[from Science, First Release Notification for July 21]
Proton-Coupled Energy Transfer in Molecular Triads
Abstract
A photochemical mechanism was experimentally discovered and denoted proton-coupled energy transfer (PCEnT). A series of anthracene–phenol–pyridine triads formed the local excited anthracene state after light excitation at ca. 400 nm, which led to fluorescence around 550 nm from the phenol–pyridine unit. Direct excitation of phenol–pyridine would have required light around 330 nm, but the coupled proton transfer within the phenol–pyridine unit lowered its excited state energy so that it could accept excitation energy from anthracene. Singlet-singlet energy transfer thus occurred despite the lack of spectral overlap between the anthracenefluorescence and the phenol–pyridine absorption. Moreover, theoretical calculations indicated negligible charge transfer between the anthracene and phenol–pyridine units. PCEnT was suggested as an elementary reaction of possible relevance to biological systems and future photonic devices.
The 2022 Monkeypox outbreak continues to expand with case counts mounting in many countries. This seminar will cover where we are in the global fight against monkeypox, where we may be headed as a nation, and what we need to do right now to mitigate the growing threat of monkeypox. Join Belfer Fellow Dr. Syra Madad in conversation with Kai Kupferschmidt, Dr. Krutika Kuppalli, Dr. Anne Rimoin, Dr. Boghuma Kabisen Titanji, and Dr. Jay K. Varma.
Kai Kupferschmidt is a sciencejournalist based in Berlin, Germany. He is a contributing correspondent for Science where he often covers infectious diseases. Kai received a diploma in molecular biomedicine from the University of Bonn, Germany and later visited the Berlin Journalism School. He has won several awards for his work, including the Journalism Prize of the German AIDS Foundation. Together with two colleagues he runs a podcast on global health called Pandemia [German]. He has also written two books, one about infectious diseases and one about the science of the color blue.
Dr. Kuppalli was previously awarded the NIH Fogarty International Clinical Research Fellowship and conducted research in Southern India to understand barriers to care and how emerging infections impacted persons living with HIV/AIDS. She was the medical director of a large Ebola Treatment Unit in Sierra Leone during the 2014 West Africa Ebola outbreak, helped lead the development and implementation of pandemic response preparedness activities in resource limited settings, and has consulted on the development of therapeutics for emerging pathogens. Her clinical and research interests focus on health systems strengthening in resource limited settings, research and clinical care for emerging infections, outbreak preparedness and response, and policy. She has worked in numerous countries including Ethiopia, India, Sierra Leone, Uganda, and Haiti.
During the COVID-19 pandemic Dr. Kuppalli served as a consultant for the San Francisco Department of Health and helped develop and operationalize a field hospital. She served as an expert witness to the U.S. Congress, Financial Services Committee Task Force on Artificial Intelligence (AI) about how digital technologies may be leveraged for exposure notification and contact tracing to improve the pandemic response. She also collaborated with the Brennan Center for Justice to develop guidelines to inform “Healthy in-person Voting” in advance of the 2020 U.S. election and testified before the U.S. House Select Subcommittee regarding these recommendations. Prior to her position at WHO, she was the medical lead for COVID-19 vaccine rollout at the Medical University of South Carolina (MUSC) and helped coordinate vaccine education events for the staff and community and oversaw the reporting of adverse vaccine events.
Since joining WHO in August 2021, Dr. Kuppalli has been part of the WHO headquarters incident management team (IMST) for COVID-19, the clinical characterization and management working group for COVID-19, the COVID-19 therapeutics steering committee, and is the technical focal point for the post COVID-19 condition (Long COVID) steering committee. She is a member of the secretariat on the scientific advisory group on the origins of emerging and re-emerging infectious diseases (SAGO) which was convened by the Director General to understand and investigate the origins of SARS-CoV-2 and other novel pathogens. More recently since the development of the multi-country monkeypox outbreak she has been part of the IMST at WHO as one of the clinical management focal points. In this capacity she was part of the WHO core group that helped write the recently published Clinical Management and Infection Prevention and Control guidelines for Monkeypox and advising on the clinical endpoints for the global CORE therapeutics protocol.
Yesterday, an advisory committee to the U.S. Food and Drug Administration met to discuss whether vaccine developers should update their jabs to include a portion of the omicron variant—the version of the coronavirus that currently dominates the globe. The verdict: The omicron variant is different enough that it’s time to change the vaccines. Exactly how is up in the air; the FDA still has to weigh in and decide what versions of the coronavirus will be in the shot.
“This doesn’t mean that we are saying that there will be boosters recommended for everyone in the fall,” Amanda Cohn, chief medical officer for vaccine policy at the U.S. Centers for Disease Control and Prevention said at the June 28 advisory meeting. “But my belief is that this gives us the right vaccine for preparation for boosters in the fall.”
The decision to update COVID-19 vaccines didn’t come out of nowhere. In the two-plus years that the coronavirus has been spreading around the world, it has had a few “updates” of its own—mutating some of its proteins that allow the virus to more effectively infect our cells or hide from our immune systems.
Vaccine developers had previously crafted vaccines to tackle the beta variant that was first identified in South Africa in late 2020. Those were scrapped after studies showed that current vaccines remained effective.
The shots still largely protect people from developing severe symptoms, but there has been an uptick in hospitalizations and deaths among older age groups, Heather Scobie, deputy team lead of the CDC’s Surveillance and Analytics Epidemiology Task Force said at the meeting. And while it’s impossible to predict the future, we could be in for a tough fall and winter, epidemiologist Justin Lessler of the University of North Carolina at Chapel Hill said at the meeting. From March 2022 to March 2023, simulations project that deaths from COVID-19 in the United States might number in the tens to hundreds of thousands.
