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Discovery of a protein that causes early dementia

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Discovery of a protein that causes early dementia

Discovery of a protein that causes early dementia. Scientists at the MRC Molecular Biology Laboratory have succeeded in identifying a protein that plays a major role in early-onset dementia and could revolutionize the diagnosis and treatment of this disease.

Discovery of a protein that causes early dementia

According to SD, scientists at the MRC Molecular Biology Laboratory have identified protein aggregations known as TAF15 as a key factor in frontotemporal dementia, a discovery that could revolutionize the diagnosis and treatment of this disease.

This study also investigates the potential involvement of TAF15 in both frontotemporal dementia and motor neuron disease.

Therefore, the researchers of this laboratory have created the first potential therapeutic target for a form of early dementia.

Most neurodegenerative diseases, including dementia, are caused by proteins that accumulate in strands called amyloids.

In most of these diseases, researchers have identified proteins that accumulate, allowing them to target these proteins for diagnostic tests and treatments. But in about 10% of cases of frontotemporal dementia, scientists have not yet identified the rogue protein that causes it.

Now scientists have identified the TAF15 protein aggregate structures as the cause of this disease.

The nature of frontotemporal dementia

Frontotemporal dementia is caused by damage to the frontal and temporal lobes of the brain, which control emotions, personality, and behavior, as well as speech and word comprehension.

The disease usually starts at a younger age than Alzheimer’s disease and is most often diagnosed in people between the ages of 45 and 65, although it can affect younger or older people as well.

In an article recently published in the journal Nature, research led by scientists at the Medical Research Council (MRC) Molecular Biology Laboratory in Cambridge, UK, has identified protein aggregation structures that could be a target for the future development of diagnostic tests and treatments.

Advances in molecular understanding

Dr Benjamin Riskeldi-Falcon, who led the study at the MRC Laboratory of Molecular Biology, said: “This discovery changes our understanding of the molecular basis of frontotemporal dementia. This is a rare finding of a new member of a small group of proteins that accumulate in neurodegenerative diseases.

He added: “Now that we have identified this key protein and its structure, we can target it to diagnose and treat this type of dementia, exactly the same as the strategies currently used to target the entire amyloid beta and tau proteins that The symptoms of Alzheimer’s disease are in progress.

Advanced techniques reveal new insights

Scientists used advanced cryo-electron microscopy (cryo-EM) to study protein clumps from donated brains of four people with this type of frontotemporal dementia at atomic resolution.

Scientists have long thought that a protein called FUS builds up in this type of dementia, based on similarities it has with other neurodegenerative diseases.

Using advanced cryo-electron microscopy, researchers at the MRC Molecular Biology Laboratory were able to determine that the protein aggregates of each brain have the same atomic structure, and surprisingly, this protein was not FUS, but another protein called TAF15.

Dr. Stephen Teter from the MRC’s Laboratory of Molecular Biology, who is the lead author of the paper, said: “This is an unexpected result because, before this study, TAF15 was not known to form amyloid fibrils in neurodegenerative diseases and no structure of this protein was available. did not have.

“Advanced cryo-electron microscopy is changing our understanding of the molecular pathology of dementia and neurodegenerative diseases more broadly by providing insights beyond the capabilities of our previous technologies,” he added.

“The technical challenge of doing this with advanced cryo-electron microscopy meant we could only look at the brains of four people,” says Dr Riskeldi-Falcon. However, now that we know this key protein and its structure, we have the potential to develop tools to screen these abnormal protein clumps in hundreds of patient samples to test how widespread they are.

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Discovery of a protein that causes early dementia

Frontotemporal dementia and Lou Gehrig’s disease

Some people with frontotemporal dementia also have Lou Gehrig’s disease, or motor neuron disease, which is a condition in which people gradually lose control of their muscles.

In this study, two of the people who donated their brains had symptoms of both diseases and for these people, the researchers identified the same TAF15 aggregate structure in brain regions associated with motor neuron disease.

The presence of identical TAF15 clusters in two individuals with frontotemporal dementia and symptoms of motor neuron disease raises the possibility that TAF15 may play a role in both diseases, says Dr. Riskeldi-Falcon.

He added: “We are currently studying whether there is aberrant accumulation of TAF15 in people who only have motor neuron disease and do not have frontotemporal dementia.”

Dr Charlotte Durkin, Chair of the Molecular and Cellular Medicine Board at the Medical Research Council, said: “Decades of world-leading research at the MRC Molecular Biology Laboratory led to the development of advanced cryo-electron microscopy, which won Dr Richard Henderson the 2017 Nobel Prize.

