Comment

Comment by Dr. Krishna Kumari Challa on January 26, 2022 at 11:10am

Next, the researchers combined a computer program called dTERMen with X-ray crystallography in order understand how and why PCARE binds to ENAH over ENAH's two nearly identical sister proteins (VASP and EVL). Researchers saw that the amino acids flanking PCARE's core SliM caused ENAH to change shape slightly when the two made contact, allowing the binding sites to latch onto one another. VASP and EVL, by contrast, could not undergo this structural change, so the PCARE SliM did not bind to either of them as tightly.

Inspired by this unique interaction, researchers designed their own protein that bound to ENAH with unprecedented affinity and specificity. "It was exciting that we were able to come up with such a specific binder," she says. "This work lays the foundation for designing synthetic molecules with the potential to disrupt protein-protein interactions that cause disease—or to help scientists learn more about ENAH and other SLiM-binding proteins.

Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH, eLife, DOI: 10.7554/eLife.70680 , elifesciences.org/articles/70680

A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers, eLife, DOI: 10.7554/eLife.70601 , elifesciences.org/articles/70601

https://phys.org/news/2022-01-probing-proteins-pair-cells.html?utm_...

Part 3

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Comment by Dr. Krishna Kumari Challa on January 26, 2022 at 11:07am

The ability to test hundreds of thousands of potential SLiMs for binding provides a powerful tool to explore why proteins prefer specific SLiM partners over others.

As we gain an understanding of the tricks that a protein uses to select its partners, we can apply these in protein design to make our own binders to modulate protein function for research or therapeutic purposes.

The researchers also suspected that the amino acids on either side of the SLiM's core 4-6 amino acid sequence might play an underappreciated role in binding. To test their theory, they used MassTitr to screen the human proteome in longer chunks comprised of 36 amino acids, in order to see which "extended" SLiMs would associate with the protein ENAH.

ENAH, sometimes referred to as Mena, helps cells to move. This ability to migrate is critical for healthy cells, but cancer cells can coopt it to spread. Scientists have found that reducing the amount of ENAH decreases the cancer cells's ability to invade other tissues—suggesting that formulating drugs to disrupt this protein and its interactions could treat cancer.

Part 2

Comment by Dr. Krishna Kumari Challa on January 26, 2022 at 10:58am

How proteins pair up inside cells

A  single cell contains billions of molecules that bustle around and bind to one another, carrying out vital functions. The human genome encodes about 20,000 proteins, most of which interact with partner proteins to mediate upwards of 400,000 distinct interactions. These partners don't just latch onto one another haphazardly; they only bind to very specific companions that they must recognize inside the crowded cell. If they create the wrong pairings—or even the right pairings at the wrong place or wrong time—cancer or other diseases can ensue. Scientists are hard at work investigating these protein-protein relationships, in order to understand how they work, and potentially create drugs that disrupt or mimic them to treat disease.

The average human protein is composed of approximately 400 building blocks called amino acids, which are strung together and folded into a complex 3D structure. Within this long string of building blocks, some proteins contain stretches of 4-6 amino acids called short linear motifs (SLiMs), which mediate protein-protein interactions. Despite their simplicity and small size, SLiMs and their binding partners facilitate key cellular processes. However, it's been historically difficult to devise experiments to probe how SLiMs recognize their specific binding partners.

To address this problem, a group of researchers designed a screening method to understand how SLiMs selectively bind to certain proteins, and even distinguish between those with similar structures. Using the detailed information they gleaned from studying these interactions, the researchers created their own synthetic molecule capable of binding extremely tightly to a protein called ENAH, which is implicated in cancer metastasis. The team shared their findings in a pair of eLife studies, one published on January 25, 2022 and the other on December 2, 2021.

Part 1

Comment by Dr. Krishna Kumari Challa on January 25, 2022 at 11:41am

New antimicrobial therapeutics to fight superbugs

Researchers  have discovered a potential new way to prevent antibiotic resistance and reduce antibiotic intake.

Antimicrobial resistance occurs when pathogens (bacteria, viruses, fungi and parasites) change over time and no longer respond to medicines, consequently infections become increasingly difficult or impossible to treat.

The study, "A Polytherapy based approach to combat antimicrobial resistance using cubosomes," published in Nature Communications, has found that the use of nanoparticles in combination with other antibiotics, is an effective strategy to improve bacterial killing.

