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Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 11:35am

substituted the gene encoding a piece of tetanus toxin for the gene fragment encoding a component that normally gets displayed in this giant treelike protein's foliage. Now it's this fragment—a harmless chunk of a highly toxic bacterial protein—that's waving in the breeze."

Would the mice's immune systems "see" it and develop a specific antibody response to it?
And it did!
The mice swabbed with bioengineered S. epidermidis, but not the others, developed extremely high levels of antibodies targeting tetanus toxin. When the researchers then injected the mice with lethal doses of tetanus toxin, the mice given natural S. epidermidis all succumbed; the mice that received the modified version remained symptom-free.

A similar experiment, in which the researchers snapped in the gene for diphtheria toxin instead of the one for tetanus toxin into the Aap "cassette player," likewise induced massive antibody concentrations targeting the diphtheria toxin.

The scientists eventually found they could still get life-saving antibody responses in mice after only two or three applications.

They also showed, by colonizing very young mice with S. epidermidis, that the bacteria's prior presence on these mice's skin (as is typical in humans but not mice) didn't interfere with the experimental treatment's ability to spur a potent antibody response. This implies that their species' virtually 100% skin colonization by S. epidermidis should pose no problem to the construct's use in people.
In a change of tactics, the researchers generated the tetanus-toxin fragment in a bioreactor, then chemically stapled it to Aap so it dotted S. epidermidis's surface. To their surprise, this turned out to generate a surprisingly powerful antibody response.
Topical application of this bug generated enough antibodies to protect mice from six times the lethal dose of tetanus toxin.
it works in mice. Now they are trying to experiment with monkeys.
If things go well, they expect to see this vaccination approach enter clinical trials within two or three years.
The researchers think this will work for viruses, bacteria, fungi and one-celled parasites. Most vaccines have ingredients that stimulate an inflammatory response and make you feel a little sick. These bugs don't do that. Scientists expect that you wouldn't experience any inflammation at all.

Discovery and engineering of the antibody response to a prominent skin commensal, Nature (2024). DOI: 10.1038/s41586-024-08489-4 , www.nature.com/articles/s41586-024-08489-4

Skin autonomous antibody production regulates host-microbiota interactions, Nature (2024). DOI: 10.1038/s41586-024-08376-y , www.nature.com/articles/s41586-024-08376-y

Part 4

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Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:58am

Step by step, the research team turned S. epidermidis into a living, plug-and-play vaccine that can be applied topically. They learned that the part of S. epidermidis most responsible for tripping off a powerful immune response is a protein called Aap. This great, treelike structure, five times the size of an average protein, protrudes from the bacterial cell wall.

They think it might expose some of its outermost chunks to sentinel cells of the immune system that periodically crawl through the skin, sample hair follicles, snatch samples of whatever is flapping in Aap's "foliage," and spirit them back inside to show to other immune cells responsible for cooking up an appropriate antibody response aiming at that item.
This companion study identifies the sentinel immune cells, called Langerhans cells, that alert the rest of the immune system to the presence of S. epidermidis on the skin.

Aap induces a jump in not only blood-borne antibodies known to immunologists as IgG, but also other antibodies, called IgA, that home in on the mucosal linings of our nostrils and lungs.
Having identified Aap as the antibodies' main target, the scientists looked for a way to put it to work.

Respiratory pathogens responsible for the common cold, flu and COVID-19 tend to get inside our bodies through our nostrils. Normal vaccines can't prevent this. They go to work only once the pathogen gets into the blood. It would be much better to stop it from getting in in the first place.

Part 3

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Discovery and engineering of the antibody response to a prominent skin commensal, Nature (2024). DOI: 10.1038/s41586-024-08489-4 , www.nature.com/articles/s41586-024-08489-4

Skin autonomous antibody production regulates host-microbiota interactions, Nature (2024). DOI: 10.1038/s41586-024-08376-y , www.nature.com/articles/s41586-024-08376-y

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:56am

Researchers conducted experiments to know this. 

The mice's antibody response to S. epidermidis was "a shocker".Those antibodies' levels increased slowly, then some more—and then even more." At six weeks, they'd reached a higher concentration than one would expect from a regular vaccination—and they stayed at those levels.

It's as if the mice had been vaccinated. Their antibody response was just as strong and specific as if it had been reacting to a pathogen.