A switch to omicron-containing jabs may give people an extra layer of protection for the upcoming winter. Pfizer–BioNTech presented data at the meeting showing that updated versions of its mRNA shot gave clinical trial participants a boost of antibodies that recognize omicron. One version included omicron alone, while the other is a twofer, or bivalent, jab that mixes the original formulation with omicron. Moderna’s bivalent shot boosted antibodies too. Novavax, which developed a protein-based vaccine that the FDA is still mulling whether to authorize for emergency use, doesn’t have an omicron-based vaccine yet, though the company said its original shot gives people broad protection, generating antibodies that probably will recognize omicron.
Pfizer and Moderna both updated their vaccines using a version of omicron called BA.1, which was the dominant variant in the United States in December and January. But BA.1 has siblings and has already been outcompeted by some of them.
Now, omicron subvariants BA.2, BA.2.12.1, BA.4 and BA.5 are the dominant versions in the United States and other countries. The CDC estimates that roughly half of new U.S.infections the week ending June 25 were caused by either BA.4 or BA.5. By the time the fall rolls around, yet another new version of omicron—or a different variant entirely—may join their ranks. The big question is which of these subvariants to include in the vaccines to give people the best protection possible.
BA.1, the version already in the updated vaccines, may be the right choice, virologist Kanta Subbarao said at the FDA meeting. An advisory committee to the World Health Organization, which Subbarao chairs, recommended on June 17 that vaccines may need to be tweaked to include omicron, likely BA.1. “We’re not trying to match [what variants] may circulate,” Subbarao said. Instead, the goal is to make sure that the immune system is as prepared as possible to recognize a wide variety of variants, not just specific ones. The hope is that the broader the immune response, the better our bodies will be at fighting the virus off even as it evolves.
The variant that is farthest removed from the original virus is probably the best candidate to accomplish that goal, said Subbarao, who is director of the WHO’s Collaborating Center for Reference and Research on Influenza at the Doherty Institute in Melbourne, Australia. Computational analyses of how antibodies recognize different versions of the coronavirus suggest that BA.1 is probably the original coronavirus variant’s most distant sibling, she said.
Some members of the FDA advisory committee disagreed with choosing BA.1, instead saying that they’d prefer vaccines that include a portion of BA.4 or BA.5. With BA.1 largely gone, it may be better to follow the proverbial hockey puck where it’s going rather than where it’s been, said Bruce Gellin, chief of Global Public Health Strategy with the Rockefeller Foundation in Washington, D.C. Plus, BA.4 and BA.5 are also vastly different from the original variant. Both BA.4 and BA.5 have identical spike proteins, which the virus uses to break into cells and the vaccines use to teach our bodies to recognize an infection. So when it comes to making vaccines, the two are somewhat interchangeable.
There are some real-world data suggesting that current vaccines offer the least amount of protection from BA.4 and BA.5 compared with other omicron subvariants, Marks said. Pfizer also presented data showing results from a test in mice of a bivalent jab with the original coronavirus strain plus BA.4/BA.5. The shot sparked a broad immune response that boosted antibodies against four omicron subvariants. It’s unclear what that means for people.
Plenty of other open questions remain too. The FDA could authorize either a vaccine that contains omicron alone or a bivalent shot, although some data hinted that a bivalent dose might spark immunity that could be more durable. Pfizer and Moderna tested their updated shots in adults. It’s unclear what the results mean for kids. Also unknown is whether people who have never been vaccinated against COVID-19 could eventually start with such an omicron-based vaccine instead of the original two doses.
Maybe researchers will get some answers before boosters start in the fall. But health agencies need to make decisions now so vaccine developers have a chance to make the shots in the first place. Unfortunately, we’re always lagging behind the virus, said pediatrician Hayley Gans of Stanford University. “We can’t always wait for the data to catch up.”
In the early weeks of the 2020 U.S. COVID-19 outbreak, guidance from the scientific establishment and government agencies included a number of dubious claims—masks don’t work, there’s no evidence of human-to-human transmission, and the risk to the public is low. These statements were backed by health authorities, as well as public intellectuals, but were later disavowed or disproven, and the initial under-reaction was followed by an equal overreaction and imposition of draconian restrictions on human social activities.
In a recent paper, LML Fellow Harry Crane examines how these early mis-steps ultimately contributed to higher death tolls, prolonged lockdowns, and diminished trust in science and government leadership. Even so, the organizations and individuals most responsible for misleading the public suffered little or no consequences, or even benefited from their mistakes. As he discusses, this perverse outcome can be seen as the result of authorities applying a formulaic procedure of “naïve probabilism” in facing highly uncertain and complex problems, and largely assuming that decision-making under uncertainty boils down to probability calculations and statistical analysis.
This attitude, he suggests, might be captured in a few simple “axioms of naïve probabilism”:
Axiom 1: more complex the problem, the more complicated the solution.
This idea is a hallmark of naïve decision making. The COVID-19 outbreak was highly complex, being a novel virus of uncertain origins, and spreading through the interconnected global society. But the potential usefulness of masks was not one of these complexities. The mask mistake was consequential not because masks were the antidote to COVID-19, but because they were a low cost measure the effect of which would be neutral at worst; wearing a mask can’t hurt in reducing the spread of a virus.
Yet the experts neglected common sense in favor of a more “scientific response” based on rigorous peer review and sufficient data. Two months after the initial U.S. outbreak, a study confirmed the obvious, and masks went from being strongly discouraged to being mandated by law. Precious time had been wasted, many lives lost, and the economy stalled.
Axiom 2: Until proven otherwise, assume that the future will resemble the past.
In the COVID-19 pandemic, of course, there was at first no data that masks work, no data that travel restrictions work, no data of human-to-human transmission. How could there be? Yet some naïve experts took this as a reason to maintain the status quo. Indeed, many universities refused to do anything in preparation until a few cases had been detected on campus—at which point they had some data, as well as hundreds or thousands of other as yet undetected infections.
