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Zika and Dengue Neutralizing Human Antibody Distorts Dengue but Not Zika

A study led by scientists at Penn State University reveals a new strategy that antibodies use to disable viruses. The researchers investigate the interactions between a human monoclonal antibody (HMAb C10) and the zika and dengue viruses. The study that..

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Scientists have identified a new way in which antibodies disable viruses. In addition to latching on to antigenic proteins on the surface of a virus and blocking the virus from infecting host cells, a new study shows antibodies can also burrow in and distort the viral surface, effectively preventing the virus from docking on and entering host cells.

An international team of researchers led by scientists at Penn State report this new finding in an article in the journal Cell, titled “Human antibody C10 neutralizes by diminishing zika 2 but enhancing dengue dynamics.” The authors show the same antibody can neutralize zika and dengue in two different ways.

The same antibody can neutralize zika and dengue viruses in two different ways — one where it binds to the virus and deactivates it (left), which is the traditional way we think about antibody activity, and the other where it burrows in and distorts the virus (right). [Source: Ganesh Anand, Penn State]
“This study reveals a new mode of virus neutralization by antibodies. Antibodies have been traditionally assumed to neutralize their targets by a sole mechanism of blocking the surface, so that the virus cannot access its target receptor site. We have demonstrated that antibodies show additional mechanisms of virus neutralization. They distort their virus targets by burrowing into the target surface,” says Ganesh Anand, PhD, associate professor of chemistry at Penn State and co-corresponding author of the paper.

“Furthermore,” says Anand, “different concentrations of antibodies elicit different conformational changes in the entire virus particle. This study emphasizes how a virus represents a moving target for antibodies, which in turn alters the modes of antibody engagement. This also reveals that viruses offer a nonuniform epitope landscape for antibodies to bind and neutralize.”

Anand and his colleagues investigate the interactions between human monoclonal antibody (HMAb) C10 and the two disease-causing viruses that the antibody strongly neutralizes.

Combining cryogenic electron microscopy (cryo-EM) and hydrogen/deuterium exchange mass spectrometry (HDXMS), the researchers visualize the two viruses and explore their movement in presence of the antibody.

“Cryo-EM involves flash-freezing a solution containing molecules of interest and targeting them with electrons to generate numerous images of individual molecules in different orientations,” says Anand. “These images are then integrated into one snapshot of what the molecule looks like. The technique provides more accurate pictures of molecules than other forms of microscopy.” The team collected high resolution, static cryo-EM snapshots of the viruses in increasing concentrations of the HMAb C10 antibody.

“The notion that viruses are highly mobile targets, that certain antibodies enhance the virus’ mobility and achieve neutralization through distortion came from amide HDXMS. HDXMS is a method that can be leveraged to measure the movements of virus surface proteins,” says Anand. HDXMS involves submerging molecules of interest — in this case zika and dengue virus with HMAb C10 antibodies—in “heavy water” that has had its hydrogen atoms replaced with deuterium, hydrogen’s heavier isotope.

“When you submerge a virus in heavy water, the hydrogen atoms on the surface of the virus exchange with deuterium,” says Anand. “You can then use mass spectrometry to measure the heaviness of the virus as a function of this deuterium exchange. By doing this, we observed that dengue virus, but not zika virus, became heavier with deuterium as more antibodies were added to the solution. This suggests that for dengue virus, the antibodies are distorting the virus and allowing more deuterium to get in. It’s as if the virus is getting squished and more surface area becomes exposed where hydrogen can be exchanged for deuterium.”

Although HMAb C10 effectively neutralizes both zika and dengue viruses, this HDXMS data shows while the antibody squishes the dengue virus, it does not result in increased incorporation of heavy water in the zika virus, indicating the antibody does not squish the zika surface.

“The combination of static imaging with dynamic visualization by mass spectrometry is novel and provided orthogonal complementary insights into virus behavior in solution,” says Anand. “It’s like those cartoon flipbooks, where each page has a slightly different image, and when you flip through the book, you see a short movie. Imagine a flipbook with drawings of a racehorse. Cryo-EM shows you what the racehorse looks like and HDXMS shows you how fast the racehorse is moving. You need both techniques to be able to describe a racehorse in motion. This complementary set of tools enabled us to understand how one type of antibody differentially affects two types of viruses.”

