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Tuesday, 20 October 2020

The consequences of mating at the molecular level



While it is known that stem cells have the ability to develop into all tissues in a precisely regulated process, the way environmental cues affect stem cell behavior has remained poorly understood. In a new study, researchers from the University of Tsukuba discovered that neurons producing the neurotransmitter octopamine regulate the behavior of germline stem cells (GSCs) in response to environmental cues, such as mating.



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The ovaries of the fruit fly Drosophila melanogaster have been a robust model system for studying the relationship between environmental cues and stem cell biology. In fruit flies, GSCs give rise to eggs and exist in close proximity to somatic cells. Somatic cells comprise several types of cells in support of the budding eggs. As with other stem cells, when GSCs divide, one daughter cell retains its stem cell identity, while the other differentiates into multiple progeny cells. The balance between self-renewal and differentiation is tightly regulated, both by cues within and outside the environment in which GSCs reside (also called a niche). Mating is one such external cue known to increase GSCs.



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"It is well known that a molecule called sex peptide from the male seminal fluid activates neurons located in the uterine lumen. We have previously shown that these neurons are essential for stimulating the biosynthesis of ovarian steroid hormones to increase the number of GSCs," says corresponding author of the study Professor Ryusuke Niwa. "The goal of our study was to investigate how the information from mating is transmitted from these neurons to GSCs at the molecular and cellular levels."


To achieve their goal, the researchers took a genetic approach to investigate which gene is responsible for the increase of GSCs upon mating, and found that the octopamine receptor Oamb is the one through which octopamine exerts its effect on GSCs. Through a series of experiments, the researchers then found that Oamb in escort cells, one type of somatic cell adjacent to GSCs, modulates GSC increase after mating and the subsequent release of octopamine by neurons. At the molecular level, Oamb activation by octopamine resulted in an increase in calcium signaling in escort cells. Calcium is a potent biomolecule and changes in cellular calcium levels strongly affect cell behavior.


Because it had previously been shown that ovarian steroid hormones were involved in the increase of GSCs, the researchers next investigated the relationship between ovarian steroid hormones and the calcium-dependent GSC increase. Their results showed that ovarian steroid hormones are indeed required to increase the number of GSCs. Next, the researchers asked which molecules play a role in stimulation of escort cells by octopamine and found that the protein matrix metalloproteinase 2 is required upon the calcium-dependent GSC increase. Finally, the researchers showed that the neurons projecting to the ovaries to increase GSCs do so via specialized proteins, called nicotinic acetylcholine receptors. These results provide a complete picture as to how neuronal activation results in increased ovarian stem cells.


"These are striking results that show the molecular mechanism underlying the coupling of the nervous system with stem cell behavior in response to environmental cues, such as mating," says Professor Niwa. "Our results could help unravel the conserved systemic and neuronal regulatory mechanisms for stem cell homeostasis in animals."


More information: 

Yuto Yoshinari et al. Neuronal octopamine signaling regulates mating-induced germline stem cell increase in female Drosophila melanogaster, eLife (2020). DOI: 10.7554/eLife.57101


Saturday, 17 October 2020

Those funky cheese smells allow microbes to 'talk' to and feed each other


Researchers at Tufts University have found that those distinctly funky smells from cheese are one way that fungi communicate with bacteria, and what they are saying has a lot to do with the delicious variety of flavors that cheese has to offer. The research team found that common bacteria essential to ripening cheese can sense and respond to compounds produced by fungi in the rind and released into the air, enhancing the growth of some species of bacteria over others. The composition of bacteria, yeast and fungi that make up the cheese microbiome is critical to flavor and quality of the cheese, so figuring out how that can be controlled or modified adds science to the art of cheese making.



The discovery, published in Environmental Microbiology, also provides a model for the understanding and modification of other economically and clinically important microbiomes, such as in soil or the gastrointestinal tract.