Crane touches on some of the more extreme examples of his kind of thinking, which assumes that whatever can’t be explained in terms of something that happened in the past is speculative, non-scientific and unjustifiable:
“This argument was put forward by John Ioannidis in mid-March 2020, as the pandemic outbreak was already spiralling out of control. Ioannidis wrote that COVID-19 wasn’t a ‘once-in-a-century pandemic,’ as many were saying, but rather a ‘once-in-a-century data-fiasco’. Ioannidis’s main argument was that we knew very little about the disease, its fatality rate, and the overall risks it poses to public health; and that in face of this uncertainty, we should seek data-driven policy decisions. Until the data was available, we should assume COVID-19 acts as a typical strain of the flu (a different disease entirely).”
Unfortunately, waiting for the data also means waiting too long, if it turns out that the virus turns out to be more serious. This is like waiting to hit the tree before accepting that the available data indeed supports wearing a seatbelt. Moreover, in the pandemic example, this “lack of evidence” argument ignores other evidence from before the virus entered the United States. China had locked down a city of 10 million; Italy had locked down its entire northern region, with the entire country soon to follow. There was worldwide consensus that the virus was novel, the virus was spreading fast and medical communities had no idea how to treat it. That’s data, and plenty of information to act on.
Crane goes on to consider a 3rdaxiom of naïve probabilism, which aims to turn ignorance into a strength. Overall, he argues, these axioms, despite being widely used by many prominent authorities and academic experts, actually capture a set of dangerous fallacies for action in the real world.
In reality, complex problems call for simple, actionable solutions; the past doesn’t repeat indefinitely (i.e., COVID-19 was never the flu); and ignorance is not a form of wisdom. The Naïve Probabilist’s primary objective is to be accurate with high probability rather than to protect against high-consequence, low-probability outcomes. This goes against common sense principles of decision making in uncertain environments with potentially very severe consequences.
Importantly, Crane emphasizes, the hallmark of Naïve Probabilism is naïveté, not ignorance, stupidity, crudeness or other such base qualities. The typical Naïve Probabilist lacks not knowledge or refinement, but the experience and good judgment that comes from making real decisions with real consequences in the real world. The most prominent naïve probabilists are recognized (academic) experts in mathematical probability, or relatedly statistics, physics, psychology, economics, epistemology, medicine or so-called decision sciences. Moreover, and worryingly, the best known naïve probabilists are quite sophisticated, skilled in the art of influencing public policy decisions without suffering from the risks those policies impose on the rest of society.
The Brain Bank has released findings from its first three years of operation, analyzing the brains of professional and non-professional athletes who donate them after death.
The researchers say 12 of the athletes’ brains showed signs of chronic traumatic encephalopathy (CTE), a condition associated with a range of psychiatric problems, ranging from mood and behavior disorders to cognitive impairment and dementia.
“CTE was identified in the brains of older former professionals with long playing careers, but also in younger, non-professional sportsmen and in recent professionals who had played under modern concussion guidelines,” the authors found.
“Screening for CTE in all deaths by suicide is probably impractical, but our finding suggests it should be undertaken if a history of repetitive head injury is known or suspected,” the authors say.
The authors note that brains donated to the bank are more likely to show signs of trauma because donation is often done when an athlete’s family have concerns about the role head trauma may have played in a person’s death or condition.
Nonetheless, they say: “Our findings should encourage clinicians and policymakers to develop measures that further mitigate the risk of sport-related repetitive head injury.”
One Step Closer to Hydrogen-Fueled Planes
Airbus to Test Zero-Emissions Aircraft, but How Does It Work?
Hydrogen fuel, touted by some as the fuel of the future, is seen as a potential solution for the deeply polluting aviation and shipping industries in a net-zero world: hydrogen burns cleanly, producing just energy and water vapor.
But while engineers have promoted hydrogen as a possible transport fuel since at least the 1920s, real-world technologies are still in their infancy, thanks to the destructive dominance of fossil fuels over the last century.
Airbus’ announcement, then, marks an important early step in a move towards making the sector compatible with net-zero.
“This is the most significant step undertaken at Airbus to usher in a new era of hydrogen-powered flight since the unveiling of our ZEROe concepts back in September 2020,” said Sabine Klauke, Airbus Chief Technical Officer, in a statement.
“By leveraging the expertise of American and Europeanengine manufacturers to make progress on hydrogen combustion technology, this international partnership sends a clear message that our industry is committed to making zero-emission flight a reality.”
“Our ambition is to take this aircraft and add a stub in between the two rear doors at the upper level,” said Glenn Llewellyn, Airbus’ Vice President of Zero Emissions Aircraft, in a promotional video on YouTube. “That stub will have on the end of it a hydrogen powered gas turbine.”
There will be instruments and sensors around the hydrogen storage unit and engine, to monitor how the system functions both in ground tests and in-flight. Up in the cockpit, instruments will need to be modified with a new throttle to change the amount of power the engine operates at, and a display for pilots to monitor the system.
Why Hydrogen Fuel?
Hydrogen, the most abundant element in the Universe, burns cleanly, and can be produced using renewable energy through the electrolysis of water (though it can be produced using fossil fuels, too).
Given that it’s so abundant, can be made from water, and combusts to produce water vapor, it can be a closed-loop energy system; the definition of renewable.
It’s also highly reactive: hydrogen gas, made up of two hydrogen atoms, can combust at extremely low concentrations. It can combust in response to a simple spark, and it’s even been known to combust when exposed to sunlight or minor increases in temperature. That’s why it’s a suitable replacement fuel for kerosene, but it’s also why the system needs to be tested for safety.
