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Comment by Dr. Krishna Kumari Challa on January 10, 2024 at 10:31am

Fighting superbugs with medical nanomachines

Instruments smaller than a human hair are being designed to eradicate antibiotic-resistant bacteria and fight cancer.

Because even in an age of antibiotics, people are dying of infections. 'Are we going back in time?' is the question experts are posing as our antibiotics are no longer effective. This is a global challenge. Almost 5 million deaths worldwide were linked to antibiotic-resistant bugs in 2019, according to The Lancet medical journal.

Six types of resistant bacteria inflict the most harm. The World Health Organization has warned that drug-resistant diseases could directly cause 10 million deaths by 2050.

In an arms race, microorganisms evolved various defenses to survive antibiotics.

Antibiotics often latch onto a specific bacterial protein, much like a key fits into a lock. The trouble is that bacteria can undergo a physical change so that the key no longer fits the lock. The antibiotics are left outside.

So the idea behind the nanomachines is that they would be tougher for bacteria to evade as these are bug-killing machines.

Part 1

Comment by Dr. Krishna Kumari Challa on January 10, 2024 at 9:34am

In fruit bats, the compositions of the pancreas and kidneys evolved to accommodate their diet. The pancreas had more cells to produce insulin, which tells the body to lower blood sugar, as well as more cells to produce glucagon, the other major sugar-regulating hormone. The fruit bat kidneys, meanwhile, had more cells to trap scarce salts as they filtered blood.

Zooming in, the regulatory DNA in those cells had evolved to turn the appropriate genes for fruit metabolism on or off. The big brown bat, on the other hand, had more cells for breaking down protein and conserving water. The gene expression in those cells was tuned to handle a diet of bugs.

The organization of the DNA around the insulin and glucagon genes was very clearly different between the two bat species. The DNA around genes used to be considered 'junk,' but new data shows that this regulatory DNA likely helps fruit bats react to sudden increases or decreases in blood sugar.

While some of the biology of the fruit bat resembled what's found in humans with diabetes, the fruit bat appeared to evolve something that humans with a sweet tooth could only dream of: a sweet tooth without consequences. Bats biology has figured it out, and it's all in their DNA, the result of natural selection!

The study benefited from a recent ground swell of interest in studying bats to better human health.  One of the Jamaican fruit bats was used in the sugar metabolism study.

As one of the most diverse families of mammals, bats include many examples of evolutionary triumph, from their immune systems to their peculiar diets and beyond.

Bats are like superheroes, each one with an amazing super power, whether it is echolocation, flying, blood sucking without coagulation, or eating fruit and not getting diabetes.

Scientists are trying to learn all these tricks from bats.

Wei Gordon et al, Nature Communications (2024). www.nature.com/articles/s41467-023-44186-y

Part 2

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Comment by Dr. Krishna Kumari Challa on January 10, 2024 at 9:29am

How fruit bats evolved to consume so much sugar may have implications for diabetes research

A high-sugar diet is bad news for humans, leading to diabetes, obesity and even cancer. Yet fruit bats survive and even thrive by eating up to twice their body weight in sugary fruit every day.

Now scientists have discovered how fruit bats may have evolved to consume so much sugar, with potential implications for the millions of people with diabetes. The findings, published in Nature Communications, point to adaptations in the fruit bat body that prevent their sugar-rich diet from becoming harmful.

 Fruit bats have a genetic system that controls blood sugar without fail. Scientists are learning from that system to make better insulin- or sugar-sensing therapies for people.

They found that the fruit bat pancreas, compared to the pancreas of an insect-eating bat, had extra insulin-producing cells as well as genetic changes to help it process an immense amount of sugar. Additionally, fruit bat kidneys had adapted to ensure that vital electrolytes would be retained from their watery meals.

Even small changes, to single letters of DNA, make this diet viable for fruit bats. We need to understand high-sugar metabolism like this to make progress helping the people who are prediabetic.

