The neuromorphic invention is a single chip enabled by a sensing element, doped indium oxide, that's thousands of times thinner than a human hair and requires no external parts to operate.

RMIT University engineers in Australia led the work, with contributions from researchers at Deakin University and the University of Melbourne.

The team's research demonstrates a working device that captures, processes and stores visual information. With precise engineering of the doped indium oxide, the device mimics a human eye's ability to capture light, pre-packages and transmits information like an optical nerve, and stores and classifies it in a memory system like the way our brains can.

Collectively, these functions could enable ultra-fast decision making, the team says.

Team leader Professor Sumeet Walia said the new device can perform all necessary functions -- sensing, creating and processing information, and retaining memories -- rather than relying on external energy-intensive computation, which prevents real-time decision making.

"Performing all of these functions on one small device had proven to be a big challenge until now," said Walia from RMIT's School of Engineering.

"We've made real-time decision making a possibility with our invention, because it doesn't need to process large amounts of irrelevant data and it's not being slowed down by data transfer to separate processors."

What did the team achieve and how does the technology work?

The new device was able to demonstrate an ability to retain information for longer periods of time, compared to previously reported devices, without the need for frequent electrical signals to refresh the memory. This ability significantly reduces energy consumption and enhances the device's performance.

Their findings and analysis are published in Advanced Functional Materials.

First author and RMIT PhD researcher Aishani Mazumder said the human brain used analog processing, which allowed it to process information quickly and efficiently using minimal energy.

"By contrast, digital processing is energy and carbon intensive, and inhibits rapid information gathering and processing," she said.

"Neuromorphic vision systems are designed to use similar analog processing to the human brain, which can greatly reduce the amount of energy needed to perform complex visual tasks compared with today's technologies

What are the potential applications?

The team used ultraviolet light as part of their experiments, and are working to expand this technology even further for visible and infrared light -- with many possible applications such as bionic vision, autonomous operations in dangerous environments, shelf-life assessments of food and advanced forensics.

"Imagine a self-driving car that can see and recognise objects on the road in the same way that a human driver can or being able to able to rapidly detect and track space junk. This would be possible with neuromorphic vision technology."

Walia said neuromorphic systems could adapt to new situations over time, becoming more efficient with more experience.

"Traditional computer vision systems -- which cannot be miniaturised like neuromorphic technology -- are typically programmed with specific rules and can't adapt as easily," he said.

"Neuromorphic robots have the potential to run autonomously for long periods, in dangerous situations where workers are exposed to possible cave-ins, explosions and toxic air."

The human eye has a single retina that captures an entire image, which is then processed by the brain to identify objects, colours and other visual features.

The team's device mimicked the retina's capabilities by using single-element image sensors that capture, store and process visual information on one platform, Walia said.

"The human eye is exceptionally adept at responding to changes in the surrounding environment in a faster and much more efficient way than cameras and computers currently can," he said.

"Taking inspiration from the eye, we have been working for several years on creating a camera that possesses similar abilities, through the process of neuromorphic engineering."

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A germline-revertant form of SNV-42 neutralizes SNV

Previous sequence analysis determined that SNV-42, which is encoded by human antibody variable region gene segments IGHV3-48*03/IGLV1-40*01, is remarkably close in sequence to the germline-encoded sequence, with a 97 or 99% identity to the inferred heavy and light chain variable gene sequences, respectively16. To understand whether somatic mutations are necessary for potent neutralization activity, we aligned the SNV-42 coding sequence with the inferred germline gene segments and reverted all mutations in the antibody variable regions to the residue encoded by the inferred germline gene (Supplementary Fig. 1). We then performed a neutralization assay to compare the potency of SNV-42 and the germline-revertant (GR) form of that antibody (denoted as SNV-42GR). We did not detect a change in the IC50 value between SNV-42 (IC50=21.4ngml1) and SNV-42GR (IC50=14.8ngml1) (Fig. 1a). Given that some of the residues in those regions are non-templated and thus cannot be reverted, we did not alter the junctional regions of SNV-42. These results indicate that many of the residues in the antibody paratope that are critical for SNV neutralization are encoded by IGHV3-48/IGLV1-40 germline genes. We also measured the KD values for the affinity matured and the germline reverted forms of SNV-42 to the recombinant SNV Gn head domain (Fig. 1b and Supplementary Table 1) using bio-layer interferometry (BLI). SNV-42 bound to GnH with sub-picomolar affinity, while SNV-42GR demonstrated sub-nanomolar affinity (9.21010M). However, this difference in affinity does not appear to impact the neutralization potency.