The researchers note, the more antibodies they add, the more distorted the dengue virus particles become, suggesting that the relationship between the quantities of interacting molecules determines the extent of neutralization. At saturating conditions, in which antibodies are added at high enough concentrations to fill all available binding locations on the dengue viruses, the researchers show, 60% of the virus’ surface is distorted. This distortion is enough to protect host cells from infection.

“If you have enough antibodies, they will distort the virus particle enough so that it’s preemptively destabilized before it even reaches its target cells,” Anand says.

When the scientists expose BHK-21 cells—a cell line derived from the kidneys of baby hamsters–to antibody-bound dengue viruses, they see 50–70% fewer cells are infected.

Anand explains, while “antibodies can work by jamming the exits so the passenger cannot get out of the car, we have found a new mechanism in dengue virus where antibodies basically total the car so it cannot even travel to a cell.”

Unlike SARS-CoV-2, which has spike proteins protruding in all directions, Anand explains, the surfaces of both zika and dengue are smoother with easily accessible “peaks” known as five-fold vertices and progressively inaccessible “valleys” known three-fold and two-fold vertices.

“Antibodies do not like two-fold vertices because they are very mobile and difficult to bind to,” says Anand. “We found that once the five- and three-fold vertices have been fully bound with antibodies, if we add more antibodies to the solution, the virus starts to shudder. There’s this competition taking place between antibodies trying to get in and the virus trying to shake them off. As a result, these antibodies end up burrowing into the virus rather than binding onto the 2-fold vertices, and we think it’s this digging into the virus particle that causes the virus to shake and distort and ultimately become non-functional.”

Zika is a more stable and less dynamic virus than dengue, which has a lot of moving parts, explains Anand. “Dengue and Zika look similar but each one has a different give. Dengue may have evolved as a more mobile virus as a way of avoiding being caught by antibodies. Its moving parts confuse and throw off the immune system. Unfortunately for dengue, antibodies have evolved a way around this by burrowing into the virus and distorting it.”

The distortion strategy of virus neutralization is not unique to antibody engagement with dengue and zika viruses. “Dengue is just a model virus that we used in our experiments, but we think this preemptive destabilization strategy may be broadly applicable to any virus,” says Anand. “It may be that the antibodies first attempt to neutralize viruses through the barrier method and if they are unsuccessful, they resort to the distortion method.”

These new findings could be useful in designing therapeutic antibodies, Anand says. “HMAb C10 antibodies are specific to dengue and zika viruses and happen to be capable of neutralizing zika and dengue viruses in two different ways, but you could potentially design therapeutics with the same capabilities for treating other diseases, such as COVID-19. By creating a therapeutic with antibodies that can both block and distort viruses, we can possibly achieve greater neutralization.”

He adds, “You don’t want to wait for a virus to reach its target tissue, so if you can introduce such a therapeutic cocktail as a nasal spray where the virus first enters the body, you can prevent it from entering the system. By doing this, you may even be able to use less antibody since our research shows that it takes less antibody to neutralize a virus through the distortion method. You can get better bang for the buck.”

The study uncovers a new strategy that antibodies use to disable viruses. Future studies by the group will probe deeper into the terms of this novel engagement. “We are trying to define the first principles of antibody engagement on virus surfaces. We are particularly interested in identifying the rules for destabilizing or distorting antibody design. This novel mechanism would add to the antiviral arsenal. We wish to develop targeted virus-distorting antibodies. We are also interested in correlating virus mutational hotspots with mobile loci on the surface,” says Anand.

The post Zika and Dengue Neutralizing Human Antibody Distorts Dengue but Not Zika appeared first on GEN - Genetic Engineering and Biotechnology News.

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Q4 Update: Delinquencies, Foreclosures and REO

Today, in the Calculated Risk Real Estate Newsletter: Q4 Update: Delinquencies, Foreclosures and REO
A brief excerpt: I’ve argued repeatedly that we would NOT see a surge in foreclosures that would significantly impact house prices (as happened followi…

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Today, in the Calculated Risk Real Estate Newsletter: Q4 Update: Delinquencies, Foreclosures and REO

A brief excerpt:
I’ve argued repeatedly that we would NOT see a surge in foreclosures that would significantly impact house prices (as happened following the housing bubble). The two key reasons are mortgage lending has been solid, and most homeowners have substantial equity in their homes..
...
And on mortgage rates, here is some data from the FHFA’s National Mortgage Database showing the distribution of interest rates on closed-end, fixed-rate 1-4 family mortgages outstanding at the end of each quarter since Q1 2013 through Q3 2023 (Q4 2023 data will be released in a two weeks).

