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Molecular structure of one of the most important receptors in the immune system unraveled

The surface of B cells is covered with antigen receptors with which they recognize invading pathogens such as bacteria and viruses. When a B cell receptor…

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1 year ago

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The surface of B cells is covered with antigen receptors with which they recognize invading pathogens such as bacteria and viruses. When a B cell receptor binds to an antigen, that is, to a foreign structure, the B cell is activated and triggers the production of antibodies. Antibodies are essential for our survival and protect us against severe diseases from infections with pathogens such as COVID-19. Vaccinations have a protective effect as they activate antigen receptors, thereby triggering an immune response. An international team of researchers from the Cluster of Excellence CIBSS of the University of Freiburg and Harvard Medical School, USA, has now published the exact molecular structure of an IgM-type B cell receptor. Their findings indicate that the receptor on the surface of the B cell interacts with further receptors, thus controlling its signal transduction. The study was published in the renowned journal Nature.

Credit: Hao Wu/Harvard Medical School

The surface of B cells is covered with antigen receptors with which they recognize invading pathogens such as bacteria and viruses. When a B cell receptor binds to an antigen, that is, to a foreign structure, the B cell is activated and triggers the production of antibodies. Antibodies are essential for our survival and protect us against severe diseases from infections with pathogens such as COVID-19. Vaccinations have a protective effect as they activate antigen receptors, thereby triggering an immune response. An international team of researchers from the Cluster of Excellence CIBSS of the University of Freiburg and Harvard Medical School, USA, has now published the exact molecular structure of an IgM-type B cell receptor. Their findings indicate that the receptor on the surface of the B cell interacts with further receptors, thus controlling its signal transduction. The study was published in the renowned journal Nature.

Connection of Signaling Subunits with the Immunoglobulin

The B cell antigen receptor consists of an antibody bound to the cell membrane and two smaller proteins, Ig alpha and Ig beta. These smaller subunits pass on signals to the inside of the cell as soon as the B cell receptor identifies a pathogen. “Exactly how these signaling subunits are connected with the immunoglobulin was previously unknown,” says Prof. Dr. Michael Reth from the University of Freiburg’s Faculty of Biology, who has been conducting research on the receptor for over 30 years and originally discovered its signaling subunits. He is a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies and co-director of the Cluster of Excellence BIOSS. “For a long time, we did not have the technical possibilities to study the exact structure of membrane proteins. Now, cryo-electron microscopy has enabled us to create a high-resolution image of the B cell receptor,” says Reth.

With cryo-electron microscopy, the sample to be studied is cooled very rapidly to minus 183 °C. This reduces the natural movement of the molecules and prevents the formation of tiny ice crystals that otherwise would destroy the protein structure. In this way, it is possible to achieve resolutions that are many times higher than with other electron microscopic methods. In their current study, the researchers achieved a resolution of 3.3 ångströms, which corresponds to the width of just a few atoms. To do so, they combined hundreds of thousands of images of the entire receptor with those of a truncated version that lacked two flexible regions. They then used these data to calculate the complete three-dimensional structure of the B cell receptor on the computer.

Symmetrical membrane-bound antibody binds only on one side

The striking thing about the three-dimensional structure is that the symmetrical membrane-bound antibody only binds to Ig alpha and Ig beta on one side, thus forming an asymmetrical complex. This asymmetry resembles that of the T cell receptor, another important immune receptor whose structure was first elucidated in 2019. “It is astounding that both types of antigen receptor form asymmetrical complexes,” explains Reth. “This leads us to conclude that the structure now elucidated is part of a larger receptor complex and that it interacts with still other molecules on the B cell surface.”

Such larger structures, which are held together through less powerful forces, cannot yet be studied with techniques like cryo-electron microscopy. However, the newly published molecular structure provides further evidence in favor of such an interaction with other molecules: It shows that the outside of the B cell receptor contains conserved amino acids. Amino acids are described as conserved if they hardly change in the course of evolution and are therefore identical in the antigen receptors of different organisms. “The presence of conserved amino acids that are directed outward suggests that the IgM B cell receptor has further binding partners,” says Reth. “In other words, we only know part of the machine so far – and now we want to identify the other building blocks and determine how they influence the signaling effect of the receptor.”