a, Representative neutralization curves of SNV-42, germline reverted (GR) SNV-42 and negative control DENV 2D22 to VSV/SNV determined through real-time cellular analysis using the Vero CCL-81 cell line. IC50 values were calculated on the basis of a nonlinear regression and error bars denote means.d. The assay was performed three independent times with similar results. b, Affinity measurements of SNV-42 and SNV-42GR for binding to SNV GnH ectodomain, measured by bio-layer interferometry. Representative curves and KD values are shown for SNV-42GR, while the KD value for SNV-42 could not be determined because the Koff could not be measured. Dashed line indicates dissociation step at 300s. c, Representative neutralization curves of SNV-42, SNV-42GR, positive control (oligoclonal mix of SNV-reactive antibodies) and DENV 2D22 to mutant VSV/SNV viruses. Error bars denote means.d. The assay was performed three independent times with similar results. d, SNV-42 binding in the presence of SNV M-segment mutant constructs determined by flow cytometry. The percent binding (% WT) of each mAb to the mutant constructs was compared to the WT SNV construct. An oligoclonal mix of SNV-reactive antibodies was included to control for expression of each mutant construct. The data are shown as means.d.; from left to right, n=9, 9, 9, 9, 9, 9, 6, 9, 9, 9, 9, 9, 9 and 6 technical replicates. The assay was performed three to four independent times with similar results. e, Top view of escape mutants mapped to the ANDV Gn/Gc spike (PDB: 6ZJM). The blue residues designate escape mutants. Gn is shown in white and Gc is shown in grey. All numbering for SNV sequences was based on GenBank KF537002.1.

Identifying potential escape mutants for antibodies is a crucial part of therapeutic development, and methods of immune evasion employed by hantaviruses are not well understood. To identify the critical binding residues involved in the recognition of SNV Gn by SNV-42, we used two different methods to identify escape mutants resistant to neutralization mediated by SNV-42. First, we implemented a high-throughput, single-passage neutralization escape mapping method using a real-time cellular analysis (RTCA) cell-impedance-based technology. We identified escape mutants in 32 of 88 replicates tested for escape, as manifested by cytopathic effect (CPE) in the presence of neutralizing concentrations of SNV-42 (Supplementary Fig. 2). We sequenced the gene encoding Gn in the virus in the supernatants in 6 wells. The neutralization-resistant viruses contained Gn gene mutations encoding K357Q or T312K alterations (Fig. 1c,e). To further identify escape mutants, we also selected a similar escape mutant (T312A) by serial passaging of a recombinant vesicular stomatitis virus (VSV/SNV) in increasing concentrations of SNV-42. We expressed recombinant forms of Gn with these mutations on the surface of cells and tested binding of SNV-42 to the mutant Gn constructs in flow cytometric binding assays. All three mutations completely ablated mAb binding, further supporting that these two residues are critical binding contacts (Fig. 1d). The binding of SNV-42 was not impacted by escape mutations selected for other SNV-neutralizing mAbs recognizing different antigenic sites (SNV-53 and SNV-24). Taken together, these two methods identified critical residues on SNV Gn that may be under pressure by some antibodies elicited in the human immune response to infection. However, SNV field strains with mutations at T312 or K357 have not been reported.

To understand the structural basis for SNV Gn recognition of SNV-42, a construct encoding the SNV GnH head domain (residues 21377) was produced recombinantly, purified and complexed with the Fab component of SNV-42. The SNV GnHSNV-42 complex was subjected to size exclusion purification and crystallized, and the structure was determined to approximately 1.8 resolution.