"Humans have appreciated the diverse aromas of cheeses for hundreds of years, but how these aromas impact the biology of the cheese microbiome had not been studied," said Benjamin Wolfe, professor of biology in the School of Arts and Science at Tufts University and corresponding author of the study. "Our latest findings show that cheese microbes can use these aromas to dramatically change their biology, and the findings' importance extends beyond cheese making to other fields as well."

Many microbes produce airborne chemical compounds called volatile organic compounds, or VOCs, as they interact with their environment. A widely recognized microbial VOC is geosmin, which is emitted by soil microbes and can often be smelled after a heavy rain in forests. As bacteria and fungi grow on ripening cheeses, they secrete enzymes that break down amino acids to produce acids, alcohols, aldehydes, amines, and various sulfur compounds, while other enzymes break down fatty acids to produce esters, methyl ketones, and secondary alcohols. All of those biological products contribute to the flavor and aroma of cheese and they are the reason why Camembert, Blue cheese and Limburger have their signature smells.

The Tufts researchers found that VOCs don't just contribute to the sensory experience of cheese, but also provide a way for fungi to communicate with and "feed" bacteria in the cheese microbiome. By pairing 16 different common cheese bacteria with 5 common cheese rind fungi, the researchers found that the fungi caused responses in the bacteria ranging from strong stimulation to strong inhibition. One bacteria species, Vibrio casei, responded by growing rapidly in the presence of VOCs emitted by all five of the fungi. Other bacteria, such as Psychrobacter, only grew in response to one of the fungi (Galactomyces), and two common cheese bacteria decreased significantly in number when exposed to VOCs produced by Galactomyces.

The researchers found that the VOCs altered the expression of many genes in the bacteria, including genes that affect the way they metabolize nutrients. One metabolic mechanism that was enhanced, called the glyoxylate shunt, allows the bacteria to utilize more simple compounds as "food" when more complex sources such as glucose are unavailable. In effect, they enabled the bacteria to better "eat" some of the VOCs and use them as sources for energy and growth.

"The bacteria are able to actually eat what we perceive as smells," said Casey Cosetta, post-doctoral scholar in the department of biology at Tufts University and first author of the study. "That's important because the cheese itself provides little in the way of easily metabolized sugars such as glucose. With VOCs, the fungi are really providing a useful assist to the bacteria to help them thrive."

There are direct implications of this research for cheese producers around the world. When you walk into a cheese cave there are many VOCs released into the air as the cheeses age. These VOCs may impact how neighboring cheeses develop by promoting or inhibiting the growth of specific microbes, or by changing how the bacteria produce other biological products that add to the flavor. A better understanding of this process could enable cheese producers to manipulate the VOC environment to improve the quality and variety of flavors.

The implications of the research can even extend much further. "Now that we know that airborne chemicals can control the composition of microbiomes, we can start to think about how to control the composition of other microbiomes, for example in agriculture to improve soil quality and crop production and in medicine to help manage diseases affected by the hundreds of species of bacteria in the body," said Wolfe.



More information: 
Casey M. Cosetta et al, Fungal volatiles mediate cheese rind microbiome assembly, Environmental Microbiology (2020). DOI: 10.1111/1462-2920.15223

Thursday, 15 October 2020

Exposure to COVID-19 does not guarantee immunity, reinfection causes more severe symptoms

 

COVID-19 patients infected with the novel coronavirus for a second time might experience more severe symptoms, according to a study which is the first to confirm a case of reinfection with the virus in the US.

The study, published in the journal Lancet Infectious Diseases, found evidence that an individual with no known immune disorders or underlying conditions was infected with the SARS-CoV-2 virus in two separate occurrences.



According to the scientists, including those from the University of Nevada in the US, the patient, a 25-year old male, was infected with two distinct SARS-CoV-2 variants within a 48-day time frame, while testing negative in between infections.