The same thing appears to be occurring naturally in humans. The researchers got blood from human donors and found that their circulating levels of antibodies directed at S. epidermidis were as high as anything we get routinely vaccinated against.

This is intriguing. Our ferocious immune response to these commensal bacteria loitering on the far side of that all-important anti-microbial barrier we call our skin seems to have no purpose.

It could boil down to a line scrawled by early-20th-century poet Robert Frost: "Good fences make good neighbors." Most people have thought that fence was the skin. But it's far from perfect. Without help from the immune system, it would be breached very quickly.

The best fence is those antibodies. They're the immune system's way of protecting us from the inevitable cuts, scrapes, nicks and scratches we accumulate in our daily existence.

While the antibody response to an infectious pathogen begins only after the pathogen invades the body, the response to S. epidermidis happens preemptively, before there's any problem. That way, the immune system can respond if necessary—say, when there's a skin break and the normally harmless bug climbs in and tries to thumb a ride through our bloodstream.

Part 2

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:48am

Scientists transform ubiquitous skin bacterium into a topical vaccine

Imagine a world in which a vaccine is a cream you rub onto your skin instead of a needle a health care worker pushes into one of your muscles. Even better, it's entirely pain-free and not followed by fever, swelling, redness or a sore arm. No standing in a long line to get it. Plus, it's cheap.

Thanks to Stanford University researchers' domestication of a bacterial species that hangs out on the skin of close to everyone on Earth, that vision could become a reality.

Staphylococcus epidermidis is a generally harmless skin-colonizing bacterial species. These bugs reside on every hair follicle of virtually every person on the planet.

In recent years, researchers have discovered that the immune system mounts a much more aggressive response against S. epidermidis than anyone expected.

In a study published Dec. 11 in Nature, they zeroed in on a key aspect of the immune response—the production of antibodies. These specialized proteins can stick to specific biochemical features of invading microbes, often preventing them from getting inside of cells or traveling unmolested through the bloodstream to places they should not go.

Individual antibodies are extremely picky about what they stick to. Each antibody molecule typically targets a particular biochemical feature belonging to a single microbial species or strain.

But  would the immune system of a mouse, whose skin isn't normally colonized by S. epidermidis, mount an antibody response to that microorganism if it were to turn up there?

Part 1

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:30am

The researchers found that Nsp13 promotes robust human cell death activation; mutating the RHIM in Nsp13 therefore enhanced cell survival.

Nsp13 was found to work in synergy with host RHIM proteins called ZBP1 and RIPK3 to promote cell death activation, which might possibly be contributing to the respiratory damage and disease progression seen in COVID-19. The researchers also found that RNA segments in the Z conformation (Z-RNA) in the virus's genome were driving the Nsp13-mediated cell death activation.

Since bats express host RHIM proteins similar to humans, they can serve as the source for RHIM mimics to mutate and evolve, the study suggests. Interestingly, bats show mild clinical symptoms and tissue damage compared to humans despite harboring viruses with RHIM mimics. To understand this conundrum, the authors tested whether and how Nsp13-RHIM regulates bat cell death.
Nsp13 could also activate cell death in bat cells like in human cells. Researchers found the nature of bat cell death to be preferably non-inflammatory and Nsp13-RHIM independent, possibly just enough to clear the viral replication niche but not cause severe inflammation.
These insights on how cell death is regulated differently in bats and humans provide some clues to why some pathogenic viruses are tolerated in bats but cause more severe diseases in humans.
Understanding fundamental differences in cellular responses to viruses in bats and humans is critical to guide pandemic preparedness for such zoonotic virus infections.

Sanchita Mishra et al, Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling, iScience (2024). DOI: 10.1016/j.isci.2024.111444

Part 2

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:28am

How bat-origin pathogenic viruses manipulate human cell death and inflammation

A study by researchers at the Indian Institute of Science (IISc) offers insights into cell death regulation by viruses like SARS-CoV-2, and how bats and humans respond differently to tricks that such viruses use to manipulate the host's defense.

The paper is published in the journal iScience.

Zoonotic virus infections pose a serious concern to human health. Bats and birds are among the main reservoirs for several pathogenic viruses that show zoonotic transmission potential. When they reach the human host, these viruses can cause either mild or severe disease.