This shows the surge in the percent of loans under 3%, and also under 4%, starting in early 2020 as mortgage rates declined sharply during the pandemic. Currently 22.6% of loans are under 3%, 59.4% are under 4%, and 78.7% are under 5%.

With substantial equity, and low mortgage rates (mostly at a fixed rates), few homeowners will have financial difficulties.
There is much more in the article. You can subscribe at https://calculatedrisk.substack.com/

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‘Bougie Broke’ – The Financial Reality Behind The Facade

‘Bougie Broke’ – The Financial Reality Behind The Facade

Authored by Michael Lebowitz via RealInvestmentAdvice.com,

Social media users claiming…

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'Bougie Broke' - The Financial Reality Behind The Facade

Authored by Michael Lebowitz via RealInvestmentAdvice.com,

Social media users claiming to be Bougie Broke share pictures of their fancy cars, high-fashion clothing, and selfies in exotic locations and expensive restaurants. Yet they complain about living paycheck to paycheck and lacking the means to support their lifestyle.

Bougie broke is like “keeping up with the Joneses,” spending beyond one’s means to impress others.

Bougie Broke gives us a glimpse into the financial condition of a growing number of consumers. Since personal consumption represents about two-thirds of economic activity, it’s worth diving into the Bougie Broke fad to appreciate if a large subset of the population can continue to consume at current rates.

The Wealth Divide Disclaimer

Forecasting personal consumption is always tricky, but it has become even more challenging in the post-pandemic era. To appreciate why we share a joke told by Mike Green.

Bill Gates and I walk into the bar…

Bartender: “Wow… a couple of billionaires on average!”

Bill Gates, Jeff Bezos, Elon Musk, Mark Zuckerberg, and other billionaires make us all much richer, on average. Unfortunately, we can’t use the average to pay our bills.

According to Wikipedia, Bill Gates is one of 756 billionaires living in the United States. Many of these billionaires became much wealthier due to the pandemic as their investment fortunes proliferated.

To appreciate the wealth divide, consider the graph below courtesy of Statista. 1% of the U.S. population holds 30% of the wealth. The wealthiest 10% of households have two-thirds of the wealth. The bottom half of the population accounts for less than 3% of the wealth.

The uber-wealthy grossly distorts consumption and savings data. And, with the sharp increase in their wealth over the past few years, the consumption and savings data are more distorted.

Furthermore, and critical to appreciate, the spending by the wealthy doesn’t fluctuate with the economy. Therefore, the spending of the lower wealth classes drives marginal changes in consumption. As such, the condition of the not-so-wealthy is most important for forecasting changes in consumption.

Revenge Spending

Deciphering personal data has also become more difficult because our spending habits have changed due to the pandemic.

A great example is revenge spending. Per the New York Times:

Ola Majekodunmi, the founder of All Things Money, a finance site for young adults, explained revenge spending as expenditures meant to make up for “lost time” after an event like the pandemic.

So, between the growing wealth divide and irregular spending habits, let’s quantify personal savings, debt usage, and real wages to appreciate better if Bougie Broke is a mass movement or a silly meme.

The Means To Consume 

Savings, debt, and wages are the three primary sources that give consumers the ability to consume.

Savings

The graph below shows the rollercoaster on which personal savings have been since the pandemic. The savings rate is hovering at the lowest rate since those seen before the 2008 recession. The total amount of personal savings is back to 2017 levels. But, on an inflation-adjusted basis, it’s at 10-year lows. On average, most consumers are drawing down their savings or less. Given that wages are increasing and unemployment is historically low, they must be consuming more.

Now, strip out the savings of the uber-wealthy, and it’s probable that the amount of personal savings for much of the population is negligible. A survey by Payroll.org estimates that 78% of Americans live paycheck to paycheck.

More on Insufficient Savings

The Fed’s latest, albeit old, Report on the Economic Well-Being of U.S. Households from June 2023 claims that over a third of households do not have enough savings to cover an unexpected $400 expense. We venture to guess that number has grown since then. To wit, the number of households with essentially no savings rose 5% from their prior report a year earlier.  

Relatively small, unexpected expenses, such as a car repair or a modest medical bill, can be a hardship for many families. When faced with a hypothetical expense of $400, 63 percent of all adults in 2022 said they would have covered it exclusively using cash, savings, or a credit card paid off at the next statement (referred to, altogether, as “cash or its equivalent”). The remainder said they would have paid by borrowing or selling something or said they would not have been able to cover the expense.