The study noted that the patient's second infection was more severe, resulting in hospitalisation with oxygen support, indicating previous exposure to COVID-19 may not translate to guaranteed total immunity.

The patient tested negative for the virus after testing positive for SARS-CoV-2 in April 2020, the researchers said.

Then in June 2020, after experiencing severe COVID-19 symptoms, including fever, headache, dizziness, cough, nausea, and diarrhea, the patient was hospitalised and tested positive for a second time.

The patient has since been discharged from the hospital and has recovered from the second infection, the study noted.

While further research into reinfections is required, the scientists believe all individuals -- whether previously diagnosed or not -- should take identical precautions to prevent infection with SARS-CoV-2.

"There are still many unknowns about SARS-CoV-2 infections and the immune system's response, but our findings signal that a previous SARS-CoV-2 infection may not necessarily protect against future infection," said Mark Pandori, lead author of the study from the University of Nevada.

"It is important to note this is a singular finding and does not provide generalisability of this phenomenon," Pandori said.

While more research is needed, the scientists said the possibility of reinfections could have significant implications for understanding COVID-19 immunity, especially in the absence of an effective vaccine.

"It also strongly suggests that individuals who have tested positive for SARS-CoV-2 should continue to take serious precautions when it comes to the virus, including social distancing, wearing face masks, and handwashing," Pandori explained.

According to the scientists, at least four other reinfection cases have been confirmed globally in Belgium, the Netherlands, Hong Kong, and Ecuador with the latter being the only other instance in which the second infection displayed worse disease outcomes than the first.

"We need more research to understand how long immunity may last for people exposed to SARS-CoV-2, and why some of these second infections, while rare, are presenting as more severe," Pandori said.

"So far, we've only seen a handful of reinfection cases, but that doesn't mean there aren't more, especially as many cases of COVID-19 are asymptomatic. Right now, we can only speculate about the cause of reinfection," he added.

The study noted several hypotheses that may explain the severity of the second infection, including the possibility the patient subsequently encountered a very high dose of the virus which caused a more acute reaction the second time.

According to the researchers, the patient may also have come in contact with a more virulent variant of the virus.

They said another plausible explanation could be the mechanism of antibody dependent enhancement in which some protective proteins produced by the immune system during the first encounter with the virus could make a subsequent infection worse.

This mechanism, the researchers noted, was seen previously with the 2002-03 SARS pandemic virus, as well as other diseases, such as dengue fever.

Citing the limitation of the study, the researchers said they were unable to undertake any evaluation of the immune response to the first episode of infection.

Since the confirmed reinfection cases occurred among patients who displayed COVID-19 symptoms, the scientists believe there is a possibility that many similar cases among individuals may be asymptomatic, and therefore likely to remain undetected under current testing and monitoring practices.


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Reference: 

What reinfections mean for COVID-19
 Published:October 12, 2020 

Monday, 12 October 2020

New key player in long-term memory


A McGill-led multi-institutional research team has discovered that during memory consolidation, there are at least two distinct processes taking place in two different brain networks -- the excitatory and inhibitory networks. The excitatory neurons are involved in creating a memory trace, and the inhibitory neurons block out background noise and allow long-term learning to take place.



The team, led by McGill University Professors Nahum Sonenberg and Arkady Khoutorsky, Université de Montréal Professor Jean-Claude Lacaille, and University of Haifa Professor Kobi Rosenblum, senior authors on the paper published today in Nature, also found that each neuronal system can be selectively manipulated to control long-term memory. The research, which answers a long-standing question about which neuronal subtypes are involved in memory consolidation, has potential implications for novel targets for medication for disorders such as Alzheimer's disease and autism, which involve altered memory processes.

Looking for the neurons involved in memory consolidation


How do short-term memories (which last just a few hours) transform into long-term memories (which may last years)? It's been known for decades that this process, called memory consolidation, requires the synthesis of new proteins in brain cells. But until now, it hasn't been known which subtypes of neurons were involved in the process.