Host cell death after viral infections is a defense strategy to limit viral spread and mount protective immune responses. However, uncontrolled cell death response can drive excessive tissue damage, leading to disease severity. Scientists have strived to pinpoint how zoonotic viruses that originate from bats manipulate the human host to cause excessive cell death and tissue damage.

The study has uncovered how such viruses mimic components of the host's cell death machinery. They zeroed in on protein motifs called RIP homotypic interaction motifs (RHIMs) that regulate host cell death and inflammation.

Several viruses that originate in bats show mimics of these RHIMs. SARS-CoV-2, for example, contains Nsp13—an enzyme protein critical for virus replication—that has an RHIM similar to those found in humans.

Part 1

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:10am

Astronomers discover magnetic loops around supermassive black hole

NGC 1068 is a well-known, relatively nearby, bright galaxy with a supermassive black hole at its center. Despite its status as a popular target for astronomers, however, its accretion disk is obscured by thick clouds of dust and gas. A few light-years in diameter, the outer accretion disk is dotted by hundreds of distinct water maser sources that hinted for decades at deeper structures.

Masers are distinct beacons of electromagnetic radiation that shine in microwave or radio wavelengths; in radio astronomy, water masers observed at a frequency of 22 GHz are particularly useful because they can shine through much of the dust and gas that obscures optical wavelengths.

an international team of astronomers and students set out to observe NGC 1068 with twin goals in mind: astrometric mapping of the galaxy's radio continuum and measurements of polarization for its water masers.

NGC 1068 is a bit of a VIP among active galaxies. It is unusually powerful, with a black hole and an edge-on accretion disk.  And because it is so nearby, it has been really, really well-studied in detail.

By measuring the polarization of water masers as well as the continuum of radio emissions from NGC 1068, the team generated a map revealing the compact radio source now known as NGC 1068* as well as mysterious extended structures of more faint emissions.

Mapping the astrometric distribution of NGC 1068 and its water masers revealed that they are spread along filaments of structure. "It really came out in these new observations, that these filaments of maser spots line up like beads on a string.

The team was stunned to see that there's a clear offset—a displacement angle—between the radio continuum showing the structures at the galaxy's core and the locations of the masers themselves. The configuration is unstable, so the researchers  are probably observing the source of a magnetically-launched outflow.

HSA measurements of the polarization of these water masers revealed striking evidence of magnetic fields. No one has ever seen polarization in water masers outside of our galaxy till now. 

Similar to the looping structures seen on our sun's surface as prominences, the polarization pattern of these water masers clearly indicates that magnetic fields are also at the root of these light-year-scale structures as well.

Looking at the filaments, and seeing that the polarization vectors are perpendicular to them, that's the key to confirming that they are magnetically driven structures. 

Jack F. Gallimore et al, The Discovery of Polarized Water Vapor Megamaser Emission in a Molecular Accretion Disk, The Astrophysical Journal Letters (2024). DOI: 10.3847/2041-8213/ad864f

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 10:01am

Air pollution in India linked to millions of deaths

A new study from Karolinska Institutet shows that long-term exposure to air pollution contributes to millions of deaths in India. The research, published in The Lancet Planetary Health, emphasizes the need for stricter air quality regulations in the country.

Air pollution consisting of particles smaller than 2.5 micrometers in diameter, PM_2.5, can enter the lungs and bloodstream and is a major health risk in India. Researchers have now examined the link between these particles and mortality over a 10-year period. The study is based on data from 655 districts in India between 2009 and 2019.

The study  found that every 10 microgram per cubic meter increase in PM_2.5 concentration led to an 8.6% increase in mortality.

The research analyzed the relationship between changes in air pollution levels and mortality. The results show that around 3.8 million deaths over the period can be linked to air pollution levels above India's own air quality guidelines of 40 micrograms per cubic meter.

When compared to the stricter guidelines recommended by the World Health Organization (WHO)—only 5 micrograms per cubic meter—the figure rises to 16.6 million deaths. That's almost 25% of all mortality during the study period.

The study also highlights that the entire population of India lives in areas where PM_2.5 levels exceed WHO guidelines. This means that almost 1.4 billion people are exposed year after year to air pollution that can negatively affect health. In some regions, levels of up to 119 micrograms per cubic meter were measured, significantly higher than what both the WHO and India consider safe.

