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Comment by Dr. Krishna Kumari Challa on March 20, 2023 at 10:41am

To manipulate the enzyme's role in microglia energy production, the  researchers developed a light-activated tool. Their tool involves shining blue light onto a genetically modified version of the hexokinase-2 enzyme to "switch off" one of its functions.

When this happens, it blocks the enzyme's ability to stick to the energy-generating parts of the microglia and forces the cells to stop relying on an inefficient method of energy production. Experimental results showed that this improves their ability to clear beta amyloid by nearly 20 percent.

However, if hexokinase-2's sticking ability is not blocked and its function is disrupted by simply inactivating the enzyme, it does not help the microglia to clear away waste. This insight provides a critical clue for future drug targets.

Lauren H. Fairley et al, Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2209177120

Part 2

Comment by Dr. Krishna Kumari Challa on March 20, 2023 at 10:41am

Study shows new way to spur brain immune cells to clear toxic waste linked to Alzheimer's disease

A newly discovered "energy switch" in the immune cells of the brain may lead to the development of drugs for Alzheimer's disease, the most common form of dementia.

Scientists discovered that after blocking and turning off this "switch," brain immune cells called microglia were able to remove toxic proteins that can build up and lead to Alzheimer's disease.

Microglia tend to be damaged in people with the disease, which makes them less capable of clearing cellular toxic waste. To restore the clean-up function, the scientists "switched off" their inefficient metabolism by preventing a key enzyme from attaching to energy-generating parts of the immune cells.

The findings from lab experiments set the stage for developing drugs that can specifically target metabolism in brain immune cells in order to treat Alzheimer's disease, which contributes to 60% to 70% of all dementia cases globally. Such drugs are of high interest in health care. 

Researchers had previously shown that drugs that activated the toxic protein led to less toxic waste build-up in the brain, which improved the condition of mice with Alzheimer's disease. But how this worked was not clear.

The researchers now cracked the puzzle with their latest experiments on cells from mice with Alzheimer's. Their work revealed that the translocator protein is critical for the microglia immune cells of the brain to generate their own energy.

Microglia perform the important function of "gobbling up" and removing beta amyloid, a toxic protein whose build-up in the brain causes damage and death to nerve cells, resulting in Alzheimer's disease. To do their job properly and remove the toxic waste, the immune cells need a lot of energy.

The researchers showed that without the translocator protein, microglia from mice with Alzheimer's had an energy problem and could not remove the beta amyloid, which resulted in the disease worsening in the mice.

 Microglia lacking the translocator protein resembled damaged microglia observed in aging and Alzheimer's disease. These damaged microglia inefficiently produced energy and could not clean up toxic waste in mice with Alzheimer's disease.

The experiments also demonstrated that when the translocator protein is absent, an enzyme called hexokinase-2, which metabolizes sugar, kicks into action in microglia to compensate. The enzyme promotes an inefficient way for cells to produce energy. What was surprising was that hexokinase-2 became activated when it stuck to the energy-generating parts of cells called mitochondria.

The researchers found that hexokinase-2 was also activated in microglia when exposed to more toxic forms of beta amyloid, just as happens in Alzheimer's disease. The scientists believe this finding helps to partly explain how microglia fail in patients with Alzheimer's disease and when people age.
Part1

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 1:36pm

How DNA-PK Facilitates Repair from Double-Stranded DNA Breaks

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 1:34pm

When someone sneezes on Everest, their germs can last for centuries

Almost five miles above sea level in the Himalayan mountains, the rocky dip between Mount Everest and its sister peak, Lhotse, lies windswept, free of snow. 

According to new research, mountaineers visiting this place are leaving behind a frozen legacy of hardy microbes, which can withstand harsh conditions at high elevations and lie dormant in the soil for decades or even centuries.

The research not only highlights an invisible impact of tourism on the world’s highest mountain, but could also lead to a better understanding of environmental limits to life on Earth, as well as where life may exist on other planets or cold moons.

The research not only highlights an invisible impact of tourism on the world’s highest mountain, but could also lead to a better understanding of environmental limits to life on Earth, as well as where life may exist on other planets or cold moons. The findings were published last month in Arctic, Antarctic, and Alpine Research.

There is a human signature frozen in the microbiome of Everest, even at that elevation.

In decades past, scientists have been unable to conclusively identify human-associated microbes in samples collected above 26,000 feet. This study marks the first time that next-generation gene sequencing technology has been used to analyze soil from such a high elevation on Mount Everest, enabling researchers to gain new insight into almost everything and anything that’s in them.

The researchers weren’t surprised to find microorganisms left by humans. Microbes are everywhere, even in the air, and can easily blow around and land some distance away from nearby camps or trails.