The paper makes an important new contribution to the field of antimicrobial resistance, finding a new way forward to fight multidrug-resistant bacteria.

Researchers now have demonstrated that nanoparticle-based polytherapy treatments disrupt the outer membrane of superbug bacteria, and offer an improved alternative to the conventional use of loading the antibiotic within lipid nanoparticles.

When bacteria becomes resistant, the original antibiotics can no longer kill them. Instead of looking for new antibiotics to counteract superbugs, we can use the nanotechnology approach to reduce the dose of antibiotic intake, effectively killing multidrug-resistant organisms.

 Xiangfeng Lai et al, A polytherapy based approach to combat antimicrobial resistance using cubosomes, Nature Communications (2022). DOI: 10.1038/s41467-022-28012-5

https://phys.org/news/2022-01-antimicrobial-therapeutics-superbugs....

Comment by Dr. Krishna Kumari Challa on January 25, 2022 at 8:21am

Benjamin Charvet et al, SARS-CoV-2 induces human endogenous retrovirus type W envelope protein expression in blood lymphocytes and in tissues of COVID-19 patients, medRxiv (2022). DOI: 10.1101/2022.01.18.21266111

https://phys.org/news/2022-01-sars-cov-spike-protein-human-endogeno...

Part 4

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Comment by Dr. Krishna Kumari Challa on January 25, 2022 at 8:20am

But which HERV-W, exactly? Over 1 percent of our genomes are HERV-W remnants, more than all our protein-coding regions put together. In fact, there are at least 13 HERV-W loci with full-length ENV genes in the human genome. One of these, which hails from chromosome region 7q21.2, has an uninterrupted open reading frame for a complete HERV-W ENV protein. This protein, Syncytin-1, figures famously and essentially in normal placental development. To complicate things, MS now seems to have many eclectic potential origins. Researchers revealed this week, to considerable acclaim, that infection with Epstein-Barr virus is an important upstream, or downstream, or perhaps altogether independent trigger for MS.

HERV-W is not the only retroviral game in town. Researchers recently discovered that a retrovirus-like protein known as PEG10 directly binds to and secretes its own mRNA in extracellular virus-like capsids. This behavior is eerily similar to that of the ARC1 retroviral protein now understood to be critical in the formation of memory at synaptic sites. Incredibly, researchers are already well on their way to pseudotyping these virus-like particles with fusogens to create an endogenous vector for delivering functional mRNA cargos as a gene therapy. Clearly, some caution in these affairs is warranted.

In heart tissue samples from COVID-19 patients, HERV-W ENV was mainly found in endothelial cells from numerous small blood vessels and in the pericardial fatty tissue. The endothelial nature of HERV-W ENV positive cells was confirmed in this case with CD31 staining. Ominously, significant HERV-W ENV in patients was found in blood clots, nasal mucosa and also in the central nervous system, particularly in microglial cells, even when SARS-CoV-2 could not be detected in those tissues. The authors note that SARS-CoV-2 induced HERV-W ENV expression in human lymphoid cells, cells that neither express the canonical ACE2 receptor, nor the TMPRSS2 protease. This suggests other routes for the virus into these cells. One recent clue to other candidate mechanisms might come from alternative receptors like ASGR1, which is highly expressed in liver cells.

It is now of the utmost importance to find out how SARS-CoV-2 activates HERVs. In light of the known penchant for transposable elements to both be activated by, and further integrate into sites of active DNA repair, it may be worth revisiting earlier studies that purported to show that reverse transcribed SARS-CoV-2 RNA could integrate into the genome of cultured human cells and subsequently express in patient-derived tissues. These authors found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites—features consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism.

Part 3

Comment by Dr. Krishna Kumari Challa on January 25, 2022 at 8:19am

Researchers had previously observed a correlation in the expression of HERV-W ENV protein in T lymphocytes with severe respiratory distress in SARS-CoV-2 patients. However, the exact mechanisms involved were not clear. Now, the real culprit in HERV-W activation has been discovered. Researchers added a recombinant trimeric spike protein without stabilizing mutations to cultured peripheral blood mononuclear cells (PBMCs) from SARS-CoV-2 patients. They found immediate and significant upregulation of the RNAs for the ENV protein from both HERV-W and HERV-K. Curiously, only the RNAs for HERV-W resulted in subsequent ENV protein expression.