One complex of SNV GnSNV-42 was observed in the asymmetric unit of the unit cell (Fig. 2). The structure of SNV GnH has not been reported previously and consists of a compact fold formed of three domains: domains A and B and a -ribbon domain (Fig. 2). Despite a relatively low level of sequence identity (ranging from 43 to 63%), the SNV GnH is very similar to previously characterized hantavirus Gn glycoproteins5,6,7,14, where the equivalent regions of MAPV GnH, ANDV GnH, PUUV GnH or HNTV GnH exhibit root-mean-square deviations of 0.7, 0.9, 1.0 or 1.0 over equivalent C residues, respectively (Fig. 2b). Regions of SNV GnH that exhibit the greatest level of structural deviation from other GnH structures are in solvent exposed loop regions, consistent with these areas of the molecule being naturally flexible or requiring stabilizing contacts from the higher-order (GnGc)4 assembly.

a, Structure of the GnFab complex. The Fab is displayed with the backbone of the light and heavy chains coloured light grey or dark grey, respectively. The CDR loops are thicker and coloured according to the key in c. The Gn is displayed as a ribbon diagram with each of the three domains coloured according to the key in c. The two N-linked glycosylation sites are displayed in green and the location of the two previously described escape mutants (T312K and K357Q) are displayed in orange. Inset is a zoomed panel of the binding site with the side chains of the two escape mutant residues displayed. b, The backbone of the SNV GnH in pink overlaid on several previously reported GnH crystal structures from different hantavirus species in grey. These include Andes orthohantavirus (PDB ID 6Y5F), Maporal orthohantavirus (PDB ID 6Y62), Puumala orthohantavirus (PDB ID 5FXU) and Hantaan orthohantavirus (PDB ID 5OPG). Of note is the capping loop, indicated, which was replaced in SNV GnH with a much shorter GGSG linker to aid crystallogenesis. c, A domain schematic of the Sin Nombre glycoprotein precursor protein that is cleaved at the WAASA cleavage site to form Gn and Gc. The crystallized GnH region is outlined in bold and coloured according to domain. Transmembrane regions are displayed in dark grey and N-linked glycosylation sites displayed in green. The sequence of the capping loop between residues 8699 is displayed alongside the shorter GGSG linker that has been used in its place for this experiment.

Consistent with the epitope mapping analysis (Fig. 1d), SNV-42 binds to domain B and the E3-like domain of SNV Gn (Fig. 2a). The residues implicated in antibody escape identified above, T312 and K357, form key hydrogen bonding interactions with CDRH3 and CDRH1/3, respectively. These hydrogen bonding interactions appear to be perturbed when the mutations T312K and K357Q are modelled, and some rotomeric configurations of K312 may sterically interfere with the antibody, providing a structural rationale for antibody escape (Supplementary Fig. 4). The epitope comprises a large glycan-independent interface, which occludes ~8002 of buried surface area. While all complementarity-determining regions (CDRs) contribute to the epitope, residues comprising the CDRH3 of SNV-42 form the bulk of the interaction through insertion of a 9-residue-long loop into a cleft formed on the SNV Gn surface (Supplementary Fig. 3). CDRH3 possesses a low number of sequence somatic mutations from the putative germline, with only a single amino acid change from the germline D-gene (IGHD5-12*01). This change is one of only five amino acid changes from the germline-encoded sequence present in the paratope region including CDRH1 (T36), CDRH1 (E38), CDRH2 (R57) and CDRH3 (T112) that were all originally encoded as serine residues, plus CDRL1 (Y38) that was originally encoded as aspartate. However, these mutations do not impact the neutralization potency of SNV-42 (Fig. 1a and Supplementary Fig. 1). Interestingly, none of these five paratope residues were observed to sterically hinder antigen recognition when modelled back to the germline-encoded sequence (Supplementary Fig. 5).

SNV-42 is highly specific to SNV and did not demonstrate reactivity to or neutralize any other hantaviruses tested previously16. Assessment of sequence conservation at the epitope provides a structural rationale for this observation, since only 12 of 20 residues in the SNV-42 epitope were conserved with ANDV and 8 of 20 with HTNV. Furthermore, among these non-conserved residues, there exist non-complementary side chains which would probably sterically preclude mAb recognition (Supplementary Fig. 6).

