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Drugs of the future will be easier and faster to make, thanks to mRNA − after researchers work out a few remaining kinks

The COVID-19 pandemic demonstrated the promise of using mRNA as medicine. But before mRNA drugs can go beyond vaccines, researchers need to identify the…

Two hurdles mRNA drugs face are a short half-life and impurities that trigger immune responses. BlackJack3D/iStock via Getty Images Plus

Vaccines have been reliably and affordably protecting people from diseases worldwide for centuries. Until the COVID-19 pandemic, however, vaccine development was still a long and idiosyncratic process. Traditionally, researchers had to tailor manufacturing processes and facilities for each vaccine candidate, and the scientific knowledge gained from one vaccine was often not directly transferable to another.

But the COVID-19 mRNA vaccines brought a new approach to vaccine development that has far-reaching implications for how researchers make drugs to treat many other diseases.

I am a biochemist, and my lab at UMass Chan Medical School focuses on developing better ways to use mRNA as a drug. Although there are many possibilities for what researchers can use mRNA to treat, some important limitations remain. Better understanding how mRNA-based drugs interact with the immune system and how they are degraded in human cells can help lead to safe, durable and effective treatments for a wide range of diseases.

Some basics of mRNA drugs

Messenger RNA, or mRNA, is made of four building blocks denoted by the letters A, C, G and U. The sequence of letters in an mRNA molecule conveys genetic information that directs how a protein is made.

An mRNA drug comprises two essential components: mRNA molecules, which code for desired proteins, and the lipid molecules – such as phospholipids and cholesterol – that encapsulate them. These mRNA-lipid nanoparticles, or LNPs, are tiny spheres about 100 nanometers in diameter that protect mRNA from degradation and facilitate its delivery into target cells.

Once inside cells, mRNA molecules instruct the cell’s machinery to produce the target protein required for a desired therapeutic effect. For example, the mRNA in the Pfizer-BioNTech and Moderna COVID-19 vaccines directs cells to produce a harmless version of the virus’ spike protein that trains the immune system to recognize and better prepare for potential infection.

The science behind COVID-19 mRNA vaccines has been decades in the making.

From a drug development perspective, mRNA drugs offer significant advantages over traditional drugs because they are easily programmable. Hundreds of pounds of mRNA can be made from readily available DNA templates, such that producing a different mRNA drug is as simple as changing the corresponding DNA templates.

More importantly, different mRNA drugs produced by the same set of methods will have similar properties. They will be delivered to the same tissues, trigger similar levels of immune responses and degrade in similar ways. This predictability significantly reduces the development risks and financial costs of developing mRNA drugs.

In addition to being easy to program, mRNA drugs have several other unique properties. For example, just like the mRNAs your body naturally produces, therapeutic mRNAs have a short half-life in cells: about one day. As a result, current mRNA technology is ideal for treatments that aren’t meant to last long in the body.

This is why vaccines are popular candidates for mRNA technology: They provide long-term protection against disease after brief exposure to the drug with few side effects. There are currently more than 30 mRNA vaccine candidates, not including vaccines for COVID-19, in clinical trials.

Self vs. nonself

Another critical feature of mRNA drugs is their intrinsic ability to stimulate the immune system. This may sound paradoxical – after all, your cells already contain large amounts of mRNAs. Why would other mRNAs activate your immune system? How does your immune system distinguish between self and nonself mRNAs?

The first reason involves location. Therapeutic mRNAs enter cells using endosomes – sacs made of the cell’s membrane that take in materials from the cell’s environment. Your immune system can detect mRNA in endosomes because this is usually a sign of an RNA virus infection – cellular mRNAs normally don’t enter endosomes. When your immune system labels therapeutic mRNAs as viral material, it triggers a strong inflammatory response that can lead to severe side effects.

