Comment

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:54am

The tumour microenvironment is an inhospitable ecosystem. “For bacteria, they kind of don't care about all of that. They are really, at a very general level, looking for a place where they can survive in the body that's away from the immune system.

The hypoxic, minimally surveilled core of a solid tumor is the perfect bacterial bungalow. However, some bacterial strains can still inhabit healthy organs, so researchers need to explore ways to modify the bacterial genome to reduce virulence and toxicity. Although attenuated bacteria proved safer in both mice and humans, researchers observed poor tumor colonization and no tumor regression. Now, to improve tumor targeting and specificity, researchers are searching for synthetic biology solutions.

Bacteria already have a proclivity for the tumor microenvironment.

So researchers engineered the probiotic strain Escherichia coli Nissle 1917, which was equipped with Danino’s quorum sensing lysis circuit. Once the bacteria reached quorum, they released synthetic antigens that stuck to the tumor. Specifically, the researchers fused a green fluorescent protein (GFP) to the heparin binding domain (HBD) of a placental growth factor protein.¹⁰ The sticky HBD anchored to collagens and polysaccharides, ubiquitous components in the tumor environment, thus planting GFP flags on the tumor. Although these molecules are found in healthy tissue, they are highly abundant in the tumour.

Part 2

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:51am

Bugs as Drugs to Boost Cancer Therapy

Bioengineered bacteria sneak past solid tumor defenses to guide CAR T cells’ attacks.

n the 1890s, physician William Coley injected patients who had cancer with bacteria after learning about patients who experienced spontaneous tumor regression following a concurrent bacterial infection.  He was one of the first scientists to link immune system activation with an antitumor response, which earned him the appellation, “the father of immunotherapy.” Despite some successes in the clinic, safety concerns and the rise of radiotherapy caused these bacterial elixirs, known as Coley’s toxins, to fall by the wayside.

Over the last few decades, advancements across immunology, microbiology, and synthetic biology renewed interest in bioengineering bugs for cancer therapies. In a paper published in Science, researchers designed probiotics to colonize tumors and guide engineered T cells to the cancer site.

 Their novel platform not only shows that engineered bacteria can help existing immunotherapies gain access to difficult-to-treat solid tumors, but also highlights the broader potential of living drugs.

Part 1

Comment by Dr. Krishna Kumari Challa on January 20, 2024 at 9:18am

Energy supply in human cells is subject to quality control, researchers discover

Researchers have discovered a new quality control mechanism that regulates energy production in human cells. This process takes place in mitochondria, the power plants of the cell.

Malfunctions of mitochondria lead to serious diseases of the nerves, the muscles and the heart. The findings could contribute to the development of new therapies for affected patients. The results have been published in Molecular Cell.

Mitochondria play a central role for cellular metabolism. Therefore, malfunctions of the mitochondria lead to serious, often fatal, heart, muscle or nerve diseases. Mitochondria are surrounded by two membranes, an outer and an inner one, which separate them from the surrounding cell. The final conversion of food into energy takes place in the inner membrane. Proteins are involved in this process. Central proteins for energy production are formed in the mitochondria, transported to the inner membrane and inserted there.

The protein OXA1L is mainly responsible for the insertion of proteins into the membrane, where larger complex structures are formed with other proteins that interact with each other and ensure energy production. How the incorporation and assembly of these structures works in detail has been poorly investigated thus far.

Scientists have now discovered that the process of energy production depends on the interaction of the protein OXA1L with the protein TMEM126A.

If TMEM126A is missing, a quality control mechanism is activated in the inner membrane of the mitochondria, which ensures that OXA1L and proteins newly generated for the energy production machinery are degraded and thus cannot be incorporated into the membrane. This shows that the protein TMEM126A is critical for energy production in mitochondria. "This finding is an important step in the search for new therapeutic approaches for affected patients. Understanding how proteins interact with each other in mitochondria could help to identify the causes of certain diseases. If we know what is missing in the cell or which process is not working properly in certain diseases, we can develop treatment measures to 'repair' this defect.

Sabine Poerschke et al, Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria, Molecular Cell (2024). DOI: 10.1016/j.molcel.2023.12.013

Comment by Dr. Krishna Kumari Challa on January 20, 2024 at 9:07am

To test the efficacy of the Paride phage, the researchers paired it with an antibiotic called meropenem. This disrupts cell wall synthesis and so it interferes only with cellular processes that don't damage the phages. The antibiotic has no effect on dormant bacteria, as these don't synthesize a new cell wall.

When tested in cell culture dishes, the virus was able to kill 99% of all dormant bacteria but left 1% alive. Only the combination of Paride phages and meropenem was able to eradicate the bacterial culture completely, even though the latter had no detectable effect on its own.

In a further experiment  other researchers tested this combination on mice with a chronic infection. Neither the phage nor the antibiotic alone worked particularly well in the mice, but the interaction between phages and antibiotics proved to be very effective in living organisms as well.

In the case of chronic infections, that means it would be important to know the physiological state of the bacteria in question. Then the right phages, combined with antibiotics, could be used in a targeted manner. However, you need to know exactly how a phage attacks a bacterium before you can select the right phages for a particular treatment.