If somebody even blew their nose or coughed, that's the kind of thing that might show up. Certain microbes which have evolved to thrive in warm and wet environments like our noses and mouths were resilient enough to survive in a dormant state in such harsh conditions.

Most of the microbial DNA sequences they found were similar to hardy, or “extremophilic” organisms previously detected in other high-elevation sites in the Andes and Antarctica. The most abundant organism they found using both old and new methods was a fungus in the genus Naganishia that can withstand extreme levels of cold and UV radiation.

But researchers also found microbial DNA for some organisms heavily associated with humans, including Staphylococcus, one of the most common skin and nose bacteria, and Streptococcus, a dominant genus in the human mouth.

At high elevation, microbes are often killed by ultraviolet light, cold temperatures and low water availability. Only the hardiest critters survive. Most—like the microbes carried up great heights by humans—go dormant or die, but there is a chance that organisms like Naganishia may grow briefly when water and the perfect ray of sunlight provides enough heat to help it momentarily prosper. But even for the toughest of microbes, Mount Everest is a Hotel California: “You can check out any time you like/ But you can never leave.”

The researchers don’t expect this microscopic impact on Everest to significantly affect the broader environment. But this work does carry implications for the potential for life far beyond Earth, if one day humans step foot on Mars or beyond.

https://www.colorado.edu/today/2023/03/14/when-someone-sneezes-ever...

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 1:17pm

Sweetener reduces mouse immune response

In high doses, the calorie-free sugar substitute sucralose suppresses the immune system in mice. The sweetener impairs the rodents’ T cells, immune cells that fight.... Once the mice stopped being fed sucralose, their T-cell responses recovered. The researchers say that it is unlikely that eating sucralose in normal amounts is harmful to humans. There might even be a bright side for autoimmune conditions: mice predisposed to type 1 diabetes were less likely to develop the condition after consuming the sweetener.

https://www.nature.com/articles/s41586-023-05801-6.epdf?sharing_tok...

https://www.nature.com/articles/d41586-023-00784-w?utm_source=Natur...

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 12:45pm

How tumors transform blood vessels

Increasingly dense cell clusters in growing tumors convert blood vessels into fiber-filled channels. This makes immune cells less effective, as findings by researchers suggest.

It was almost ten years ago that researchers first observed that tumours occurring in different cancers—including colorectal cancer, breast cancer and melanoma—exhibit channels leading from the surface to the inside of the cell cluster. But how these channels form, and what functions they perform, long remained a mystery.

Through a series of elaborate and detailed experiments, scientists  have found possible answers to these questions. There is a great deal of evidence to suggest that these channels, which the researchers have dubbed tumour tracks, were once blood vessels.

These blood vessels start out by supplying the fast-growing cell clusters with glucose and oxygen. But then the vessels undergo a process that strips them of their original function of transporting blood: the vessel walls change and the vessel cavity gradually fills up.

This filler material consists mainly of cells and newly formed protein fibers, which make up what is known as the extracellular matrix. Collagen fibers are found here, as are fibronectin fibers. The latter play a role in growth processes that take place mainly during embryonic development or wound healing. In their article, the researchers show that the fibers within the tumor tracks are capable of trapping immune cells.

While this happens, the immune cells stretch out along the channels and stick to the loose fibronectin fibers. In this elongated form, the immune cells switch from fighting diseases to supporting healing processes. Instead of attacking the tumour cells, they excrete molecules that stimulate growth, thus helping the cancer cells to multiply.

It becomes clear that the tension of extracellular matrix fibers plays a key and previously unknown role in tumor development: in healthy tissue, the fibronectin fibers are stretched extremely taut; only in tumor tissue are they slack. In this looser, more relaxed form, surrounded by transformed blood vessel walls, the fibronectin fibers evidently create a recess in which cancer cells can grow undisturbed.

Charlotte M. Fonta et al, Infiltrating CD8+ T cells and M2 macrophages are retained in tumor matrix tracks enriched in low tension fibronectin fibers, Matrix Biology (2023). DOI: 10.1016/j.matbio.2023.01.002

Devadarssen Murdamoothoo et al, Tenascin‐C immobilizes infiltrating T lymphocytes through CXCL12 promoting breast cancer progression, EMBO Molecular Medicine (2021). DOI: 10.15252/emmm.202013270

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 12:34pm

An extra X chromosome-linked gene may explain decreased viral infection severity in females

It has long been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery—until possibly now. The key may lie in an epigenetic regulator that boosts the activity of specialized anti-viral immune cells known as natural killer (NK) cells.