These other building blocks could explain how the receptor is normally kept quiescent and is activated only when it binds to an antigen. “That will be one of the next important tasks in the study of adaptive immunity,” summarizes Reth. “A better understanding of B cell activation could also help us to further improve the development of vaccines or to understand the formation of lymphoma in which the B cell receptor is activated in an uncontrolled manner.”

 

About the Cluster of Excellence CIBSS

The Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies has the goal of gaining a comprehensive understanding of biological signaling processes across scales – from interactions between individual molecules and cells to processes in organs and entire organisms. Researchers use the knowledge thus gained to develop strategies for controlling signals in a targeted manner. These technologies enable them not only to gain insights in research but also to develop innovations in medicine and plant sciences.

 

Fact sheet:

  • Original publication: Dong, Y. Pi,X. Bartels-Burgahn, F. Saltukoglu, D. Liang, Z. Yang, J. Alt, F.W., Reth, M. Wu, H. (2022). Structural principles of B-cell antigen receptor assembly. In: Nature. Doi: https://doi.org/10.1038/s41586-022-05412-7
  • Michael Reth is a senior professor for molecular immunology at the University of Freiburg’s Faculty of Biology, a member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies, and co-director of the signaling research center BIOSS – Centre for Biological Signalling Studies. His research focuses on the function and activation of the B cell receptor.
  • Hao Wu is a professor for structural biology as well as biochemistry and molecular biology at Harvard Medical School, Boston, USA.
  • The study was funded by the National Institutes of Health (NIH) and the German Research Foundation (DFG).

 

Contact:
Michal Rössler
CIBSS – Centre for Integrative Biological
University of Freiburg
Tel.: +49 761/203-97120
E-Mail: michal.roessler@cibss.uni-freiburg.de

Annette Kollefrath-Persch
University and Science Communiation
University of Freiburg
Tel.: +49 761/203-8909
E-Mail: annette.persch@zv.uni-freiburg.de

Journal

Nature

DOI

10.1038/s41586-022-05412-7

Subject of Research

Cells

Article Title

Structural principles of B-cell antigen receptor assembly

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February Employment Situation

By Paul Gomme and Peter Rupert The establishment data from the BLS showed a 275,000 increase in payroll employment for February, outpacing the 230,000…

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9 hours ago

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March 9, 2024

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By Paul Gomme and Peter Rupert

The establishment data from the BLS showed a 275,000 increase in payroll employment for February, outpacing the 230,000 average over the previous 12 months. The payroll data for January and December were revised down by a total of 167,000. The private sector added 223,000 new jobs, the largest gain since May of last year.

Temporary help services employment continues a steep decline after a sharp post-pandemic rise.

Average hours of work increased from 34.2 to 34.3. The increase, along with the 223,000 private employment increase led to a hefty increase in total hours of 5.6% at an annualized rate, also the largest increase since May of last year.

The establishment report, once again, beat “expectations;” the WSJ survey of economists was 198,000. Other than the downward revisions, mentioned above, another bit of negative news was a smallish increase in wage growth, from $34.52 to $34.57.

The household survey shows that the labor force increased 150,000, a drop in employment of 184,000 and an increase in the number of unemployed persons of 334,000. The labor force participation rate held steady at 62.5, the employment to population ratio decreased from 60.2 to 60.1 and the unemployment rate increased from 3.66 to 3.86. Remember that the unemployment rate is the number of unemployed relative to the labor force (the number employed plus the number unemployed). Consequently, the unemployment rate can go up if the number of unemployed rises holding fixed the labor force, or if the labor force shrinks holding the number unemployed unchanged. An increase in the unemployment rate is not necessarily a bad thing: it may reflect a strong labor market drawing “marginally attached” individuals from outside the labor force. Indeed, there was a 96,000 decline in those workers.