Diagram showing molecules entering a depression in the cell membrane which closes off to form a sac
Endocytosis is the process by which material outside the cell, such as mRNA molecules, is engulfed within the cell. alfa md/iStock via Getty Images Plus

One solution to this problem is to modify mRNA’s building blocks – specifically, changing the U, or uridine, to its chemical cousins, pseudouridine and N1-methylpseudouridine. This subtle chemical change prevents the unwanted immune response while allowing the therapeutic mRNA to direct the cell to make the protein it encodes. The 2023 Nobel Prize in physiology or medicine was awarded to the scientists who made this breakthrough discovery. Both the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines use this technique.

The second source of unwanted immune response is impurities from mRNA production. To prepare mRNA from a DNA template, scientists use a protein called RNA polymerase that tends to make a small amount of side product called double-stranded RNA. Unlike mRNA, which is single-stranded, double-stranded RNA has two chains that form a double helix. RNA viruses also form double-stranded RNA when they replicate, and exposing cells to double-stranded RNA can lead to a strong immune response.

Removing double-stranded RNA is challenging, especially at the industrial scale. Fortuitously, for mRNA vaccines, the residual amount of double-stranded RNA can stimulate the immune system to enhance antibody responses. However, for applications other than vaccines, a cleaner RNA product is necessary to reduce side effects.

Moving beyond vaccines

Although mRNA has the potential to transform drug development for various medical purposes, careful consideration is required to identify targets that align with the technology’s strengths.

For example, because there is currently a limit to how long mRNA can last in the body, treatments that need a protein to be present for only a short period of time to achieve a lasting therapeutic effect are ideal. One promising example in development is using mRNA that encodes CRISPR-Cas9 gene-editing proteins to knock out genes that cause specific diseases.

Researchers are exploring this strategy to develop a single-dose treatment for hereditary transthyretin amyloidosis, a rare genetic disease caused by the accumulation of misfolded proteins in the heart and nerves. This disease is an ideal target for mRNA-based CRISPR gene therapy because the target protein is produced by the liver. Because most drugs pass through the liver, this makes it easier to deliver CRISPR-Cas9 mRNA to its target. In the next few years, a new generation of more precise mRNA-based genome editing therapies will enter clinical trials.

Microscopy image of SARS-CoV-2 virus particles lining the a few vesicles in a cell
Because the virus that causes COVID-19 (gold) and other RNA viruses enter cells through endosomes, mRNA drug impurities can elicit similar immune responses. NIAID/Flickr, CC BY

For treatments that need a specific protein to be present in the body for long periods of time or need to prompt little to no immune reaction, further advancements in mRNA technology are necessary to extend mRNA’s half-life and eliminate immune-triggering contaminants. Notable new developments in these areas include using computational algorithms to optimize mRNA sequences in ways that enhance their stability and engineering RNA polymerases that introduce fewer side products that may cause an immune response.

Further advancements have the potential to enable a new generation of safe, durable and effective mRNA therapeutics for applications beyond vaccines.

Li Li receives funding from NIH.

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Wendy’s teases new $3 offer for upcoming holiday

The Daylight Savings Time promotion slashes prices on breakfast.

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Daylight Savings Time, or the practice of advancing clocks an hour in the spring to maximize natural daylight, is a controversial practice because of the way it leaves many feeling off-sync and tired on the second Sunday in March when the change is made and one has one less hour to sleep in.

Despite annual "Abolish Daylight Savings Time" think pieces and online arguments that crop up with unwavering regularity, Daylight Savings in North America begins on March 10 this year.

Related: Coca-Cola has a new soda for Diet Coke fans

Tapping into some people's very vocal dislike of Daylight Savings Time, fast-food chain Wendy's  (WEN)  is launching a daylight savings promotion that is jokingly designed to make losing an hour of sleep less painful and encourage fans to order breakfast anyway.

Wendy's has recently made a big push to expand its breakfast menu.

Image source: Wendy's.

Promotion wants you to compensate for lost sleep with cheaper breakfast

As it is also meant to drive traffic to the Wendy's app, the promotion allows anyone who makes a purchase of $3 or more through the platform to get a free hot coffee, cold coffee or Frosty Cream Cold Brew.