In a study published March 16 in the peer-reviewed journal Nature Immunology, a collaborative team of  researchers have found that female mouse and human NK cells have an extra copy of an X chromosome-linked gene called UTX. UTX acts as an epigenetic regulator to boost NK cell anti-viral function, while repressing NK cell numbers.

While it is well-known that males have more NK cells compared to females, researchers did not understand why the increased number of NK cells was not more protective during viral infections. It turns out that females have more UTX in their NK cells than do males, which allows them to fight viral infections more efficiently.

The researchers noted that this held true whether or not the mice had gonads (ovaries in females; testes in males), indicating that the observed trait was not linked to hormones. Furthermore, female mice with lower UTX expression had more NK cells which were not as capable of controlling viral infection.

This implicates UTX as a critical molecular determinant of sex differences in NK cells.

The findings suggest that therapies involving immune responses need to move beyond a "one-size-fits-all" approach and toward a precision medicine model, also known as personalized medicine, that tailors treatments that take into account people's individual differences, such as genetics, environment and other factors that influence health and disease risk, the researchers write.

Mandy I. Cheng et al, The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences, Nature Immunology (2023). DOI: 10.1038/s41590-023-01463-8

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 12:23pm

The authors discuss some limitations of their study. The findings' generalizability to soccer players playing today is uncertain. As neurodegenerative disease usually occurs later in life, most players in the study who were old enough to have developed one of these conditions played elite soccer during the mid-20th century. Since then, soccer has changed in many ways that may impact the risk of neurodegenerative disease. It may be that switching from leather to synthetic balls (that do not soak up water and become heavier), having more rigorous training and better equipment, or switching towards a playstyle associated with less head trauma may have reduced the risk. On the other hand, the risk might be higher among soccer players who nowadays train and play more intensely from a young age. The study also looked at male elite soccer players only, so the study's generalizability to female elite players and to male and female amateur and youth players is uncertain.

Neurodegenerative disease among male elite football (soccer) players in Sweden: a cohort study, The Lancet Public Health (2023). DOI: 10.1016/S2468-2667(23)00027-0 , www.thelancet.com/journals/lan … (23)00027-0/fulltext

Part 2

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Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 12:23pm

Elite soccer players are more likely to develop dementia, suggests new study

Elite male soccer players were 1.5 times more likely to develop neurodegenerative disease than population controls, according to an observational study published in The Lancet Public Health journal.

Among male soccer players playing in the Swedish top division, 9% (537 out of 6,007) were diagnosed with neurodegenerative disease, compared to 6% (3,485 out of 56,168) population controls.

The soccer players were both amateur and professional. Sweden was a prominent soccer nation during the 20th century and many of the players from the top division were competing at the highest international level. However, due to ideals of sportsmanship and amateurism, soccer clubs in Sweden were not allowed to pay salaries to their soccer players until the late 1960s.

In recent years, there have been growing concerns about exposure to head trauma in soccer (soccer) and whether it can lead to increased risk of neurodegenerative disease later in life. A previous study from Scotland suggested that soccer players were 3.5 times more likely to develop neurodegenerative disease. Following this evidence, certain footballing associations implemented measures to reduce heading in younger age groups and training settings.

While the risk increase in this study is slightly smaller than in the previous study from Scotland, it confirms that elite [soccer players] have a greater risk of neurogenerative disease later in life. As there are growing calls from within the sport for greater measures to protect brain health, this new study adds to the limited evidence base and can be used to guide decisions on how to manage these risks.

The authors caution that although 9% of soccer players and 6% of controls were diagnosed with neurodegenerative disease during their study, most participants were still alive at the end of data collection, so the lifetime risks of developing neurodegenerative disease for both groups are likely to be higher.

The risk of neurodegenerative disease was 1.5 times higher for outfield players than controls but was not significantly higher for goalkeepers compared to controls. Accordingly, in a direct comparison, outfield players had a risk of neurodegenerative disease 1.4 times higher than that of goalkeepers.

Soccer players had a risk of Alzheimer's disease and other dementias 1.6 times that of controls—with 8% (491 out of 6,007) of soccer players being diagnosed with the condition compared to 5% (2889 out of 56,168) of controls.

Part 1

Comment by Dr. Krishna Kumari Challa on March 18, 2023 at 12:17pm

New tool for organ repair: curvature of the environment

A ball, a saddle, or a flat plate. The curvature of biomaterials inhibits or stimulates bone cells to make new tissue. This is what TU Delft engineers show in research published in Nature Communications. This study of geometries could be an important step in research into repairing damaged tissues. In this video, Amir Zadspoor (professor of Biomaterials and Tissue Biomechanics) and Lidy Fratila-Apachitei (assistant professor of Biomaterials) explain exactly how this new tool for organ repair works.

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