Part 1

Comment by Dr. Krishna Kumari Challa on January 10, 2024 at 9:21am

Researchers engineer skin bacteria that are able to secrete and produce molecules that treat acne

International research has succeeded in efficiently engineering Cutibacterium acnes, a type of skin bacterium, to produce and secrete a therapeutic molecule suitable for treating acne symptoms.

The engineered bacterium has been validated in skin cell lines and its delivery has been validated in mice. This finding opens the door to broadening the way for engineering non-tractable bacteria to address skin alterations and other diseases using living therapeutics.

The results of the study, published in Nature Biotechnology, show that researchers have successfully edited the genome of Cutibacterium acnes to secrete and produce NGAL protein known to be a mediator of the acne drug isotretinoin, which has been shown to reduce sebum by inducing the death of sebocytes.

Delivery of a sebum modulator by an engineered skin microbe in mice, Nature Biotechnology (2024). DOI: 10.1038/s41587-023-02072-4

Comment by Dr. Krishna Kumari Challa on January 10, 2024 at 9:03am

Different biological variants discovered in Alzheimer's disease

Scientists recently have discovered five biological variants of Alzheimer's disease, which may require different treatments. As a result, previously tested drugs may incorrectly appear to be ineffective or only minimally effective.

In those with Alzheimer's disease, the amyloid and tau proteins clump in the brain. In addition to these clumps, other biological processes such as inflammation and nerve cell growth are also involved. Using new techniques, the researchers have been able to measure these other processes in the cerebrospinal fluid of patients with amyloid and tau clumps.

Researchers examined 1,058 proteins in the cerebrospinal fluid of 419 people with Alzheimer's disease. They found that there are five biological variants within this group. The first variant is characterized by increased amyloid production. In a second type, the blood-brain barrier is disrupted, and there is reduced amyloid production and less nerve cell growth.
Furthermore, the variants differ in the degree of protein synthesis, the functioning of the immune system, and the functioning of the organ that produces cerebrospinal fluid. Patients with different Alzheimer's variants also showed differences in other aspects of the disease. For example, the researchers found a faster course of the disease in certain subgroups.

The findings are of great importance for drug research. They could mean that a certain drug might only work in one variant of Alzheimer's disease. For example, medication that inhibits amyloid production may work in the variant with increased amyloid production, but may be harmful in the variant with decreased amyloid production. It is also possible that patients with one variant would have a higher risk of side effects, while that risk would be much lower with other variants.

The next step for the research team is to show that the Alzheimer's variants do indeed react differently to medicines, in order to treat all patients with appropriate medicines in the future.

Cerebrospinal fluid proteomics in Alzheimer's disease patients reveals five molecular subtypes with distinct genetic risk profiles, Nature Aging (2024).

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

One common one was polyethylene terephthalate or PET. This was not surprising, since that is what many water bottles are made of. (It is also used for bottled sodas, sports drinks and products such as ketchup and mayonnaise.) It probably gets into the water as bits slough off when the bottle is squeezed or gets exposed to heat. One recent study suggests that many particles enter the water when you repeatedly open or close the cap, and tiny bits abrade.
However, PET was outnumbered by polyamide, a type of nylon that probably comes from plastic filters used to supposedly purify the water before it is bottled. Other common plastics the researchers found: polystyrene, polyvinyl chloride and polymethyl methacrylate, all used in various industrial processes.
A somewhat disturbing thought: the seven plastic types the researchers searched for accounted for only about 10% of all the nanoparticles they found in samples; they have no idea what the rest are. If they are all nanoplastics, that means they could number in the tens of millions per liter.

But they could be almost anything, "indicating the complicated particle composition inside the seemingly simple water sample," the authors write. "The common existence of natural organic matter certainly requires prudent distinguishment."

Rapid single-particle chemical imaging of nanoplastics by SRS microscopy, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2300582121. doi.org/10.1073/pnas.2300582121

Part 2

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

Bottled water can contain hundreds of thousands of previously uncounted tiny plastic bits, study finds

In recent years, there has been rising concern that tiny particles known as microplastics are showing up basically everywhere on Earth, from polar ice to soil, drinking water and food. Formed when plastics break down into progressively smaller bits, these particles are being consumed by humans and other creatures, with unknown potential health and ecosystem effects.