Debt

After periods where consumers drained their existing savings and/or devoted less of their paychecks to savings, they either slowed their consumption patterns or borrowed to keep them up. Currently, it seems like many are choosing the latter option. Consumer borrowing is accelerating at a quicker pace than it was before the pandemic. 

The first graph below shows outstanding credit card debt fell during the pandemic as the economy cratered. However, after multiple stimulus checks and broad-based economic recovery, consumer confidence rose, and with it, credit card balances surged.

The current trend is steeper than the pre-pandemic trend. Some may be a catch-up, but the current rate is unsustainable. Consequently, borrowing will likely slow down to its pre-pandemic trend or even below it as consumers deal with higher credit card balances and 20+% interest rates on the debt.

The second graph shows that since 2022, credit card balances have grown faster than our incomes. Like the first graph, the credit usage versus income trend is unsustainable, especially with current interest rates.

With many consumers maxing out their credit cards, is it any wonder buy-now-pay-later loans (BNPL) are increasing rapidly?

Insider Intelligence believes that 79 million Americans, or a quarter of those over 18 years old, use BNPL. Lending Tree claims that “nearly 1 in 3 consumers (31%) say they’re at least considering using a buy now, pay later (BNPL) loan this month.”More tellingaccording to their survey, only 52% of those asked are confident they can pay off their BNPL loan without missing a payment!

Wage Growth

Wages have been growing above trend since the pandemic. Since 2022, the average annual growth in compensation has been 6.28%. Higher incomes support more consumption, but higher prices reduce the amount of goods or services one can buy. Over the same period, real compensation has grown by less than half a percent annually. The average real compensation growth was 2.30% during the three years before the pandemic.

In other words, compensation is just keeping up with inflation instead of outpacing it and providing consumers with the ability to consume, save, or pay down debt.

It’s All About Employment

The unemployment rate is 3.9%, up slightly from recent lows but still among the lowest rates in the last seventy-five years.

The uptick in credit card usage, decline in savings, and the savings rate argue that consumers are slowly running out of room to keep consuming at their current pace.

However, the most significant means by which we consume is income. If the unemployment rate stays low, consumption may moderate. But, if the recent uptick in unemployment continues, a recession is extremely likely, as we have seen every time it turned higher.

It’s not just those losing jobs that consume less. Of greater impact is a loss of confidence by those employed when they see friends or neighbors being laid off.   

Accordingly, the labor market is probably the most important leading indicator of consumption and of the ability of the Bougie Broke to continue to be Bougie instead of flat-out broke!

Summary

There are always consumers living above their means. This is often harmless until their means decline or disappear. The Bougie Broke meme and the ability social media gives consumers to flaunt their “wealth” is a new medium for an age-old message.

Diving into the data, it argues that consumption will likely slow in the coming months. Such would allow some consumers to save and whittle down their debt. That situation would be healthy and unlikely to cause a recession.

The potential for the unemployment rate to continue higher is of much greater concern. The combination of a higher unemployment rate and strapped consumers could accentuate a recession.

Tyler Durden Wed, 03/13/2024 - 09:25

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Congress’ failure so far to deliver on promise of tens of billions in new research spending threatens America’s long-term economic competitiveness

A deal that avoided a shutdown also slashed spending for the National Science Foundation, putting it billions below a congressional target intended to…

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Science is again on the chopping block on Capitol Hill. AP Photo/Sait Serkan Gurbuz

Federal spending on fundamental scientific research is pivotal to America’s long-term economic competitiveness and growth. But less than two years after agreeing the U.S. needed to invest tens of billions of dollars more in basic research than it had been, Congress is already seriously scaling back its plans.

A package of funding bills recently passed by Congress and signed by President Joe Biden on March 9, 2024, cuts the current fiscal year budget for the National Science Foundation, America’s premier basic science research agency, by over 8% relative to last year. That puts the NSF’s current allocation US$6.6 billion below targets Congress set in 2022.

And the president’s budget blueprint for the next fiscal year, released on March 11, doesn’t look much better. Even assuming his request for the NSF is fully funded, it would still, based on my calculations, leave the agency a total of $15 billion behind the plan Congress laid out to help the U.S. keep up with countries such as China that are rapidly increasing their science budgets.

I am a sociologist who studies how research universities contribute to the public good. I’m also the executive director of the Institute for Research on Innovation and Science, a national university consortium whose members share data that helps us understand, explain and work to amplify those benefits.