“Aviation is one of these things that everyone agrees needs hydrogen for decarbonization, because it’s not going to be possible to electrify long distance air travel in the next few decades,” explains Fiona Beck, a senior lecturer at ANU and convener of the Hydrogen Fuels Project in the University’s Zero-carbon energy for the Asia Pacific grand challenge. “We just don’t have the battery technologies.
“One kilogram of hydrogen has 130 times the energy of one kilogram of batteries, so in something like air travel, where weight is really important, there’s just no way you’re going to get batteries light enough to directly electrify air travel.”
That’s a very high-profile incident in which hydrogen proved deadly, but a proverbial boatload of hydrogen gas encased within a fabric covering is nothing like the fuel cells proponents of hydrogen fuel are creating in the modern era.
Nonetheless, the incident demonstrates why it’s important to ensure the safety and impregnability of fuel storage; a single spark can prove fatal (though that’s the case with existing fuels, too).
“The key will be to have really good storage containers for the hydrogen, and you’re going to have to re-engineer all the fuel delivery lines,” says Beck, “because you can’t assume that the systems that deliver kerosene safely to an engine are going to be suitable for delivering hydrogen.”
Ultimately, Beck says pre-existing, sophisticated hydrogen technologies, even if they aren’t derived from aviation, mean engineers aren’t going into this blind.
“We already use quite a lot of hydrogen in industry, which is very different than flying a plane full of hydrogen, but still, we know how to handle it relatively safely.
“So, it’s just about designers and engineers making sure that they consider all the safety aspects of it. It’s different, but not necessarily more challenging.”
Two Paths to a Hydrogen Fueled Future of Flight?
Beck notes that Airbus aren’t the only commercial entity exploring hydrogen as a fuel type. In fact, Boeing are incorporating hydrogen into their vision of a cleaner future, but in a different way.
“There’s a difference between just getting hydrogen and burning it in a modified jet engine and what Boeing are doing, which is using sustainable air fuels,” she says.
But what are sustainable air fuels (SAFs)? Beck says they’re made by combining hydrogen with carbon dioxide to make a sustainably-produced kerosene.
“The difference is that instead of getting fossil fuels and refining them, you start with hydrogen, which you would hope comes from green sources, and then you take some carbon dioxide captured from another industrial process, and you’re cycling the carbon dioxide one more time before it gets released.”
So, CO2 is still released into the atmosphere, but the individual flight is not adding its own new load of greenhouse gases to the amount. Instead, it essentially piggy-backs off a pre-existing quantity of emissions that were already produced somewhere else.
The type of fuel that wins out remains to be seen.
“It’ll be really interesting to see which approach we go for in the longer term,” Beck muses. “With synthetic air fuels, your plane engine doesn’t need to change at all, nothing about the demand side needs to change–it’s just kerosene.
“But then there’s issues, because you’re still using carbon dioxide.”
Some commentators see Boeing’s bet on SAFs as a more pragmatic approach that may help us usher in a less polluting age, quicker. On the other hand, if successful, the Airbus system can be fully carbon-neutral from fuel production through to combustion.
“Climate Adaptation by Itself Is Not Enough”: The Latest IPCC Report Installment
The Second of Three Reports Shows Our Vulnerabilities and How We Can Protect Them.
In the next part of its Sixth Assessment Report, released today, the IPCC has examined the world population’s vulnerability to climate change, and what must be done to adapt to current and future changes.
It’s the second of three sections of this report (Working group II)–Working Group I’s section, released last August, demonstrates that anthropogenic climate change is continuing, while Working Group III’s component, on mitigation, will be released in April. An overall report is coming in September.
The IPCC reports represent a phenomenal amount of work from hundreds of researchers and government officials. It synthesizes information from over 10,000 studies, with over 62,000 comments from expert peer reviewers.
Literally every sentence of the summary for policymakers has been agreed upon by consensus from a group of experts and government delegations–the line-by-line approval process alone takes a fortnight. The report in its entirety is a product of several years.
Given the time and expertise involved in making the report, its conclusions aren’t revelatory: the world is becoming increasingly vulnerable to the effects of climate change, poorest people are often the most at risk, and adaptation to these effects will force changes in our lifestyle, infrastructure, economy and agriculture.
While adaptation is necessary, it’s also insufficient. “It’s increasingly clear that the pace of adaptation across the globe is not enough to keep up with climate change,” says Professor Mark Howden, Working Group II’s vice-chair and director of the Institute for Climate, Energy & Disaster Solutions at the Australian National University.
Under the IPCC’s projected emissions scenarios, the climate could warm much more or slightly more, based on the volume of greenhouse gas released into the atmosphere.
“Depending on which of those trajectories we go on, our adaptation options differ,” says Howden.
On our current, business-as-usual trajectory, we can’t avoid the crisis, no matter how much we change our human systems to prepare for or recover from the ravages of climate change.
“Climate adaptation, risk management, by itself is not enough,” says Howden.
The report comes at a pertinent time for Australia, as southern Queensland and northern New South Wales experience dramatic flooding from high, La Niña-related rainfall.
“One of the clear projections is an increase in the intensity of heavy rainfall events,” says Professor Brendan Mackey, director of National Climate Change Adaptation Research Facility at Griffith University, and a lead author on the Australasian chapter of the report.
Mackey also notes that he has extended family members in Lismore, NSW, who today needed to be rescued from their rooftops as the town floods.
Howden says that while it’s hard to link individual disasters to climate change as they occur, he agrees that there are more floods projected for northern Australia.
“I think we can say that climate change is already embedded in this event,” adds Howden.
“These events are driven by, particularly, ocean temperatures, and we know very well that those have gone up due to climate change due to human influence.”
He points out that flooding is a common side effect of a La Niña event, of which more are expected as the climate warms.
Flooding is not the only extreme weather event that can be linked to climate change.