To identify which neuronal networks are essential in memory consolidation, the researchers used transgenic mice to manipulate a particular molecular pathway, eIF2α, in specific types of neurons. This pathway had already been shown to play a key role in controlling the formation of long-term memories and regulating protein synthesis in neurons. Moreover, earlier research had identified eIF2α as pivotal for both neurodevelopmental and neurodegenerative diseases.

Excitatory and inhibitory systems both play a role in memory consolidation

"We found that stimulation of protein synthesis via eIF2α in excitatory neurons of the hippocampus was sufficient to enhance memory formation and modification of synapses, the sites of communication between neurons," says Dr. Kobi Rosenblum.

However, interestingly, "we also found that stimulation of protein synthesis via eIF2α in a specific class of inhibitory neurons, somatostatin interneurons, was also sufficient to augment long-term memory by tuning the plasticity of neuronal connections," says Dr. Jean-Claude Lacaille.

"It is fascinating to be able to show that these new players -- inhibitory neurons -- have an important role in memory consolidation," added Dr. Vijendra Sharma, a research associate in Prof. Sonenberg's lab and the first author on the paper. "It had been assumed, until now, that eIF2α pathway regulates memory via excitatory neurons."

"These new findings identify protein synthesis in inhibitory neurons, and specifically somatostatin cells, as a novel target for possible therapeutic interventions in disorders such as Alzheimer's disease and autism," concluded Dr. Nahum Sonenberg. "We hope that this will help in the design of both preventative and post-diagnosis treatments for those who suffer from disorders involving memory deficits."

The research was funded by: Canada's International Development Research Centre (IDRC), in partnership with the Azrieli Foundation, the Canadian Institutes of Health Research (CIHR), and the Israel Science Foundation (ISF) to K.R. and N.S., JCL is supported by a CIHR Project grant and a Canada Research Chair in Cellular and Molecular Neurophysiology.



Reference:

Vijendra Sharma, Rapita Sood, Abdessattar Khlaifia, Mohammad Javad Eslamizade, Tzu-Yu Hung, Danning Lou, Azam Asgarihafshejani, Maya Lalzar, Stephen J. Kiniry, Matthew P. Stokes, Noah Cohen, Alissa J. Nelson, Kathryn Abell, Anthony P. Possemato, Shunit Gal-Ben-Ari, Vinh T. Truong, Peng Wang, Adonis Yiannakas, Fatemeh Saffarzadeh, A. Claudio Cuello, Karim Nader, Randal J. Kaufman, Mauro Costa-Mattioli, Pavel V. Baranov, Albert Quintana, Elisenda Sanz, Arkady Khoutorsky, Jean-Claude Lacaille, Kobi Rosenblum, Nahum Sonenberg. eIF2α controls memory consolidation via excitatory and somatostatin neurons. Nature, 2020; DOI: 10.1038/s41586-020-2805-8

Saturday, 10 October 2020

Scientists find upper limit for the speed of sound


A research collaboration between Queen Mary University of London, the University of Cambridge and the Institute for High Pressure Physics in Troitsk has discovered the fastest possible speed of sound.
 
The result- about 36 km per second—is around twice as fast as the speed of sound in diamond, the hardest known material in the world.



Waves, such as sound or light waves, are disturbances that move energy from one place to another. Sound waves can travel through different mediums, such as air or water, and move at different speeds depending on what they're travelling through. For example, they move through solids much faster than they would through liquids or gases, which is why you're able to hear an approaching train much faster if you listen to the sound propagating in the rail track rather than through the air.

Einstein's theory of special relativity sets the absolute speed limit at which a wave can travel which is the speed of light, and is equal to about 300,000 km per second. However until now it was not known whether sound waves also have an upper speed limit when travelling through solids or liquids.

The study, published in the journal Science Advances, shows that predicting the upper limit of the speed of sound is dependent on two dimensionless fundamental constants: the fine structure constant and the proton-to-electron mass ratio.