More Food + Dining:

Available during the Wendy's breakfast hours of 6 a.m. and 10:30 a.m. (which, naturally, will feel even earlier due to Daylight Savings), the deal also allows customers to buy any of its breakfast sandwiches for $3. Items like the Sausage, Egg and Cheese Biscuit, Breakfast Baconator and Maple Bacon Chicken Croissant normally range in price between $4.50 and $7.

The choice of the latter is quite wide since, in the years following the pandemic, Wendy's has made a concerted effort to expand its breakfast menu with a range of new sandwiches with egg in them and sweet items such as the French Toast Sticks. The goal was both to stand out from competitors with a wider breakfast menu and increase traffic to its stores during early-morning hours.

Wendy's deal comes after controversy over 'dynamic pricing'

But last month, the chain known for the square shape of its burger patties ignited controversy after saying that it wanted to introduce "dynamic pricing" in which the cost of many of the items on its menu will vary depending on the time of day. In an earnings call, chief executive Kirk Tanner said that electronic billboards would allow restaurants to display various deals and promotions during slower times in the early morning and late at night.

Outcry was swift and Wendy's ended up walking back its plans with words that they were "misconstrued" as an intent to surge prices during its most popular periods.

While the company issued a statement saying that any changes were meant as "discounts and value offers" during quiet periods rather than raised prices during busy ones, the reputational damage was already done since many saw the clarification as another way to obfuscate its pricing model.

"We said these menuboards would give us more flexibility to change the display of featured items," Wendy's said in its statement. "This was misconstrued in some media reports as an intent to raise prices when demand is highest at our restaurants."

The Daylight Savings Time promotion, in turn, is also a way to demonstrate the kinds of deals Wendy's wants to promote in its stores without putting up full-sized advertising or posters for what is only relevant for a few days.

Related: Veteran fund manager picks favorite stocks for 2024

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Inside The Most Ridiculous Jobs Report In Recent History: Record 1.2 Million Immigrant Jobs Added In One Month

Inside The Most Ridiculous Jobs Report In Recent History: Record 1.2 Million Immigrant Jobs Added In One Month

Last month we though that the…

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Inside The Most Ridiculous Jobs Report In Recent History: Record 1.2 Million Immigrant Jobs Added In One Month

Last month we though that the January jobs report was the "most ridiculous in recent history" but, boy, were we wrong because this morning the Biden department of goalseeked propaganda (aka BLS) published the February jobs report, and holy crap was that something else. Even Goebbels would blush. 

What happened? Let's take a closer look.

On the surface, it was (almost) another blockbuster jobs report, certainly one which nobody expected, or rather just one bank out of 76 expected. Starting at the top, the BLS reported that in February the US unexpectedly added 275K jobs, with just one research analyst (from Dai-Ichi Research) expecting a higher number.

Some context: after last month's record 4-sigma beat, today's print was "only" 3 sigma higher than estimates. Needless to say, two multiple sigma beats in a row used to only happen in the USSR... and now in the US, apparently.

Before we go any further, a quick note on what last month we said was "the most ridiculous jobs report in recent history": it appears the BLS read our comments and decided to stop beclowing itself. It did that by slashing last month's ridiculous print by over a third, and revising what was originally reported as a massive 353K beat to just 229K,  a 124K revision, which was the biggest one-month negative revision in two years!

Of course, that does not mean that this month's jobs print won't be revised lower: it will be, and not just that month but every other month until the November election because that's the only tool left in the Biden admin's box: pretend the economic and jobs are strong, then revise them sharply lower the next month, something we pointed out first last summer and which has not failed to disappoint once.

To be fair, not every aspect of the jobs report was stellar (after all, the BLS had to give it some vague credibility). Take the unemployment rate, after flatlining between 3.4% and 3.8% for two years - and thus denying expectations from Sahm's Rule that a recession may have already started - in February the unemployment rate unexpectedly jumped to 3.9%, the highest since February 2022 (with Black unemployment spiking by 0.3% to 5.6%, an indicator which the Biden admin will quickly slam as widespread economic racism or something).