“We’ve observed further warming and sea level rise, we’ve observed more flood days and heat waves, we’ve observed less snow,” says Mackey.
“Interestingly, [we’ve observed] more rainfall in the north, less winter rainfall in the southwest and southeast, and more extreme fire weather days in the south and east.”
All of these trends are expected to continue, especially under high-emissions scenarios.
For Australians, the predictions the IPCC has made with very high or high confidence include: both a decline in agricultural production and increase in extreme fire weather across the south of the continent; a nation-wide increase in heat-related mortality; increased stress on cities, infrastructure and supply chains from natural disasters; and inundation of low-lying coastal communities from sea level rise.
The final high-confidence prediction is that Australian institutions and governments aren’t currently able to manage these risks.
“Climate change impacts are becoming more complex and difficult to manage,” says Professor Lauren Rickards, director of the Urban Futures Enabling Capability Platform at RMIT, also a lead author on the Australasian chapter.
“Not only are climatic hazards becoming more severe–including, sometimes, nonlinear effects such as, for example, tipping over flood levees that have historically been sufficient–but also those climatic hazards are intersecting in very, very complex ways. And in turn, the flow-on effects on the ground are interacting, causing what’s called cascading and compounding impacts.”
She adds that many local and state governments and the private sector have both recognized the importance of changing their practices to prepare for or react to climate extremes.
“We have these systems, these infrastructural systems–energy, transport, water, communications, for example–and it’s the need to adapt those at the base of a lot of the adaptation that’s needed,” says Rickards.
Australia is missing a large investment in research on how different places and systems can adapt to the changing climate.
“We’ve seen a really significant reduction in the research into what actions different individuals, communities, sectors, can take,” says Howden.
“And what that means is we don’t have the portfolio of options available for people in a way that is easily communicable, and easily understood, and easily adopted.”
Without this research, as well as work from local and Indigenous experts, some adaptations can even risk worsening the impacts of climate change.
“The evidence that we’ve looked at shows really clearly that adaptation strategies, when they build on Indigenous and local knowledge and integrate science, that’s when they are most successful,” says Dr. Johanna Nalau, leader of the Adaptation Science Research Theme at Cities Research Institute, Griffith University.
While the risks Australia faces are dramatic, things are much worse for other parts of the world. Nalau, who was a lead author on the report’s chapter on small islands, says that “most of the communities and countries are constrained in what they can do in terms of adaptation”.
In April, we will have access to the IPCC’s dossier on mitigating climate change and emissions reduction. But in the meantime, Working Group II’s battalion of researchers advocate for better planning for climate disaster, more research into ways human systems can adapt, sustainable and just development worldwide, and rapid emissions reduction.
“Adaptation can’t be divorced from mitigation, conceptually or in practice,” says Rickards.
“We need adaptation to enable effective mitigation. We need effective mitigation to enable adaptation to give it a chance of succeeding. At present, we’re not on track and we need to pivot quickly.”
Piecing Together Pandemic Origins
New Research Asserts Market, Not Laboratory, Is the “Unambiguous” Birthplace of SARS-CoV-2
by Jamie Priest
Now in our third year of woe, most of us are naturally focused on the end of the pandemic. The global death toll is approaching 6 million, and the world is desperately searching for signs the ordeal’s over.
But amid the future watching, a team of researchers have turned their attention back to the beginning, tackling the question that was once on everyone’s lips: where did SARS-CoV-2 originate?
Outlining their evidence in two preprints, researchers assert an “unambiguous” origin in the Huanan market in Wuhan, spilling over not once, but twice into the human population and kicking off a global health crisis.
The paired papers, which have yet to undergo peer review and publication in a scientific journal, critically undermine the competing, and controversial, alternative origin story that involves a leak–intentional or otherwise–from a nearby Wuhan virology lab where scientists study coronaviruses.
The Huanan market was an immediate suspect when COVID first emerged in late 2019. Workers at the market were amongst the first individuals to present with the pneumonia that was quickly linked to a novel coronavirus, and Chinese officials, fearing a repeat of the 2002 SARS epidemic that killed 774 people, were quick to close the market down.
But by the time Chinese researchers descended on the Huanan market in 2020 to collect genetic samples, they found no wildlife present at all. Although they were able to detect traces of the virus in samples taken from surfaces and sewers in the market, the lack of direct evidence of infection in market animals sparked a debate over whether this truly was the epicenter of the outbreak. Alternative theories centered around the Wuhan Institute of Virology.
In the face of this absence of evidence, researchers working on the new reports turned to alternative information sources.
Using data pulled from the Chinesesocial media app Weibo, they were able to map the location of 737 COVID-positive Wuhan residents who turned to the app to seek health advice during the first three months of the outbreak.
Plotting the geographic concentrations of cases through time, the researchers clearly identified the market as the centre of origin, with the virus spreading radially through surrounding suburbs and across the city as time progressed. Through statistical analysis, the researchers demonstrated that the chances of such a pattern arising through mere chance was exceedingly unlikely.
However, the pattern alone was open to interpretation, with questions remaining about pathways of introduction to the market–was the virus carried in inside a caged animal, on the coat of an unwitting scientist, or via some as-yet unidentified vector?
To dig further into the mystery, the researchers looked at the genetic samples obtained from market surfaces in January 2020 by Chinese scientists, tracing the locations of individual positive samples to their exact location within the market complex.
This second map revealed a strong concentration of positive samples in one corner of the market, a sector that had been previously documented to house a range of wild mammals that are considered potential coronavirus hosts.
Finally, the researchers created an evolutionary family tree of the earliest coronavirus lineages that emerged in the first few panicked weeks of the pandemic.
Even in its very earliest stages SARS-CoV-2 was a variable beast, with evidence of two distinct lineages, dubbed A and B. Looking closely at the mutations that separate the two, the researchers found something surprising–rather than one descending from the other, it appears that they had separate origins and entries into the human population, with lineage B making the leap in late November and lineage A following suit shortly afterwards.