Our data shows how underfunding basic research, especially in high-priority areas, poses a real threat to the United States’ role as a leader in critical technology areas, forestalls innovation and makes it harder to recruit the skilled workers that high-tech companies need to succeed.

A promised investment

Less than two years ago, in August 2022, university researchers like me had reason to celebrate.

Congress had just passed the bipartisan CHIPS and Science Act. The science part of the law promised one of the biggest federal investments in the National Science Foundation in its 74-year history.

The CHIPS act authorized US$81 billion for the agency, promised to double its budget by 2027 and directed it to “address societal, national, and geostrategic challenges for the benefit of all Americans” by investing in research.

But there was one very big snag. The money still has to be appropriated by Congress every year. Lawmakers haven’t been good at doing that recently. As lawmakers struggle to keep the lights on, fundamental research is quickly becoming a casualty of political dysfunction.

Research’s critical impact

That’s bad because fundamental research matters in more ways than you might expect.

For instance, the basic discoveries that made the COVID-19 vaccine possible stretch back to the early 1960s. Such research investments contribute to the health, wealth and well-being of society, support jobs and regional economies and are vital to the U.S. economy and national security.

Lagging research investment will hurt U.S. leadership in critical technologies such as artificial intelligence, advanced communications, clean energy and biotechnology. Less support means less new research work gets done, fewer new researchers are trained and important new discoveries are made elsewhere.

But disrupting federal research funding also directly affects people’s jobs, lives and the economy.

Businesses nationwide thrive by selling the goods and services – everything from pipettes and biological specimens to notebooks and plane tickets – that are necessary for research. Those vendors include high-tech startups, manufacturers, contractors and even Main Street businesses like your local hardware store. They employ your neighbors and friends and contribute to the economic health of your hometown and the nation.

Nearly a third of the $10 billion in federal research funds that 26 of the universities in our consortium used in 2022 directly supported U.S. employers, including:

  • A Detroit welding shop that sells gases many labs use in experiments funded by the National Institutes of Health, National Science Foundation, Department of Defense and Department of Energy.

  • A Dallas-based construction company that is building an advanced vaccine and drug development facility paid for by the Department of Health and Human Services.

  • More than a dozen Utah businesses, including surveyors, engineers and construction and trucking companies, working on a Department of Energy project to develop breakthroughs in geothermal energy.

When Congress shortchanges basic research, it also damages businesses like these and people you might not usually associate with academic science and engineering. Construction and manufacturing companies earn more than $2 billion each year from federally funded research done by our consortium’s members.

A lag or cut in federal research funding would harm U.S. competitiveness in critical advanced technologies such as artificial intelligence and robotics. Hispanolistic/E+ via Getty Images

Jobs and innovation

Disrupting or decreasing research funding also slows the flow of STEM – science, technology, engineering and math – talent from universities to American businesses. Highly trained people are essential to corporate innovation and to U.S. leadership in key fields, such as AI, where companies depend on hiring to secure research expertise.

In 2022, federal research grants paid wages for about 122,500 people at universities that shared data with my institute. More than half of them were students or trainees. Our data shows that they go on to many types of jobs but are particularly important for leading tech companies such as Google, Amazon, Apple, Facebook and Intel.

That same data lets me estimate that over 300,000 people who worked at U.S. universities in 2022 were paid by federal research funds. Threats to federal research investments put academic jobs at risk. They also hurt private sector innovation because even the most successful companies need to hire people with expert research skills. Most people learn those skills by working on university research projects, and most of those projects are federally funded.

High stakes

If Congress doesn’t move to fund fundamental science research to meet CHIPS and Science Act targets – and make up for the $11.6 billion it’s already behind schedule – the long-term consequences for American competitiveness could be serious.

Over time, companies would see fewer skilled job candidates, and academic and corporate researchers would produce fewer discoveries. Fewer high-tech startups would mean slower economic growth. America would become less competitive in the age of AI. This would turn one of the fears that led lawmakers to pass the CHIPS and Science Act into a reality.

Ultimately, it’s up to lawmakers to decide whether to fulfill their promise to invest more in the research that supports jobs across the economy and in American innovation, competitiveness and economic growth. So far, that promise is looking pretty fragile.

This is an updated version of an article originally published on Jan. 16, 2024.

Jason Owen-Smith receives research support from the National Science Foundation, the National Institutes of Health, the Alfred P. Sloan Foundation and Wellcome Leap.

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