One big focus of research: bottled water, which has been shown to contain tens of thousands of identifiable fragments in each container.

Now, using newly-refined technology, researchers have entered a whole new plastic world: the poorly known realm of nanoplastics, the spawn of microplastics that have broken down even further.

For the first time, they counted and identified these minute particles in bottled water. They found that on average, a liter contained some 240,000 detectable plastic fragments—10 to 100 times greater than previous estimates, which were based mainly on larger sizes.

The study was published in the journal Proceedings of the National Academy of Sciences.

Nanoplastics are so tiny that, unlike microplastics, they can pass through intestines and lungs directly into the bloodstream and travel from there to organs including the heart and brain. They can invade individual cells, and cross through the placenta to the bodies of unborn babies. Medical scientists are racing to study the possible effects on a wide variety of biological systems.

Unlike natural organic matter, most plastics do not break down into relatively benign substances; they simply divide and redivide into smaller and smaller particles of the same chemical composition. Beyond single molecules, there is no theoretical limit to how small they can get.

Microplastics are defined as fragments ranging from 5 millimeters (less than a quarter inch) down to 1 micrometer, which is 1 millionth of a meter, or 1/25,000th of an inch. (A human hair is about 70 micrometers across.) Nanoplastics, which are particles below 1 micrometer, are measured in billionths of a meter.

Plastics in bottled water became a public issue largely after a 2018 study detected an average of 325 particles per liter; later studies multiplied that number many times over. Scientists suspected there were even more than they had yet counted, but good estimates stopped at sizes below 1 micrometer—the boundary of the nano world.

The new study uses a technique called stimulated Raman scattering microscopy .This involves probing samples with two simultaneous lasers that are tuned to make specific molecules resonate. Targeting seven common plastics, the researchers created a data-driven algorithm to interpret the results. It is one thing to detect, but another to know what you are detecting .

The researchers tested three popular brands of bottled water sold in the United States (they declined to name which ones), analyzing plastic particles down to just 100 nanometers in size.
They spotted 110,000 to 370,000 particles in each liter, 90% of which were nanoplastics; the rest were microplastics. They also determined which of the seven specific plastics they were, and charted their shapes—qualities that could be valuable in biomedical research.

Part 1

Comment by Dr. Krishna Kumari Challa on January 9, 2024 at 9:06am

Harnessing haywire cells: The implications of these insights expanded in January 2020. They thought of programming macrophages to eat cancer cells as a novel treatment for the disease, an approach called CAR-M.
They found that adding a CAR receptor to macrophages promoted this behavior. But it was also clear that inducing the macrophages to eat more would make the approach more effective—especially if they would specifically consume, and kill, entire cancer cells.
There is a current cancer treatment called CAR-T, which uses the CAR receptor and a patient's own T-cells to attack and destroy cancers. It is highly effective against some cancers, but there are many that do not respond. CAR-M, a newer cousin to CAR-T, has recently entered into clinical trials in humans and so far seems safe.
Researchers now are interested in harnessing Rac-enhanced CAR macrophages to increase the efficacy of CAR-M treatments. They've filed a provisional patent for the technique—which they call Race CAR-M—and are inviting biotech companies to partner in further developing the approach.
This new multifaceted paper raises both basic science and practical questions, which the lab has begun to tackle. They're investigating whether the technique, which is so effective in the lab, will also work in freshly collected human immune cells and in animal cancer models, in mice and zebrafish. The team is also exploring how Rac2 is making this all happen at the molecular level, deep inside the cells.

 Abhinava K. Mishra et al, Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2310221120

Part 3

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Comment by Dr. Krishna Kumari Challa on January 9, 2024 at 9:02am

Around the time that they made their breakthrough, these researchers caught wind of an intriguing study in the journal Blood. This paper found that three unrelated people suffering from recurrent infections had the exact same mutation, which hyperactivates Rac2, a Rac protein produced in blood cells. They suspected their lab's recent revelation in fruit flies might shed light on this enigma.