The researchers will now investigate precisely how the new phage brings bacteria out of deep sleep, infects them and makes them susceptible to antibiotics.

Enea Maffei et al, Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication, Nature Communications (2024). DOI: 10.1038/s41467-023-44157-3

Comment by Dr. Krishna Kumari Challa on January 20, 2024 at 9:05am

Researchers discover rare phages that attack dormant bacteria

In nature, most bacteria live on the bare minimum. If they experience nutrient deficiency or stress, they shut down their metabolism in a controlled manner and go into a resting state. In this stand-by mode, certain metabolic processes still take place that enable the microbes to perceive their environment and react to stimuli, but growth and division are suspended.

This also protects bacteria from, say, antibiotics or from viruses that prey exclusively on bacteria. Such bacteria-infecting viruses, known as phages, are considered a possible alternative to antibiotics that are no longer (sufficiently) effective due to drug resistance. Until now, expert consensus held that phages successfully infect bacteria only when the latter are growing.

Then researchers asked themselves now whether evolution might have produced bacteriophages that specialize in dormant bacteria and could be used to target them. They began their search in 2018. Now, in a new publication in the journal Nature Communications, they show that such phages, though rare, do indeed exist.

They found them first in rotting plant material and this virus can infect and destroy dormant bacteria. This is the first phage described in the literature that has been shown to attack bacteria in a dormant state. They have named their new phage Paride.

The virus the researchers found infects Pseudomonas aeruginosa, a bacterium commonly found in many environments. Various strains colonize bodies of water, plants, the soil—and people. In the human body, certain strains can cause serious respiratory diseases such as pneumonia, which can be fatal. How the new phage takes dormant P. aeruginosa germs by surprise, however, is not yet clear to the researchers. They suspect that the virus uses a specific molecular key to awaken the bacteria, and then hijacks the cell's multiplication machinery for its own reproduction. However, the researchers have not yet been able to clarify exactly how this works.

They now aim to elucidate the genes or molecules that underlie this awakening mechanism. Based on this, they could develop substances in a test tube that take over the wake-up process. Such a substance could then be combined with a suitable antibiotic that completely eliminates the bacteria.

Part 1

Comment by Dr. Krishna Kumari Challa on January 19, 2024 at 9:56am

What's more, they found the state of the patient's gut microbiome as well as the clearance of the tuberculosis bacteria itself are linked to recovery from tuberculosis-driven inflammation. Blooms of bacteria from the Enterobacteriaceae family post-treatment led to more widespread inflammation, whereas microbiomes with more Clostridia and fewer Enterobacteriaceae were associated with a faster drop in the inflammation that drives tuberculosis symptoms.

Further tests in mice involving fecal transplants from the patients revealed their microbiomes had acquired a resistance to subsequent antibiotic disruption. These resistance genes were still seen in some of the friendly bacterial species a year after antibiotic treatments had ceased in the mice.
These mutations may have a fitness benefit in the microbiome ecosystem established by long-term antibiotics.

https://www.science.org/doi/10.1126/scitranslmed.adi9711

part 2

Comment by Dr. Krishna Kumari Challa on January 19, 2024 at 9:55am

Gut Bacteria Is Surprisingly Resilient to Antibiotics, Long-Term Study Shows

Antibiotic resistance is causing us all sorts of havoc. It's turning once manageable pathogens into superbugs, hitting our most vulnerable people the hardest. Superbugs were involved with nearly 5 million deaths globally in 2019, so antibiotic resistance is generally not something we at all want to promote in the slightest. But while it's boosting our bacterial nemeses, resistance factors mean our good bacteria are becoming more resistant to antibiotics as well. A new study has found antibiotic resistance genes is also giving our gut bacteria an advantage, allowing them stay on top in their never ending battle against microbes that cause us harm. Antimicrobial resistance mutations in commensals can have paradoxically beneficial effects by promoting microbiome resilience to antimicrobials. researchers investigated the war between good and bad gut bacteria within 24 patients who have multidrug-resistant tuberculosis (Mycobacterium tuberculosis), detailing the battle in a blow-by-blow account. The patients had received numerous types of antibiotics to keep their illness at bay, a regime they were required to maintain for 20 months. Treatment initially devastated their gut microbiomes, causing disruptions in the metabolism, composition, and diversity of bacterial species. Unpleasant side effects included diarrhea and gut inflammation, which isn't surprising given antibiotic use has also been linked to increased cases of irritable bowel syndrome. Yet over time, something rather surprising was observed among the patients. The study findings document an unexpected resilience of the microbiome to disruption by long-term antibiotics, write the researchers, explaining how the microbiomes in the patients spontaneously reestablished the dominance of friendly bacteria in the wake of initial imbalance.

Part 1

Comment by Dr. Krishna Kumari Challa on January 18, 2024 at 12:26pm

In an investigation led by Ocean University of China geophysicist Lin Liu, researchers amassed 'up-and-down' S-wave and shear-wave splitting data from 94 broadband seismic stations arranged west-to-east across southern Tibet, and combined it with previously collected 'back-and-forth' P-wave data to come up with a more nuanced view of the dynamics below.