These two numbers are already known to play an important role in understanding our Universe. Their finely-tuned values govern nuclear reactions such as proton decay and nuclear synthesis in stars and the balance between the two numbers provides a narrow 'habitable zone' where stars and planets can form and life-supporting molecular structures can emerge. However, the new findings suggest that these two fundamental constants can also influence other scientific fields, such as materials science and condensed matter physics, by setting limits to specific material properties such as the speed of sound.

The scientists tested their theoretical prediction on a wide range of materials and addressed one specific prediction of their theory that the speed of sound should decrease with the mass of the atom. This prediction implies that the sound is the fastest in solid atomic hydrogen. However, hydrogen is an atomic solid at very high pressure above 1 million atmospheres only, pressure comparable to those in the core of gas giants like Jupiter. At those pressures, hydrogen becomes a fascinating metallic solid conducting electricity just like copper and is predicted to be a room temperature superconductor. Therefore, researchers performed state-of-the-art quantum mechanical calculations to test this prediction and found that the speed of sound in solid atomic hydrogen is close to the theoretical fundamental limit.

Professor Chris Pickard, Professor of Materials Science at the University of Cambridge, said: "Soundwaves in solids are already hugely important across many scientific fields. For example, seismologists use sound waves initiated by earthquakes deep in the Earth interior to understand the nature of seismic events and the properties of Earth composition. They're also of interest to materials scientists because sound waves are related to important elastic properties including the ability to resist stress."



More information: 

"Speed of sound from fundamental physical constants" Science Advances (2020). DOI: 

A hydrogel that could help repair damaged nerves


Medicine has been tackling the problem of nerve reconstruction and brain plasticity for many years. These are areas of research in which the latest advances have given new hope that one day it will be possible to heal lesions hitherto considered definitive. Recently, researchers have developed a conductive hydrogel that could help repair certain nerve damage.


Injuries to peripheral nerves -- tissues that transmit bioelectrical signals from the brain to the rest of the body -- often result in chronic pain, neurologic disorders, paralysis or disability. Now, researchers have developed a stretchable conductive hydrogel that could someday be used to repair these types of nerves when there's damage. They report their results in ACS Nano.

Injuries in which a peripheral nerve has been completely severed, such as a deep cut from an accident, are difficult to treat. A common strategy, called autologous nerve transplantation, involves removing a section of peripheral nerve from elsewhere in the body and sewing it onto the ends of the severed one. 


However, the surgery does not always restore function, and multiple follow-up surgeries are sometimes needed. Artificial nerve grafts, in combination with supporting cells, have also been used, but it often takes a long time for nerves to fully recover. Qun-Dong Shen, Chang-Chun Wang, Ze-Zhang Zhu and colleagues wanted to develop an effective, fast-acting treatment that could replace autologous nerve transplantation. For this purpose, they decided to explore conducting hydrogels -- water-swollen, biocompatible polymers that can transmit bioelectrical signals.

The researchers prepared a tough but stretchable conductive hydrogel containing polyaniline and polyacrylamide. The crosslinked polymer had a 3D microporous network that, once implanted, allowed nerve cells to enter and adhere, helping restore lost tissue. The team showed that the material could conduct bioelectrical signals through a damaged sciatic nerve removed from a toad. Then, they implanted the hydrogel into rats with sciatic nerve injuries. 

Two weeks later, the rats' nerves recovered their bioelectrical properties, and their walking improved compared with untreated rats. Because the electricity-conducting properties of the material improve with irradiation by near-infrared light, which can penetrate tissues, it could be possible to further enhance nerve conduction and recovery in this way, the researchers say.