The results show that current guidelines in India are not sufficient to protect health. Stricter regulations and measures to reduce emissions are of the utmost importance, say the researchers. 

The Indian government has been running a national air pollution control program since 2017 to improve air quality, but the study shows that PM_2.5 concentrations have continued to increase in many areas. The researchers emphasize the importance of both reducing emissions locally and taking into account the long range of air pollution—PM_2.5 particles can travel hundreds of kilometers.

 Estimating the effect of annual PM2-5 exposure on mortality in India: a difference-in-differences approach, The Lancet Planetary Health (2024). DOI: 10.1016/S2542-5196(24)00248-1. www.thelancet.com/journals/lan … (24)00248-1/fulltext

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 9:53am

Drug-free pain relief: Solvent molecules offer non-addictive alternative

Researchers have made a discovery regarding the TRPV1 (transient receptor potential vanilloid 1) ion channel and its role in pain perception. The study reveals how solvent molecules can modulate pain signals, offering a potential pathway for a safer, non-addictive pain management approach.

Pain management is a critical aspect of health care, directly impacting quality of life and overall well-being. The TRPV1 ion channel, essential for pain sensing, undergoes pore expansion when activated, allowing ions and larger molecules to pass through. However, the ability of water molecules to permeate the TRPV1 channel has remained uncertain.

To address this, the research team developed an upconversion nanoprobe capable of distinguishing between ordinary water (H₂O) and deuterated water (D₂O). This advanced technology enabled real-time tracking of water dynamics at both the single-cell and single-molecule levels. 

The study showed that when D₂O passed through the TRPV1 channel, it suppressed pain signal transmission and achieved effective analgesia.

The findings were published in the journal Nature Biomedical Engineering on 21 November 2024.

Administering D₂O to pre-clinical models, the team successfully reduced both acute and chronic inflammatory pain transmission without affecting other neurological responses. This solvent-mediated analgesia mechanism provides an effective, biocompatible, and non-addictive alternative to traditional pain medications, circumventing issues related to drug dependency and tolerance.

The solvent-mediated analgesia mechanism represents an innovative breakthrough in pain relief, potentially driving the development of safer, non-addictive pain therapies for clinical use.

Yuxia Liu et al, Solvent-mediated analgesia via the suppression of water permeation through TRPV1 ion channels, Nature Biomedical Engineering (2024). DOI: 10.1038/s41551-024-01288-2

Comment by Dr. Krishna Kumari Challa on December 12, 2024 at 9:26am

Personalized blood count could lead to early intervention for common diseases

A complete blood count (CBC) screening is a routine exam requested by most physicians for healthy adults. This clinical test is a valuable tool for assessing a patient's overall health from one blood sample.

Currently, the results of CBC tests are analyzed using a one-size-fits-all reference interval, but a new study led by researchers from Mass General Brigham suggests that this approach can lead to overlooked deviations in health. In a retrospective analysis, researchers show that these reference intervals, or setpoints, are unique to each patient.

The study revealed that one healthy patient's CBC setpoints can be distinguishable from 98% of other healthy adults. Results are published in Nature.

Complete blood counts are common tests, and this study suggests CBCs vary a lot from person to person even when completely healthy, and a more personalized and precision medicine approach could give more insight into a person's health or disease.

The long-term stability and patient-specificity of setpoints may provide new opportunities for the personalized management of healthy adults envisioned by precision medicine.

CBC indices are known to shift due to genetics, disease history, and age. But the new study suggests that individual patients have a "setpoint"—a stable value around which measures fluctuate.

By considering CBC setpoints tailored to an individual, clinicians may be able to diagnose diseases in their early stages in adults that appear otherwise healthy, including disorders such as diabetes, heart disease, and kidney failure, all of which can benefit from early intervention.

The study found that for multiple diseases, setpoints produce a two- to four-fold relative risk stratification which is comparable to that provided by common disease screening factors.

The researchers note that these setpoints create new opportunities to investigate the mechanisms of varying CBC thresholds and that the information from CBC setpoints could be used to create more specific treatment plans, including determining if additional screening is needed for an accurate diagnosis.

Foy BH et al, Haematological setpoints are a stable and patient-specific deep phenotype, Nature (2024). DOI: 10.1038/s41586-024-08264-5. www.nature.com/articles/s41586-024-08264-5

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