He added: This latest study, which identifies a protein associated with a type of frontotemporal dementia, continues our center’s success in elucidating protein structures associated with dementia by advanced cryo-electron microscopy.
In the end, he said: knowing the identity and main structure of these fibers in this rare form of early dementia is crucial for the development of early diagnostic tests and drugs to combat their formation.

The study was funded and supported by the Medical Research Council, Alzheimer’s Research England, the US National Institutes of Health, the Alzheimer’s Association, the Frontotemporal Dementia Association, and the Swiss National Science Foundation.

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The study that first showed the benefits of ADHD

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ADHD

In a new study, it has been hypothesized that some genetic traits associated with attention deficit hyperactivity disorder (ADHD) can actually be beneficial by increasing exploratory behaviors.

The study that first showed the benefits of ADHD

While current diagnostic definitions of attention-deficit/hyperactivity disorder (ADHD) are relatively new, the condition has been recognized and defined by clinicians under various names for centuries.

According to NA, recent genetic studies have shown that this disease is highly hereditary, which means that most people with this disease genetically inherited it from their parents.

Depending on the diagnostic criteria, between 2% and 16% of children can be classified as having ADHD. In fact, the increase in diagnosis rates in recent years has led some doctors to argue that the disease is overdiagnosed.

What is relatively clear, however, is that the behavioral traits that underlie ADHD have potentially been genetically present in human populations for a long time, leading some researchers to speculate on the evolutionary advantages of this What could be the conditions?

Imagine you are part of a wandering tribe of early humans. Your group comes across a field full of one type of fruit and everyone is faced with one big question. Do you settle on a farm and exploit its fruit supply until it’s all gone, or do you quickly pick up what you can and continue exploring for more diverse foods?

This opposition to exploitation or exploration is fundamental to the survival of all animals. At what point does the risk of staying in one place outweigh the risk of moving to find what’s next?

In the early 2000s, a team of scientists studied the genetics of a unique tribe of people in northern Kenya. This tribe, known as Ariaal, has traditionally been incredibly nomadic and nomadic since ancient times, and they have continued to live in this way. Some members of the Arial tribe settled down during the 20th century and adopted modern farming methods, while others continued to live as nomadic herders.

Read More: Flu-killer cells have been discovered in the lungs

Scientists compared the genetic and health differences between these two groups of the Arial tribe and discovered something incredibly interesting. In general, all people of the Arial tribe carry a unique genetic mutation called DRD4/7R. This genetic trait has previously been commonly identified in people with ADHD.

This genetic mutation in today’s children who have been diagnosed with ADHD is generally associated with restlessness and distraction, and in those children of the Ariel tribe who were used to the behaviors of staying still settling down, and avoiding moving, this gene was associated with health. Poor and disruptive behaviors in class were related. But in Aryalees who still lived a traditional nomadic life, this gene mutation was associated with better nutritional health and strength.

The DRD4/7R mutation is associated with increased food and drug cravings, novelty seeking, and ADHD symptoms, explained Dan Eisenberg, lead author of the 2008 study. It is possible that in a nomadic environment, a boy with this gene mutation would be able to more effectively defend livestock against invaders or find water and food sources, but these same tendencies may be limited to fixed jobs such as setting up a school, farming, or selling goods. not useful

So an interesting hypothesis emerged. Whether the genetic traits of ADHD can be somewhat beneficial to a tribe, as it predisposes some individuals to “exploration” What appears in modern times as unrest and restlessness could actually have been beneficial to tribes that were looking for food.

David Barak from the University of Pennsylvania along with a team of colleagues tested this hypothesis experimentally. They produced a unique game where players were given eight minutes to collect as many berries as possible by hovering over a bush. Each time they picked berries from a bush, the player’s harvest was reduced slightly, but if they went to a new bush, there was a time penalty.

So what did most players do? Did they stick to the original bush? Or risk wasting time trying another plant to see if it bears more fruit? The same basic question, exploration or exploitation?

About 450 people participated in this experiment and all were simultaneously screened for ADHD symptoms. Not surprisingly, the researchers found that people with higher ADHD scores reached out to new plants sooner than others, but more importantly, people with ADHD tended to collect a larger volume of berries overall.

In a recently published study, Barak and his colleagues noted that participants without ADHD traits tended to overeat individual plants.

Finally, looking at the optimal withdrawal strategy for this game, it was found that players with high ADHD scores were more successful overall.

“We found that participants who screened positive for ADHD gave up the bushes more easily and achieved higher rates of reward than participants who screened negative,” the researchers wrote in their conclusion. Given that participants stayed more on a plant in general, those with high ADHD scores made more exploratory decisions, consistent with the predictions of optimal search theory, and thus behaved more optimally.
It should be noted that these findings do not represent a definitive verdict on the possible evolutionary benefits of ADHD, but they provide compelling and plausible reasons why a small percentage of humans still have these traits.