Reference:

Mei Dong, Bo Shi, Dun Liu, Jia-Hao Liu, Di Zhao, Zheng-Hang Yu, Xiao-Quan Shen, Jia-Min Gan, Ben-long Shi, Yong Qiu, Chang-Chun Wang, Ze-Zhang Zhu, Qun-Dong Shen. Conductive Hydrogel for a Photothermal-Responsive Stretchable Artificial Nerve and Coalescing with a Damaged Peripheral Nerve. ACS Nano, 2020; DOI: 10.1021/acsnano.0c05197

Thursday, 8 October 2020

Engineers create nanoparticles that deliver gene-editing tools to specific tissues and organs


One of the most remarkable recent advances in biomedical research has been the development of highly targeted gene-editing methods such as CRISPR that can add, remove, or change a gene within a cell with great precision. The method is already being tested or used for the treatment of patients with sickle cell anemia and cancers such as multiple myeloma and liposarcoma, and today, its creators Emmanuelle Charpentier and Jennifer Doudna received the Nobel Prize in chemistry.


While gene editing is remarkably precise in finding and altering genes, there is still no way to target treatment to specific locations in the body. The treatments tested so far involve removing blood stem cells or immune system T cells from the body to modify them, and then infusing them back into a patient to repopulate the bloodstream or reconstitute an immune response—an expensive and time-consuming process.

Building on the accomplishments of Charpentier and Doudna, Tufts researchers have for the first time devised a way to directly deliver gene-editing packages efficiently across the blood brain barrier and into specific regions of the brain, into immune system cells, or to specific tissues and organs in mouse models. These applications could open up an entirely new line of strategy in the treatment of neurological conditions, as well as cancer, infectious disease, and autoimmune diseases.

A team of Tufts biomedical engineers, led by associate professor Qiaobing Xu, sought to find a way to package the gene editing "kit" so it could be injected to do its work inside the body on targeted cells, rather than in a lab.

They used lipid nanoparticles (LNPs)—tiny "bubbles" of lipid molecules that can envelop the editing enzymes and carry them to specific cells, tissues, or organs. Lipids are molecules that include a long carbon tail, which helps give them an "oily" consistency, and a hydrophilic head, which is attracted to a watery environment.

There is also typically a nitrogen, sulfur, or oxygen-based link between the head and tail. The lipids arrange themselves around the bubble nanoparticles with the heads facing outside and the tails facing inward toward the center.

Xu's team was able to modify the surface of these LNPs so they can eventually "stick" to certain cell types, fuse with their membranes, and release the gene-editing enzymes into the cells to do their work.

Making a targeted LNP takes some chemical crafting.

By creating a mix of different heads, tails, and linkers, the researchers can screen— first in the lab—a wide variety of candidates for their ability to form LNPs that target specific cells. The best candidates can then be tested in mouse models, and further modified chemically to optimize targeting and delivery of the gene-editing enzymes to the same cells in the mouse.

"We created a method around tailoring the delivery package for a wide range of potential therapeutics, including gene editing," said Xu. "The methods draw upon combinatorial chemistry used by the pharmaceutical industry for designing the drugs themselves, but instead we are applying the approach to designing the components of the delivery vehicle."

In an ingenious bit of chemical modeling, Xu and his team used a neurotransmitter at the head of some lipids to assist the particles in crossing the blood-brain barrier, which would otherwise be impermeable to molecule assemblies as large as an LNP.

The ability to safely and efficiently deliver drugs across the barrier and into the brain has been a long-standing challenge in medicine. In a first, Xu's lab delivered an entire complex of messenger RNAs and enzymes making up the CRISPR kit into targeted areas of the brain in a living animal.

Some slight modifications to the lipid linkers and tails helped create LNPs that could deliver into the brain the small molecule antifungal drug amphotericin B (for treatment of meningitis) and a DNA fragment that binds to and shuts down the gene producing the tau protein linked to Alzheimer's disease.

More recently, Xu and his team have created LNPs to deliver gene-editing packages into T cells in mice. T cells can help in the production of antibodies, destroy infected cells before viruses can replicate and spread, and regulate and suppress other cells of the immune system.