And then there were average hourly earnings, which after surging 0.6% MoM in January (since revised to 0.5%) and spooking markets that wage growth is so hot, the Fed will have no choice but to delay cuts, in February the number tumbled to just 0.1%, the lowest in two years...

... for one simple reason: last month's average wage surge had nothing to do with actual wages, and everything to do with the BLS estimate of hours worked (which is the denominator in the average wage calculation) which last month tumbled to just 34.1 (we were led to believe) the lowest since the covid pandemic...

... but has since been revised higher while the February print rose even more, to 34.3, hence why the latest average wage data was once again a product not of wages going up, but of how long Americans worked in any weekly period, in this case higher from 34.1 to 34.3, an increase which has a major impact on the average calculation.

While the above data points were examples of some latent weakness in the latest report, perhaps meant to give it a sheen of veracity, it was everything else in the report that was a problem starting with the BLS's latest choice of seasonal adjustments (after last month's wholesale revision), which have gone from merely laughable to full clownshow, as the following comparison between the monthly change in BLS and ADP payrolls shows. The trend is clear: the Biden admin numbers are now clearly rising even as the impartial ADP (which directly logs employment numbers at the company level and is far more accurate), shows an accelerating slowdown.

But it's more than just the Biden admin hanging its "success" on seasonal adjustments: when one digs deeper inside the jobs report, all sorts of ugly things emerge... such as the growing unprecedented divergence between the Establishment (payrolls) survey and much more accurate Household (actual employment) survey. To wit, while in January the BLS claims 275K payrolls were added, the Household survey found that the number of actually employed workers dropped for the third straight month (and 4 in the past 5), this time by 184K (from 161.152K to 160.968K).

This means that while the Payrolls series hits new all time highs every month since December 2020 (when according to the BLS the US had its last month of payrolls losses), the level of Employment has not budged in the past year. Worse, as shown in the chart below, such a gaping divergence has opened between the two series in the past 4 years, that the number of Employed workers would need to soar by 9 million (!) to catch up to what Payrolls claims is the employment situation.

There's more: shifting from a quantitative to a qualitative assessment, reveals just how ugly the composition of "new jobs" has been. Consider this: the BLS reports that in February 2024, the US had 132.9 million full-time jobs and 27.9 million part-time jobs. Well, that's great... until you look back one year and find that in February 2023 the US had 133.2 million full-time jobs, or more than it does one year later! And yes, all the job growth since then has been in part-time jobs, which have increased by 921K since February 2023 (from 27.020 million to 27.941 million).

Here is a summary of the labor composition in the past year: all the new jobs have been part-time jobs!

But wait there's even more, because now that the primary season is over and we enter the heart of election season and political talking points will be thrown around left and right, especially in the context of the immigration crisis created intentionally by the Biden administration which is hoping to import millions of new Democratic voters (maybe the US can hold the presidential election in Honduras or Guatemala, after all it is their citizens that will be illegally casting the key votes in November), what we find is that in February, the number of native-born workers tumbled again, sliding by a massive 560K to just 129.807 million. Add to this the December data, and we get a near-record 2.4 million plunge in native-born workers in just the past 3 months (only the covid crash was worse)!

The offset? A record 1.2 million foreign-born (read immigrants, both legal and illegal but mostly illegal) workers added in February!

Said otherwise, not only has all job creation in the past 6 years has been exclusively for foreign-born workers...

Source: St Louis Fed FRED Native Born and Foreign Born

... but there has been zero job-creation for native born workers since June 2018!

This is a huge issue - especially at a time of an illegal alien flood at the southwest border...

... and is about to become a huge political scandal, because once the inevitable recession finally hits, there will be millions of furious unemployed Americans demanding a more accurate explanation for what happened - i.e., the illegal immigration floodgates that were opened by the Biden admin.

Which is also why Biden's handlers will do everything in their power to insure there is no official recession before November... and why after the election is over, all economic hell will finally break loose. Until then, however, expect the jobs numbers to get even more ridiculous.