Earlier in the week, the BLS announced JOLTS (Job Openings and Labor Turnover Survey) data for January. There isn’t much to report here as the job openings changed little at 8.9 million, the number of hires and total separations were little changed at 5.7 million and 5.3 million, respectively.

As has been the case for the last couple of years, the number of job openings remains higher than the number of unemployed persons.

Also earlier in the week the BLS announced that productivity increased 3.2% in the 4th quarter with output rising 3.5% and hours of work rising 0.3%.

The bottom line is that the labor market continues its surprisingly (to some) strong performance, once again proving stronger than many had expected. This strength makes it difficult to justify any interest rate cuts soon, particularly given the recent inflation spike.

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Mortgage rates fall as labor market normalizes

Jobless claims show an expanding economy. We will only be in a recession once jobless claims exceed 323,000 on a four-week moving average.

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1 day ago

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March 8, 2024

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Everyone was waiting to see if this week’s jobs report would send mortgage rates higher, which is what happened last month. Instead, the 10-year yield had a muted response after the headline number beat estimates, but we have negative job revisions from previous months. The Federal Reserve’s fear of wage growth spiraling out of control hasn’t materialized for over two years now and the unemployment rate ticked up to 3.9%. For now, we can say the labor market isn’t tight anymore, but it’s also not breaking.

The key labor data line in this expansion is the weekly jobless claims report. Jobless claims show an expanding economy that has not lost jobs yet. We will only be in a recession once jobless claims exceed 323,000 on a four-week moving average.

From the Fed: In the week ended March 2, initial claims for unemployment insurance benefits were flat, at 217,000. The four-week moving average declined slightly by 750, to 212,250


Below is an explanation of how we got here with the labor market, which all started during COVID-19.

1. I wrote the COVID-19 recovery model on April 7, 2020, and retired it on Dec. 9, 2020. By that time, the upfront recovery phase was done, and I needed to model out when we would get the jobs lost back.

2. Early in the labor market recovery, when we saw weaker job reports, I doubled and tripled down on my assertion that job openings would get to 10 million in this recovery. Job openings rose as high as to 12 million and are currently over 9 million. Even with the massive miss on a job report in May 2021, I didn’t waver.

Currently, the jobs openings, quit percentage and hires data are below pre-COVID-19 levels, which means the labor market isn’t as tight as it once was, and this is why the employment cost index has been slowing data to move along the quits percentage.  

2-US_Job_Quits_Rate-1-2

3. I wrote that we should get back all the jobs lost to COVID-19 by September of 2022. At the time this would be a speedy labor market recovery, and it happened on schedule, too

Total employment data

4. This is the key one for right now: If COVID-19 hadn’t happened, we would have between 157 million and 159 million jobs today, which would have been in line with the job growth rate in February 2020. Today, we are at 157,808,000. This is important because job growth should be cooling down now. We are more in line with where the labor market should be when averaging 140K-165K monthly. So for now, the fact that we aren’t trending between 140K-165K means we still have a bit more recovery kick left before we get down to those levels. 




From BLS: Total nonfarm payroll employment rose by 275,000 in February, and the unemployment rate increased to 3.9 percent, the U.S. Bureau of Labor Statistics reported today. Job gains occurred in health care, in government, in food services and drinking places, in social assistance, and in transportation and warehousing.

Here are the jobs that were created and lost in the previous month:

IMG_5092

In this jobs report, the unemployment rate for education levels looks like this:

  • Less than a high school diploma: 6.1%
  • High school graduate and no college: 4.2%
  • Some college or associate degree: 3.1%
  • Bachelor’s degree or higher: 2.2%
IMG_5093_320f22

Today’s report has continued the trend of the labor data beating my expectations, only because I am looking for the jobs data to slow down to a level of 140K-165K, which hasn’t happened yet. I wouldn’t categorize the labor market as being tight anymore because of the quits ratio and the hires data in the job openings report. This also shows itself in the employment cost index as well. These are key data lines for the Fed and the reason we are going to see three rate cuts this year.

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

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

Last month we though that the January…

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March 8, 2024

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Inside The Most Ridiculous Jobs Report In 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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