Initial studies of the Huanan market genetic samples found only lineage B, but this latest investigation detected the presence of lineage A in people who lived in close proximity to the market–a finding corroborated by a recent Chinese study that identified lineage A on a single glove collected from the market during the initial shutdown.
Questions remain about the identity of the intermediary animal host species. But by narrowing research focus to the most likely centre of origin, this research will significantly aid efforts to understand the process that saw COVID-19 enter the world, and hopefully help avert future pandemics.
Fake Viral Footage Is Spreading alongside the Real Horror in Ukraine—Here Are 5 Ways to Spot It
Manipulated or Falsified Videos and Images Can Spread Quickly—but There Are Strategies You Can Take to Evaluate Them.
By TJ Thompson, Daniel Angus and Paul Dootson
Amid the alarming images of Russia’s invasion of Ukraine over the past few days, millions of people have also seen misleading, manipulated or false information about the conflict on social media platforms such as Facebook, Twitter, TikTok and Telegram.
One example is this video of military jets posted to TikTok, which is historical footage but captioned as live video of the situation in Ukraine.
Visuals, because of their persuasive potential and attention-grabbing nature, are an especially potent choice for those seeking to mislead. Where creating, editing or sharing inauthentic visual content isn’t satire or art, it is usually politically or economically motivated.
Disinformation campaigns aim to distract, confuse, manipulate and sow division, discord, and uncertainty in the community. This is a common strategy for highly polarized nations where socioeconomic inequalities, disenfranchisement and propaganda are prevalent.
How is this fake content created and spread, what’s being done to debunk it, and how can you ensure you don’t fall for it yourself?
What Are the Most Common Fakery Techniques?
Using an existing photo or video and claiming it came from a different time or place is one of the most common forms of misinformation in this context. This requires no special software or technical skills—just a willingness to upload an old video of a missile attack or other arresting image, and describe it as new footage.
Another low-tech option is to stage or pose actions or events and present them as reality. This was the case with destroyed vehicles that Russia claimed were bombed by Ukraine.
Using a particular lens or vantage point can also change how the scene looks and can be used to deceive. A tight shot of people, for example, can make it hard to gauge how many were in a crowd, compared with an aerial shot.
Taking things further still, Photoshop or equivalent software can be used to add or remove people or objects from a scene, or to crop elements out from a photograph. An example of object addition is the below photograph, which purports to show construction machinery outside a kindergarten in eastern Ukraine. The satirical text accompanying the image jokes about the “calibre of the construction machinery”—the author suggesting that reports of damage to buildings from military ordinance are exaggerated or untrue.
Close inspection reveals this image was digitally altered to include the machinery. This tweet could be seen as an attempt to downplay the extent of damage resulting from a Russian-backed missile attack, and in a wider context to create confusion and doubt as to veracity of other images emerging from the conflict zone.
Journalists and fact-checkers are also working to verify content and raise awareness of known fakes. Large, well-resourced news outlets such as the BBC are also calling out misinformation.
Social media platforms have added new labels to identify state-run media organisations or provide more background information about sources or people in your networks who have also shared a particular story.
They have also tweaked their algorithms to change what content is amplified and have hired staff to spot and flag misleading content. Platforms are also doing some work behind the scenes to detect and publicly share information on state-linked information operations.
What Can I Do about It?
You can attempt to fact-check images for yourself rather than taking them at face value. An article we wrote late last year for the Australian Associated Press explains the fact-checking process at each stage: image creation, editing and distribution.
Here are five simple steps you can take:
Examine the metadata
This Telegram post claims Polish-speaking saboteurs attacked a sewage facility in an attempt to place a tank of chlorine for a “false flag” attack.
But the video’s metadata—the details about how and when the video was created—show it was filmed days before the alleged date of the incident.
To check metadata for yourself, you can download the file and use software such as Adobe Photoshop or Bridge to examine it. Online metadata viewers also exist that allow you to check by using the image’s web link.
One hurdle to this approach is that social media platforms such as Facebook and Twitter often strip the metadata from photos and videos when they are uploaded to their sites. In these cases, you can try requesting the original file or consulting fact-checking websites to see whether they have already verified or debunked the footage in question.
If old content has been recycled and repurposed, you may be able to find the same footage used elsewhere. You can use Google Images or TinEye to “reverse image search” a picture and see where else it appears online.
But be aware that simple edits such as reversing the left-right orientation of an image can fool search engines and make them think the flipped image is new.
Look for inconsistencies
Does the purported time of day match the direction of light you would expect at that time, for example? Do watches or clocks visible in the image correspond to the alleged timeline claimed?
You can also compare other data points, such as politicians’ schedules or verified sightings, Google Earth vision or Google Maps imagery, to try and triangulate claims and see whether the details are consistent.
Ask yourself some simple questions
Do you know where, when and why the photo or video was made? Do you know who made it, and whether what you’re looking at is the original version?
Using online tools such as InVID or Forensically can potentially help answer some of these questions. Or you might like to refer to this list of 20 questions you can use to “interrogate” social media footage with the right level of healthy skepticism.
Ultimately, if you’re in doubt, don’t share or repeat claims that haven’t been published by a reputable source such as an international news organization. And consider using some of these principles when deciding which sources to trust.