Tyler Durden Fri, 03/08/2024 - 13:30

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Shipping company files surprise Chapter 7 bankruptcy, liquidation

While demand for trucking has increased, so have costs and competition, which have forced a number of players to close.

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The U.S. economy is built on trucks.

As a nation we have relatively limited train assets, and while in recent years planes have played an expanded role in moving goods, trucks still represent the backbone of how everything — food, gasoline, commodities, and pretty much anything else — moves around the country.

Related: Fast-food chain closes more stores after Chapter 11 bankruptcy

"Trucks moved 61.1% of the tonnage and 64.9% of the value of these shipments. The average shipment by truck was 63 miles compared to an average of 640 miles by rail," according to the U.S. Bureau of Transportation Statistics 2023 numbers.

But running a trucking company has been tricky because the largest players have economies of scale that smaller operators don't. That puts any trucking company that's not a massive player very sensitive to increases in gas prices or drops in freight rates.

And that in turn has led a number of trucking companies, including Yellow Freight, the third-largest less-than-truckload operator; J.J. & Sons Logistics, Meadow Lark, and Boateng Logistics, to close while freight brokerage Convoy shut down in October.

Aside from Convoy, none of these brands are household names. but with the demand for trucking increasing, every company that goes out of business puts more pressure on those that remain, which contributes to increased prices.

Demand for trucking has continued to increase.

Image source: Shutterstock

Another freight company closes and plans to liquidate

Not every bankruptcy filing explains why a company has gone out of business. In the trucking industry, multiple recent Chapter 7 bankruptcies have been tied to lawsuits that pushed otherwise successful companies into insolvency.

In the case of TBL Logistics, a Virginia-based national freight company, its Feb. 29 bankruptcy filing in U.S. Bankruptcy Court for the Western District of Virginia appears to be death by too much debt.

"In its filing, TBL Logistics listed its assets and liabilities as between $1 million and $10 million. The company stated that it has up to 49 creditors and maintains that no funds will be available for unsecured creditors once it pays administrative fees," Freightwaves reported.

The company's owners, Christopher and Melinda Bradner, did not respond to the website's request for comment.

Before it closed, TBL Logistics specialized in refrigerated and oversized loads. The company described its business on its website.

"TBL Logistics is a non-asset-based third-party logistics freight broker company providing reliable and efficient transportation solutions, management, and storage for businesses of all sizes. With our extensive network of carriers and industry expertise, we streamline the shipping process, ensuring your goods reach their destination safely and on time."

The world has a truck-driver shortage

The covid pandemic forced companies to consider their supply chain in ways they never had to before. Increased demand showed the weakness in the trucking industry and drew attention to how difficult life for truck drivers can be.

That was an issue HBO's John Oliver highlighted on his "Last Week Tonight" show in October 2022. In the episode, the host suggested that the U.S. would basically start to starve if the trucking industry shut down for three days.

"Sorry, three days, every produce department in America would go from a fully stocked market to an all-you-can-eat raccoon buffet," he said. "So it’s no wonder trucking’s a huge industry, with more than 3.5 million people in America working as drivers, from port truckers who bring goods off ships to railyards and warehouses, to long-haul truckers who move them across the country, to 'last-mile' drivers, who take care of local delivery." 

The show highlighted how many truck drivers face low pay, difficult working conditions and, in many cases, crushing debt.

"Hundreds of thousands of people become truck drivers every year. But hundreds of thousands also quit. Job turnover for truckers averages over 100%, and at some companies it’s as high as 300%, meaning they’re hiring three people for a single job over the course of a year. And when a field this important has a level of job satisfaction that low, it sure seems like there’s a huge problem," Oliver shared.

The truck-driver shortage is not just a U.S. problem; it's a global issue, according to IRU.org.

"IRU’s 2023 driver shortage report has found that over three million truck driver jobs are unfilled, or 7% of total positions, in 36 countries studied," the global transportation trade association reported. 

"With the huge gap between young and old drivers growing, it will get much worse over the next five years without significant action."

Related: Veteran fund manager picks favorite stocks for 2024

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