In the 21st century, we may have pathologized ADHD as a negative disorder, but this could simply be because these characteristics no longer fit the world we have constructed. So in a different context, a person with ADHD may be the savior of a society with their restless exploration of new fields.

This new study is published in the journal Proceedings of the Royal Society B.​

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Flu-killer cells have been discovered in the lungs

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A hidden army of flu-killer cells has been discovered in the lung

A hidden army of flu-killer cells has been discovered in the lungs. A group of “University of California Riverside” researchers in their new research have discovered a group of virus-eating cells in the lung that can fight influenza.

A hidden army of flu-killer cells has been discovered in the lungs

Scientists have long thought of the fluid-filled sac around our lungs as merely a barrier to external damage, but new research shows that this sac also contains powerful virus-eating cells that enter when an influenza infection occurs.

According to ScienceMag, these cells should not be confused with phages that infect bacteria. These cells, called macrophages, are immune cells produced in the body.

“Juliet Morrison” (Juliet Morrison), a virologist at, “The University of California Riverside” (UC Riverside) and head of this research said: Macrophages swallow bacteria, viruses, cancer cells, and dying cells. They grab and destroy anything that looks alien. We were surprised to find them in the lungs because no one had seen anything like that before.

In this research, it is explained how macrophages leave the external cavity and enter the lungs during influenza. They reduce inflammation there and lower the level of disease. “This research shows that it’s not just what happens in the lung that matters, but what happens outside the lung as well,” Morrison said. Cells not normally associated with the lung can have important effects on lung disease and health.

He added: Since this structure contains liquid, it prevents the lungs from collapsing. Despite this, researchers haven’t thought much about the fact that it might contain an entire organ. Our research may change this perception.

Researchers initially sought to answer a more general question. The question was which type of cells are present in the lung when you get influenza? They obtained existing data on lung-related genes from research on mice that either died or survived the flu. Then, they mined the data using an algorithm to predict the types of cells that change in the lungs during influenza. “We analyzed the data to determine which immune cells were present in the lung tissues,” Morrison said. That’s when I realized that maybe we have an unknown external source of cells in the lung.

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Then, using a laser-based method, the researchers tracked the macrophages entering the mice’s lungs and found out what would happen if they took these cells out. “When you take them out of the mouse lung, you see disease progression and increased lung inflammation,” Morrison continued.

A hidden army of flu-killer cells has been discovered in the lung
Morrison hopes the research will encourage other scientists to re-evaluate data sets from older studies. He added: Our method was to make a new use of the available information and finally we were able to see something new.

In their future research, the research group hopes to understand which protein tells the macrophages to move into the lungs. Once the protein signals are identified, it may be possible to discover drugs that increase macrophage numbers or activity.

A strategy to strengthen the human defense system against infection rather than developing another antiviral drug could provide a treatment for influenza that is effective for a longer period of time. Morrison is interested in host therapy because antibiotic and antiviral drug resistance is a growing problem.

This problem occurs when microbes, such as bacteria and fungi, gain the ability to defeat drugs designed to kill them. Improper use and overdose of drugs accelerate this problem. According to the report of the “American Center for Disease Control and Prevention” (CDC), more than 2.8 million drug-resistant infections occur in this country every year, and as a result, more than 35 thousand people die.

“If we can boost what’s killing the infection in us, we’re probably going to have a better outcome and be less likely to become resistant to the drug,” Morrison said. The immune system is very complex, but our best long-term job is to work with what we have instead of chasing treatment-evasive viruses.

This research was published in the journal “PNAS”.​

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Why do we get old?

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Aging is an inevitable fate for all living organisms and many scientists are trying to reverse this process by discovering effective factors. Now a new study shows that DNA damage may be the main cause of aging. So why do we get old?

Why do we get old?

Processes and pathways that run smoothly in our youth begin to fail as we age. Over time, these breaks build up and lead to symptoms like loss of muscle mass, weakened immune systems, memory problems, and more that we will all experience in the future.

According to Forbes, what we see on the skin is reflected at the genetic level, creating obvious differences between young and old adults, but the exact reasons for these age-related genetic changes have not been well understood. A new study suggests that DNA damage may be to blame for aging. So why do we get old?

The genetic fingerprint of aging

Genes make the world go round. It sounds like an exaggeration, but it’s true. Each of the processes we depend on for life is somehow shaped by genes. Remember that genes serve as blueprints for protein production. Without proteins, everything stops, and ultimately, they are molecules that perform functions.