Previous integrative cryo-electron tomography (cryoET) and X-ray crystallography analyses of ANDV, PUUV, HTNV and Tula virus (TULV) have revealed that the ultrastructure arrangement of the hantaviral (GnGc)4 is well conserved and consists of a tetramer of GnGc heterodimers. The GnH forms the most membrane-distal region of the spike and shields fusion loops located in domain II of the Gc5,7,13. To assess the location of the SNV-42 epitope in the context of the higher-order hantaviral GnGc lattice, we overlayed the SNV Gn subcomponent of our complex onto a previously reported (GnGc)4 assembly of ANDV (PDB: 6ZJM) (Fig. 3a,b). This analysis demonstrates that SNV-42 binds to the membrane-distal region of the lattice. While spatially distinct, the SNV-42 epitope is proximal to and slightly overlaps with the epitope of the weakly neutralizing mAb, HTN-Gn114, the only other structurally characterized anti-Gn mAb (Fig. 3c). In contrast to HTN-Gn1, SNV-42 binds in an orientation that is relatively perpendicular to the membrane (Fig. 3b,c). We note that each of the SNV-42 epitopes on the (GnGc)4 tetramer is mutually accessible for binding. Furthermore, unlike for HTN-Gn1, these sites are equally accessible in a cryo-electron microscopy (cryoEM)-derived model of the entire virus with the location of the (GnGc)4 spikes mapped onto the virion surface (Fig. 3a).

a, An EM-derived model of a Sin Nombre virion decorated in Fab fragments of mAb SNV-42. The virion model is derived from previously reported cryoET data of Tula virus5. The Gc is coloured blue and the Gn coloured pink or purple for the head or stalk regions, respectively. The light or heavy chains of the Fab are coloured light or dark grey, respectively. The zoomed inset displays nine individual glycoprotein spikes with the central spike surface rendered at higher resolution. The Fab fragments bound to the central spike are displayed as a backbone trace. b, Top view (left) and side view (right) of the Sin Nombre glycoprotein spike bound to Fab fragments of SNV-42. This assembly model is based on the previously reported ANDV glycoprotein spike tetramer (PDB: 6ZJM). The location of two SNV-42 escape mutants (T312K and K357Q) are displayed in orange and the equivalent locations of other previously reported antibody escape mutants are displayed in red. The complete list of antibody escape mutants and the species they apply to are detailed in Supplementary Table 2. To enable visualization of all epitopes, two loops that are not resolved in this SNV Gn structure (residues 8699 and 221229) were replaced by their equivalents from a previously reported ANDV Gn structure (PDB: 6ZJM). c, The equivalent view of a hantavirus glycoprotein spike bound to Fab HTN-Gn1, a previously reported neutralizing antibody that binds to HNTV14.

Previous epitope mapping of a panel of human SNV Gn- and Gc-specific antibodies revealed a series of epitopes spanning across solvent-accessible surfaces of the higher-order (GnGc)4 spike15,16. Integration of these data with putative epitopes predicted on the surface of other New and Old World hantaviruses indicates a broad distribution of epitopes across both the Gn and Gc glycoproteins (Fig. 3b). While immunodominant regions that are targeted during infection and immunization have yet to be identified, one such epicentre exists at the membrane-distal region of the GnH glycoprotein and co-localizes with our structurally elucidated SNV-42 epitope.

The role of bivalent interactions in the neutralization potency of hantavirus antibodies has yet to be described. To determine how the avidity effects impact the potency of SNV-42, we performed a neutralization assay comparing SNV-42 as a full-length IgG, Fab and F(ab)2. The F(ab)2 form was included to rule out any contributing steric effects of the fragment crystallizable (Fc) domain in neutralizing the virus. We saw no difference in the neutralizing activity between the full-length IgG form and the F(ab)2 form; however, the Fab form of SNV-42 did not demonstrate detectable neutralizing activity for VSV/SNV (Fig. 4a).