By doing this, you can help limit the influence of misinformation, and help clarify the true situation in Ukraine.
by Avid Mohammadi, Sareh Bagherichimeh, Yoojin Choi, Azadeh Fazel, Elizabeth Tevlin, Sanja Huibner, Zhongtian Shao, David Zuanazzi, Jessica L. Prodger, Sara V. Good, Wangari Tharao & Rupert Kaul
Summary: In heterosexual men, the penis is the primary site of Human Immunodeficiency Virus (HIV) acquisition. Levels of inflammatory cytokines in the coronal sulcus are associated with an increased HIV risk, and we hypothesized that these may be altered after insertive penile sex. Therefore, we designed the Sex, Couples and Science Study (SECS study) to define the impact of penile–vaginal sex on the penile immune correlates of HIV susceptibility. We found that multiple coronal sulcuscytokines increased dramatically and rapidly after sex, regardless of condom use, with a return to baseline levels by 72 hours. The changes observed after condomless sex were strongly predicted by cytokine concentrations in the vaginal secretions of the female partner, and were similar in circumcised and uncircumcised men. We believe that these findings have important implications for understanding the immunopathogenesis of penile HIV acquisition; in addition, they have important implications for the design of clinical studies of penileHIV acquisition and prevention.
by Quang Vinh Phan, Boris Bogdanow, Emanuel Wyler, Markus Landthaler, Fan Liu, Christian Hagemeier & Lüder Wiebusch
Summary: Human cytomegalovirus (HCMV) infection is associated with systemic disease in immunocompromised individuals and congenitally infectedneonates. Animal CMVs and their bacterial artificial chromosome (BAC) clones have been utilized as models for CMV infection and thereby contributed immensely to the understanding of pathogenesis, host immune response and underlying molecular mechanism of CMVinfections. As the closest relative to HCMV, the chimpanzeeCMV (CCMV) holds a great potential as a model system for HCMV infection but its application was limited due to the lack of tools and data for functional genomic analyses. Here, the cloning of the CCMV as a BACvector made its viralgenome available to gene targeting techniques that allow the efficient application of reverse genetic strategies. Furthermore, the multi-omic datasets created in this study provide an in-depth view of the viralgene repertoire and the host cell responses to infection, confirming the close phylogenetic relationship between HCMV and CCMV on a system level. Taken together, the newly established CCMV–BAC system presents a framework for HCMV modeling and comparative studies to address key questions in evolutionary processes and infection mechanisms.
by Dan Wang, Xinxin Zhang, Liwen Yin, Qi Liu, Zhaoli Yu, Congjuan Xu, Zhenzhen Ma, Yushan Xia, Jing Shi, Yuehua Gong, Fang Bai, Zhihui Cheng, Weihui Wu, Jinzhong Lin & Yongxin Jin
Summary:Ribosomes provide all living organisms the capacity to synthesize proteins. The production of many ribosomal proteins is often controlled by an autoregulatory feedback mechanism. P. aeruginosa is an opportunistic human pathogen and its type III secretion system (T3SS) is a critical virulence determinant in host infections. In this study, by screening a Tn5 mutant library, we identified rplI, encoding ribosomal large subunit protein L9, as a novel repressor for the T3SS. Further exploring the regulatory mechanism, we found that the RplI protein interacts with the 5’ UTR (5’ untranslated region) of exsA, a gene coding for transcriptional activator of the T3SS. Such an interaction likely blocks ribosome loading on the exsA 5’ UTR, inhibiting the initiation of exsA translation. The significance of this work is in the identification of a novel repressor for the T3SS and elucidation of its molecular mechanism. Furthermore, this work provides evidence for individual ribosomal protein regulating mRNA translation beyond its autogenous feedback control.
by Patrick Günther, Dennis Quentin, Shehryar Ahmad, Kartik Sachar, Christos Gatsogiannis, John C. Whitney & Stefan Raunser
Summary:Bacteria have developed a variety of strategies to compete for nutrients and limited resources. One system widely used by Gram-negative bacteria is the T6 secretion system which delivers a plethora of effectors into competing bacterial cells. Known functions of effectors are degradation of the cell wall, the depletion of essential metabolites such as NAD+ or the cleavage of DNA. RhsA is an effector from the widespread plant-protecting bacteriaPseudomonas protegens. We found that RhsA forms a closed cocoon similar to that found in bacterial Tc toxins and metazoanteneurin proteins. The effector cleaves its polypeptide chain by itself in three pieces, namely the N-terminal domain including a seal, the cocoon and the actual toxic component which potentially cleaves DNA. The toxic component is encapsulated in the large cocoon, so that the effector producing bacterium is protected from the toxin. In order for the toxin to exit the cocoon, we propose that the seal, which closes the cocoon at one end, is removed by mechanical forces during injection of the effector by the T6 secretion system. We further hypothesize about different scenarios for the delivery of the toxin into the cytoplasm of the host cell. Together, our findings expand the knowledge of the mechanism of action of the T6 secretion system and its essential role in interbacterial competition.
by Catarina E. Hioe, Guangming Li, Xiaomei Liu, Ourania Tsahouridis, Xiuting He, Masaya Funaki, Jéromine Klingler, Alex F. Tang, Roya Feyznezhad, Daniel W. Heindel, Xiao-Hong Wang, David A. Spencer, Guangnan Hu, Namita Satija, Jérémie Prévost, Andrés Finzi, Ann J. Hessell, Shixia Wang, Shan Lu, Benjamin K. Chen, Susan Zolla-Pazner, Chitra Upadhyay, Raymond Alvarez & Lishan Su
Summary: In the past decade, HIV-1 has infected an estimated 1.5 to 2 million people every year, but vaccines needed to control this pandemic are unavailable. Among vaccines tested in the human efficacy trials, the RV144 vaccine regimen showed a modest efficacy and revealed non-neutralizing antibodies against the virus envelopeglycoproteins as a correlate of reduced virus acquisition. To design more efficacious HIV-1vaccines, a better understanding about antiviral mechanisms of these antibodies is needed. Here non-neutralizing monoclonal antibodies against two immunogenic sites on the virus envelope were evaluated for passive administration to humanized mice that were subsequently challenged with HIV-1. The antibodies did not block mucosal HIV-1 infection but reduced virus burden. The level of virus reduction correlated with the antibody binding potency and the effector functions mediated through their Fc fragments, which included antibody-dependent phagocytosis and complement activation, but not the commonly studied antibody-dependent cellular cytotoxicity. The importance of the Fc functions was further demonstrated by reduced virus control when mutations were introduced to decrease Fc activities. This study provides new evidence for the important contribution of multiple Fc-dependent antibody functions in immune control against HIV-1.