Native spike proteins tend to prematurely refold into a post-fusion conformation, which compromises immunogenic properties and prefusion trimer yields. mRNA vaccines therefore have slight modifications that simultaneously make the mRNA less immunogenic, and the spike protein it encodes more immunogenic. One way this has been done is to stabilize specific conformers through the addition of two strategic prolines to the code. However, more research is needed to fully characterize the fusogenic potential of stabilized spike proteins. Some vaccine manufacturers have eliminated the furin cleavage site from their mRNA construct in order to reduce potential residual fusion of a 2-PP stabilized construct. A few of these observations were initially pointed out by some researchers. 

A key finding in these studies is that not all COVID patients had significant HERV-W ENV activation; only 20 or 30 percent of them did. This finding likely reflects an underlying genetic susceptibility among the infected that absolutely needs to be defined and taken into account, particularly if HERV-W is going to be used as a general marker for disease severity, or as a therapeutic target for a humanized monoclonal antibody therapy, as is now envisioned. For example, activation of a soluble hexameric form of HERV-W was found in multiple sclerosis, and is earmarked as potentially druggable option.

Part 2

Comment by Dr. Krishna Kumari Challa on January 25, 2022 at 8:18am

Sars-CoV-2 spike protein activates human endogenous retroviruses in blood cells

Transposable elements, or jumping genes, are now known to be responsible for many human diseases. Keeping them repressed by methylation, RNA binding, or the attentions of the innate immune system is a full-time jump for cells.

Earlier researchers reviewed the activation of one particular kind of transposable element, the Line-1 retrotransposons, in an ever-expanding host of neurodegenerative conditions. Retrotransposons derive from human endogenous retrovirus (HERVs) but typically have lost their signature long terminal repeat sequences at the beginning and ends of their genes.

Recently a real zinger was dropped onto the medRxiv preprint server that could potentially explain many of the commonly observed pathogenic features of SARS-CoV-2. The authors provide solid evidence that the SARS-CoV-2 spike protein activates the envelope (ENV) protein encoded by HERV-W in blood cells, which is in turn directly responsible for many pathological features of the disease. HERV-W is named for the fact that many retroviruses in the group use a tryptophan tRNA in the primer binding site. Apparently, the shape of the letter W somehow reminded the naming committee of the shape of the ring structure of atoms in the side chain of tryptophan.

Part 1

Comment by Dr. Krishna Kumari Challa on January 24, 2022 at 9:29am

A Black Hole Igniting Star Formation in a Dwarf Galaxy

Comment by Dr. Krishna Kumari Challa on January 24, 2022 at 9:09am

The temperature differential the ice is uniquely creating across the water layer has changed what happens in the water itself, because now most of the heat from the hot plate has to go across the water to maintain that extreme differential. So only a tiny fraction of the energy can be used to produce vapor anymore.

The elevated temperature of 550 degrees Celsius for the icy Leidenfrost effect is practically important. Boiling water is optimally transporting heat away from the substrate, which is why you feel ample heat rising from a pot of water that is boiling, but not from a pot of water that is merely hot. This means that the difficulty in levitating ice is actually a good thing, as the larger temperature window for boiling will result in better heat transfer compared to using a liquid alone.

It is much harder to levitate the ice than it was to levitate the water droplet. Heat transfer plummets as soon as levitation begins, because when liquid levitates, it doesn't boil anymore. It's floating over the surface rather than touching, and touching is what causes it to boil the heat away. So, for heat transfer, levitation is terrible. Boiling is incredible.

Practical applications: 

Heat transfer comes most into play for cooling off things like computer servers or car engines. It requires a substance or mechanism that can move energy away from a hot surface, redistributing heat quickly to reduce the wear and tear on metal parts. In nuclear power plants, the application of ice to induce rapid cooling could become an easily-deployed emergency measure if power fails, or a regular practice for servicing power plant parts.

There are also potential applications for metallurgy. To produce alloys, it is necessary to quench the heat from metals that have been shaped in a narrow window of time, making the metal stronger and less brittle. If ice were applied, it would allow heat to be offloaded rapidly through the three water phases, quickly cooling the metal.

A  potential for applications in firefighting: You could imagine having a specially made hose that is spraying ice chips as opposed to a jet of water.

Physical Review Fluids, DOI: 10.1103/PhysRevFluids.00.004000

https://phys.org/news/2022-01-ice-discovery-18th-century-principle....

Part 2

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