a, Representative neutralization curves of IgG1 and Fab forms of SNV-42 to VSV/SNV determined by RTCA using the Vero CCL-81 cell line. IC50 values were calculated on the basis of a nonlinear regression and error bars denote means.d. The assay was performed three independent times with similar results. b, Representative affinity curves of the F(ab)2 and F(ab) form of SNV-42 for binding to SNV GnH, measured by bio-layer interferometry. Representative curves and KD values are shown for SNV-42 F(ab), while the KD value for SNV-42 F(ab)2 could not be determined because the Koff could not be measured. Dashed line indicates the dissociation step at 300s. c, sEC1-EC2 blocking activity of neutralizing antibodies determined through a flow cytometric assay in which mAbs were added at saturating concentration before the addition of the soluble PCDH-1 domain labelled with Alexa Fluor 647 dye. High (50gml1), medium (10gml1) or low (0.5gml1) mAb concentrations were tested. Two-way analysis of variance (ANOVA) with Dunnetts multiple comparisons, ****P<0.0001; NS, not significant. The data are shown as means.d., n=9 technical replicates. The assay was performed two independent times with similar results. d, FFWO assay testing VSV/SNV post-attachment antibody neutralization in permissive (pH 5.5) conditions at 10gml1. Vero CCL-81 cells were used and GFP expression was measured to determine relative infectivity. The data are shown as means.d. of technical replicates, n=9. The assay was performed two independent times with similar results. One-way ANOVA with Dunnetts multiple comparisons, ****P<0.0001.

To further determine whether the lack of neutralizing activity was due to loss in avidity, we measured the KD values of the Fab and F(ab)2 forms of SNV-42 to SNV GnH using BLI (Fig. 4b). In concordance with the IgG form, the F(ab)2 bound SNV GnH with a sub-picomolar avidity, while the Fab form demonstrated a fast off rate and low KD value in comparison (4.08108M). Thus, the neutralization activity of SNV-42 requires bivalent binding to the (GnGc)4 assembly.

To investigate the possibility that bivalent binding of SNV-42 disrupts fusogenic conformational changes to the GnGc complex, we assessed the likelihood of SNV-42 to cross-link neighbouring epitopes on the (GnGc)4 assembly (Supplementary Fig. 9). This analysis suggests that inter-spike, but not intra-spike, bivalent binding may be plausible.

The hantavirus Gn protein probably plays several roles in facilitating the entry of hantavirus virions into host cells17. Gn forms a heterodimer with Gc and prevents the premature membrane insertion of the virus by covering the hydrophobic residues in the fusion loop5. Although the receptor-binding site is unknown, Gn is assumed to interact with attachment factors, including PCDH-117. To understand how SNV-42 engages with Gn to neutralize SNV, we investigated two mechanisms of interfering with viral entry: receptor blocking and fusion inhibition. Previous work has shown that the first extracellular cadherin-repeat domain (EC1) of PCDH-1 interacts with SNV Gn/Gc11, so we employed a flow cytometry-based competition-binding assay to test whether SNV-42 could block the interaction of a soluble recombinant form of the EC domains (sEC1-EC2). We showed that SNV-42 and SNV-42GR both block sEC1-EC2 binding to SNV Gn/Gc in a dose-dependent manner. However, we did not see complete blocking, even at the highest concentrations tested (50gml1; Fig. 4c). Notably, the Fab form of SNV-42 also did not block receptor binding, further suggesting that bivalent binding is required for receptor blocking and viral neutralization.

Although Gc is the canonical fusogenic protein, it is possible that targeting Gn may inhibit dynamic changes necessary to expose the fusion loop and promote viral entry18,19,20. We used a fusion from without (FFWO) assay to test fusion inhibition that can measure antibody-mediated neutralization post-attachment of the virion to the cell surface. SNV-42 and SNV-42GR significantly reduced VSV/SNV infection but did not completely inhibit viral fusion even at saturating concentrations (Fig. 4d). Further, although it is uncertain whether the hantaviral Gn remains bound to the Gc throughout the host-cell entry process, superposition of the SNV GnSNV-42 complex onto the structure of ANDV Gn bound to the near post-fusion state of ANDV Gc15 suggests that SNV-42 is also capable of recognizing a post-fusion state of the GnGc complex (Supplementary Fig. 10). While the precise transitions undertaken by the GnGc assembly are not well understood, it is plausible that bivalent binding of SNV-42 to the (GnGc)4 lattice interferes with the structural transitions required for entry and fusion. As SNV-42 does not mediate complete receptor blocking or neutralization post-attachment at high concentrations, the findings suggest that both mechanisms probably contribute together to cause the exceptional potency of the antibody.

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