The patients' mutation was just mildly activating, and yet it was enough that they all suffered from multiple infections and ultimately needed bone marrow transplants. Blood tests revealed that these patients had nearly no T cells, a specialized kind of white blood cells crucial to the immune system. The team at the National Institutes of Health inserted the Rac2 mutation into mice and found the same mysterious loss of T cells. They also found that the T cells with hyperactive Rac developed normally in the animals' bone marrow, and migrated to the thymus, where they continued to mature without incident. But then they just seemed to disappear. So, the paper ended with a mystery: what was causing the T cells to disappear?

The authors of that journal study had noticed that many of the patients' neutrophils—another type of white blood cell—were enlarged. They seemed to be consuming quite a lot of material, unusual behavior in an otherwise healthy person.
The researchers wondered if the patients' T cells were disappearing because their innate immune cells like neutrophils with active Rac2 were eating them, much like the fruit fly border cells with active Rac were eating the egg chamber. So they turned their attention to macrophages—the neutrophil's more voracious counterpart—to investigate. They cultured human macrophages with and without hyperactive Rac2 together with T cells. They observed that macrophages with hyperactive Rac consumed more cells, confirming the group's hypothesis from their work with fruit flies.

To test whether this might cause the observed immunodeficiency, co-author Melanie Rodriguez (a graduate student in Montell's lab) took bone marrow samples from mice with the same hyperactive Rac2 mutation found in the patients. She then grew the marrow stem cells into macrophages, and performed a similar experiment to earlier researchers' work , but this time mixing both macrophages and T cells with and without the Rac2 mutation.

She found that macrophages with active Rac2 consumed significantly more T-cells than their normal counterparts. However, T-cells with active Rac2 were also more vulnerable to consumption from either kind of macrophage. So the most likely explanation for the patients' missing T cells was a combination of increased consumption by macrophages as well as increased vulnerability of the T cells themselves. A human medical mystery was solved based on fundamental observations in fruit flies.
part 2

Comment by Dr. Krishna Kumari Challa on January 9, 2024 at 8:58am

When bad cells go good: Harnessing cellular cannibalism for cancer treatment

Scientists have solved a cellular murder mystery nearly 25 years after the case went cold. Following a trail of evidence from fruit flies to mice to humans revealed that cannibalistic cells likely cause a rare human immunodeficiency. Now the discovery shows promise for enhancing an up-and-coming cancer treatment.

This paper takes us from very fundamental cell biology in a fly, to explaining a human disease and harnessing that knowledge for a cancer therapy.

The primary character in this story is a gene, Rac2, and the protein it encodes. Rac2 is one of three Rac genes in humans. Rac is very ancient in evolution, so it must serve a fundamental function.

Rac proteins help build a cell's scaffolding, called the cytoskeleton. The cytoskeleton is made of dynamic filaments that allow cells to maintain their shape or deform, as needed. In 1996, while studying a small group of cells in the fruit fly ovary, scientists determined that Rac proteins are instrumental in cell movement. Since then, it has become clear that Rac is a nearly universal regulator of cell motility in animal.

In nineties, they also noticed that a hyperactive form of the Rac1 protein, expressed in only a few cells in a fly's egg chamber, destroyed the whole tissue. Just expressing this active Rac in six to eight cells kills the entire tissue, which is composed of about 900 cells.

A few years ago, evidence began to mount implicating cell eating, also known as cannibalism, in tissue destruction. There's a step in normal fly egg development where certain cells similar to the border cells consume their neighbors because they are no longer needed. Indeed, cellular cannibalism is not as rare as you might expect: Millions of old red blood cells are eliminated from the human body this way every second.

Rac2 is one component of the complex eating process. Rac helps the eating cell to envelop its target. The researchers were curious if a hyperactive form of the protein was causing border cells to prematurely consume their neighbours.

For this to occur, the border cells need to recognize their targets, which requires a particular receptor. Indeed, when  this receptor was blocked by scientists, the border cells expressing activated Rac didn't consume their neighbors, and the egg chamber remained alive and healthy.

Part 1

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