by Evan John, Silke Jacques, Huyen T. T. Phan, Lifang Liu, Danilo Pereira, Daniel Croll, Karam B. Singh, Richard P. Oliver & Kar-Chun Tan
Summary:Breeding for durable resistance to fungal diseases in crops is a continual challenge for crop breeders. Fungal pathogens evolve ways to overcome host resistance by masking themselves through effector evolution and evasion of broad-spectrum defense responses. Association studies on mapping populations infected by isolate mixtures are often used by researchers to seek out novel sources of genetic resistance. Disease resistancequantitative trait loci (QTL) are often minor or inconsistent across environments. This is a particular problem with septoria diseases of cereals such as septoria nodorum blotch (SNB) of wheat caused by Parastagonospora nodorum. The fungus uses a suite of necrotrophic effectors (NEs) to cause SNB. We characterized a genetic element, called PE401, in the promoter of the major NE gene Tox1, which is present in some P. nodorum isolates. PE401 functions as a transcriptional repressor of Tox1 and exerts epistatic control on another major SNB resistance QTL in the host. In the context of crop protection, constant surveillance of the pathogen population for the frequency of PE401 in conjunction with NE diversity will enable agronomists to provide the best advice to growers on which wheat varieties can be tailored to provide optimal SNB resistance to regional pathogen population genotypes.
by Rommel J. Gestuveo, Rhys Parry, Laura B. Dickson, Sebastian Lequime, Vattipally B. Sreenu, Matthew J. Arnold, Alexander A. Khromykh, Esther Schnettler, Louis Lambrechts, Margus Varjak & Alain Kohl
Summary:Aedes aegyptimosquitoes that transmit human-pathogenicviruses rely on the exogenoussmall interfering RNA (exo-siRNA) pathway as part of antiviral responses. This pathway is triggered by virus-derived double-stranded RNA (dsRNA) produced during viral replication that is then cleaved by Dicer 2 (Dcr2) into virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs target viral RNA, leading to suppression of viral replication. The importance of Dcr2 in this pathway has been intensely studied in the Drosophila melanogaster model but is largely lacking in mosquitoes. Here, we have identified conserved and functionally relevant amino acids in the helicase and RNase III domains of Ae. aegyptiDcr2 that are important in its silencing activity and antiviral responses against Semliki Forest virus (SFV). Small RNA sequencing of SFV-infected mosquito cells with functional or mutated Dcr2 gave new insights into the nature and origin of vsiRNAs. The findings of this study, together with the different molecular tools we have previously developed to investigate the exo-siRNA pathway of mosquito cells, have started to uncover important properties of Dcr2 that could be valuable in understanding mosquito-arbovirus interactions and potentially in developing or assisting vector control strategies.
by Kwok-ho Lam, Jacqueline M. Tremblay, Kay Perry, Konstantin Ichtchenko, Charles B. Shoemaker & Rongsheng Jin
Summary:Botulinum neurotoxins (BoNTs) are extremely toxic to humans by causing flaccid paralysis of botulism. The catalytic light chain (LC) of BoNTs is the warhead of the toxin, which is mainly responsible for BoNT’s neurotoxic effects. As an endopeptidase, LC is delivered by the toxin to inside neurons where it specifically cleaves neuronal SNARE proteins and causes muscle paralysis. While the currently available equine and human antitoxin sera can prevent further intoxication, they do not promote recovery from paralysis that has already occurred. We strike to develop single-domain variable heavy-chain (VHH) antibodies targeting the LC of BoNT/A (LC/A) and BoNT/B (LC/B) as antidotes to inhibit or eliminate the intraneuronal LC protease. Here, we report the identification and characterization of large panels of new and unique VHHs that bind to LC/A or LC/B. Using a combination of X-ray crystallography and biochemical assays, we reveal that VHHs exploit diverse mechanisms to interact with LC/A and LC/B and inhibit their protease activity, and such knowledge can be harnessed to predict their specificity towards different toxin subtypes within each serotype. We anticipate that the new VHHs and their characterization reported here will contribute to the development of improved botulism therapeutics having high potencies and broad specificities.
by Clinton O. Ogega, Nicole E. Skinner, Andrew I. Flyak, Kaitlyn E. Clark, Nathan L. Board, Pamela J. Bjorkman, James E. Crowe Jr., Andrea L. Cox, Stuart C. Ray & Justin R. Bailey
Summary: Antiviral immunity relies on production of protective immunoglobulin G (IgG) by B cells, but many hepatitis C virus (HCV)-infected individuals have very low levels of HCV-specific IgG in their serum. Elucidating mechanisms underlying this suboptimal IgG expression remains paramount in guiding therapeutic and vaccine strategies. In this study, we developed a highly specific method to capture HCV-specific B cells and characterized their surface protein expression. Two proteins analyzed were Fc receptor-like protein 5 (FCRL5), a cell surface receptor for IgG, and programmed cell death protein-1 (PD-1), a marker of lymphocyte activation and exhaustion. We measured serum levels of anti-HCVIgG in these subjects and demonstrated that overexpression of FCRL5 and PD-1 on memory B cells was associated with reduced anti-E2 IgG levels. This study uses HCV as a viral model, but the findings may be applicable to many viral infections, and they offer new potential targets to enhance antiviral IgG production.