Whether a protein is produced when, where, and how much it is produced is precisely regulated by a process called gene expression. Gene expression is essentially a genetic on/off switch. For example, when a person becomes ill due to a viral infection, their body begins to turn on genes related to the immune response, thereby mobilizing the appropriate immune cells to help defend against the threat. When gene expression is properly regulated, cell function proceeds smoothly, but if the balance is disturbed, genes that should be off may remain on, and vice versa. Also, too much or too little protein may be produced.

Aging is characterized by a specific pattern of gene expression. In a sense, it can be said that aging has a specific genetic fingerprint. Just like a thief leaves his fingerprints at a crime scene, age leaves its mark, and this is true of all animal species, from tube worms to humans.

Read More: Can the aging process be slowed down?

Changes in gene expression associated with aging have been known for some time, but answering what triggers these changes in the first place has been surprisingly difficult. We know what aging looks like at the genetic level, but we don’t know why it happens.

Why do we get old?

From DNA to RNA

Protein production is a complex, multi-step process, and as with any complex process that has multiple moving parts, there is room for error. In fact, the findings of this new research show that changes in gene expression with age may be related to defects in protein production. It seems that damage to DNA is associated with damage to an important step called “transcription”.

Proteins are made from RNA, but our genes are stored in the form of DNA. Therefore, DNA must first be converted into RNA. In technical language, this work is called transcription. Why is this genetic procedure needed? Our DNA is stored in the nucleus of cells and does not leave this area of the cell to minimize damage, but protein production takes place in the cytoplasm. Therefore, genetic information must reach the cytoplasm from the nucleus.

This is where mRNA, or to be more precise, “messenger RNA” (mRNA) comes into play. While DNA is used for long-term storage, messenger RNA serves as a single-use set of genetic instructions. A messenger RNA encodes a copy of a specific gene and transfers it from the nucleus to the cytoplasm; Where the gene can be converted into a protein. The process is similar to copying part of a rare book that you need but can’t get out of the library.

The body even has its own genetic photocopying machine called RNAi polymerase II, or RNAPII. Arane polymerase II is a complex of several proteins that, depending on the gene that needs to be transcribed, attaches to a specific segment of DNA and then moves along the target gene, delivering a copy of the complementary arane. The resulting RNA strand, called the transcript, is the precursor to the messenger RNA.

In this study, Akos Gyenis, Jiang Chang, and their colleagues at the Erasmus MC Medical Center in the Netherlands discovered that in older mice, RNAi polymerase II often fails when transcribing DNA into Arani starts to stop. Analyzing the livers of two-year-old mice, they found that up to 40% of all polymerase II arane complexes were stopped. Additionally, each stalled set likely blocks three others behind it, causing the DNA strands to line up until the blockage is resolved. The researchers found that larger genes were particularly susceptible to these issues, leading to a bias towards the expression of small genes.

When transcription stops, gene expression also stops. As a result, many cellular pathways begin to fail. They are deprived of the proteins they need to function properly. This includes all pathways that malfunction with age. In other words, the genetic fingerprint created by interrupted transcription is the same as that created by aging, suggesting that they are closely related. Pathways affected include those involved in nutrient sensing, cellular debris clearance, energy metabolism, immune system function, and the ability of cells to cope with injury. All of these things play a vital role in shaping longevity.
In the next step, the researchers sought to understand the cause of the arrest of Aran polymerase II in aged mice. Their suspicions led to DNA damage that was spontaneous and internal. Gene expression patterns in cells exposed to DNA-damaging agents are very similar to those seen during normal aging. Premature aging disorders such as Cockayne syndrome are also characterized by DNA damage. Normal DNA repair mechanisms malfunction and result in the stalling of polymerase II at sites of damage known as lesions. Considering these similarities, scientists speculated that DNA damage could also be involved in normal aging.

To test their hypothesis, the researchers looked at genetically modified mice that lacked the normal DNA repair system and were prone to DNA damage. These mice showed many features of premature aging; Including their life span which was significantly shortened. As expected, the transcription speed was significantly lower in these mice compared to the healthy group.

Although we have a good understanding of how gene expression changes with age, we do not fully understand what causes these genetic changes. This situation is just like looking at the symptoms of a disease without knowing the root cause. This new research suggests one possible mechanism is the DNA damage that accumulates in RNAi polymerase II as it attempts to transcribe the template strand into RNAi. When RNAi polymerase II hits a site of damage, it stalls and interferes with transcription, disrupting several important cellular pathways.

Although this research does not yet have any immediate therapeutic implications, research of this type helps us better understand the inner workings of the aging process. The deeper our understanding, the more likely it is to develop effective drug interventions. Until then, it’s best to avoid behaviors that pose a risk of DNA damage, such as smoking and exposure to UV rays. Temporary programmed caloric restriction may also help reduce transcriptional pressure.

This research was published in “Nature Genetics” magazine.

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