They determined the Indian slab wasn't merely bobbing along smoothly below the Eurasian plate, nor was it bunching up like a rug on a slippery floor.

Instead it is delaminating, with its dense base peeling free and sinking into the mantle as its lighter top-half continued its journey just beneath the surface.

While computer models had suggested thicker sections of some plates could come apart like this, the study provides the first empirical evidence of it occurring.

The team's description is consistent with geological models based on limits of helium-3 enriched spring water and patterns of fractures and earthquakes near the surface, which taken together support a map of carnage below, where sections of the old Indian plate seem more or less intact, and others are stripping apart around 100 kilometers below, allowing the base to warp into the planet's molten heart.

Having a clear 3D description of the boundaries and borders of plates as they grind together not only makes it easier to understand how our surface came to look as it does, but could inform future methods of earthquake prediction.

The study was presented at the 2023 American Geophysical Union conference. A pre-print copy of the study is available online.

https://www.sciencealert.com/indian-tectonic-plate-is-splitting-in-...

Part 2

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Comment by Dr. Krishna Kumari Challa on January 18, 2024 at 12:25pm

Indian Tectonic Plate Is Splitting in Two Beneath Tibet, Latest Analysis Finds

The engines driving the growth of the world's highest mountains into the sky run deep beneath the planet's skin. Geologists have some idea of the mechanisms at work, but evidence has so far left plenty of room for debate over the details.

Combined with a fresh look at previous research, a recent analysis of new seismic data collected from across southern Tibet has delivered a surprising depiction of the titanic forces operating below the Himalayas.

Presenting at the American Geophysical Union conference in San Francisco last December, researchers from institutions in the US and China described a disintegration of the Indian continental plate as it grinds along the basement of the Eurasian tectonic plate that sits atop it. It's a surprising compromise on two models currently favored as explanations for the lifting of the Tibetan plateau and the colossal Himalayan mountain range.

In both cases, a collision between the chunks of crust belonging to India and Eurasia is responsible. Starting around 60 million years ago, the Indian plate was driven beneath its northern neighbor as it was carried along by currents of molten rock within the mantle.

Bit by bit, the Eurasian land mass has been lifted skyward on the shoulders of a drowned giant, giving us Earth's highest elevations.

Studies of the density of the mantle and the crust suggest the rather buoyant Indian continental plate shouldn't sink so easily, however, meaning it's likely the submerged sections of the crust should still be grinding along under the belly of the Eurasian plate rather than being plunged into the mantle's depths.

Another possibility is the Indian plate is distorting in a way that causes some parts to wrinkle and fold, and others to dip and dive.

Different perspectives emerge depending on which kinds of evidence are favored and how data is processed.

Part 1

Comment by Dr. Krishna Kumari Challa on January 18, 2024 at 11:20am

Study finds microplastics from natural fertilizers are blowing in the wind more often than once thought

Though natural fertilizers made from treated sewage sludge are used to reintroduce nutrients onto agricultural fields, they bring along microplastic pollutants too. And according to a small-scale study published in Environmental Science & Technology Letters, more plastic particles get picked up by the wind than once thought. Researchers have discovered that the microplastics are released from fields more easily than similarly sized dust particles, becoming airborne from even a slight breeze.

Microplastics, or small bits of plastic less than 5 millimeters long, have appeared everywhere from clouds to heart tissues. And with these plastics' increasing prevalence in people and water supplies, they've also been found in sewage and wastewater.

Though sewage solids might not immediately seem like a useful product, after treatment they can form "biosolids," which are applied to agricultural soils as a natural, renewable source of fertilizer.
According to estimates by the U.S. Environmental Protection Agency, over 2 million dry metric tons of biosolids—roughly half of the total amount collected by wastewater treatment plants—are applied to land each year.

As a result, microplastics in these biosolids have the chance to reenter the environment. Because the plastics could carry other pollutants from the wastewater they originated from, they can be potentially dangerous when inhaled.
Researchers analyzed airborne microplastics in wind-blown sediments that were gathered during wind-tunnel experiments on two plots of biosolid-treated land in rural areas.
The researchers discovered that these wind-blown sediments contained higher concentrations of microplastics than either the biosolids or the source soil itself. This enrichment effect is caused by the plastic particles being less dense than soil minerals, such as quartz, and less "sticky"—they're not trapped as easily by moisture as the soil minerals are.

As a result, microplastics can be picked up by a breeze more easily than soil minerals, and winds that might not be strong enough to kick up dust could still be introducing microplastics into the air.

The researchers say that previous models did not take this sticky effect and other unique properties of microplastics into account when estimating emissions from treated fields. Therefore, these older models are likely to underestimate the actual amount of plastic particles released into the air.
The present work indicate that microplastics may be emitted from barren agricultural fields from nearly two and a half times more wind events than previously estimated.

 Preferential Emission of Microplastics from Biosolid-Applied Agricultural Soils: Field Evidence and Theoretical Framework, Environmental Science & Technology Letters (2024). DOI: 10.1021/acs.estlett.3c00850

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