The LNPs they created fuse with T cells in the spleen or liver—where they typically reside—to deliver the gene-editing contents, which can then alter the molecular make-up and behavior of the T cell. It's a first step in the process of not just training the immune system, as one might do with a vaccine, but actually engineering it to fight disease better.

Xu's approach to editing T cell genomes is much more targeted, efficient, and likely to be safer than methods tried so far using viruses to modify their genome.

"By targeting T cells, we can tap into a branch of the immune system that has tremendous versatility in fighting off infections, protecting against cancer, and modulating inflammation and autoimmunity," said Xu.

Xu and his team explored further the mechanism by which LNPs might find their way to their targets in the body. In experiments aimed at cells in the lungs, they found that the nanoparticles picked up specific proteins in the bloodstream after injection.

The proteins, now incorporated into the surface of the LNPs, became the main component that helped the LNPs to latch on to their target. This information could help improve the design of future delivery particles.

While these results have been demonstrated in mice, Xu cautioned that more studies and clinical trials will be needed to determine the efficacy and safety of the delivery method in humans.


More information: 

Xuewei Zhao et al. Imidazole‐Based Synthetic Lipidoids for In Vivo mRNA Delivery into Primary T Lymphocytes, Angewandte Chemie International Edition (2020). DOI: 10.1002/anie.202008082

Wednesday, 7 October 2020

Alzheimer's Biomarkers Found in Brains of Children Exposed to Air Pollution


Researchers looking at the brainstems of children and young adults exposed lifelong to air pollution in Mexico City have discovered disturbing evidence of harm.

Previous studies have linked fine particulate air pollution exposure with Alzheimer's disease, and researchers have also reported evidence of air pollution-derived nanoparticles in the frontal cortex of the brain.



But after examining the brainstems of 186 young Mexico City residents aged between 11 months and 27 years of age, researchers, including Professor Barbara Maher from Lancaster University, found markers not only of Alzheimer's disease, but also of Parkinson's and of motor neurone disease (MND) too. These markers of disease were coupled with the presence of tiny, distinctive nanoparticles within the brainstem - their appearance and composition indicating they were likely to come from vehicle pollution.

This has led researchers to conclude that air pollution of this nature - whether inhaled or swallowed - puts people at risk of potential neurological harm. The brainstem is the posterior part of the brain which regulates the central nervous system, controls heart and breathing rates, and how we perceive the position and movement of our body, including, for example, our sense of balance.

Professor Maher said: "Not only did the brainstems of the young people in the study show the 'neuropathological hallmarks' of Alzheimer's, Parkinson's and MND, they also had high concentrations of iron-, aluminium- and titanium-rich nanoparticles in the brainstem - specifically in the substantia nigra, and cerebellum.

"The iron-and aluminium-rich nanoparticles found in the brainstem are strikingly similar to those which occur as combustion- and friction-derived particles in air pollution (from engines and braking systems).

"The titanium-rich particles in the brain were different - distinctively needle-like in shape; similar particles were observed in the nerve cells of the gut wall, suggesting these particles reach the brain after being swallowed and moving from the gut into the nerve cells which connect the brainstem with the digestive system."

The 'neuropathological hallmarks' found even in the youngest infant (11 months old) included nerve cell growths, and plaques and tangles formed by misfolded proteins in the brain. Damage to the substantia nigra is directly linked with the development of Parkinson's disease in later life. Protein misfolding linked previously with MND was also evident, suggesting common causal mechanisms and pathways of formation, aggregation and propagation of these abnormal proteins.

The one thing common to all of the young people examined in the study was their exposure to high levels of particulate air pollution. Professor Maher says that the associations between the presence of damage to cells and their individual components - especially the mitochondria (key for generation of energy, and signalling between cells) - and these metal-rich nanoparticles are a 'smoking gun'.

Such metal-rich particles can cause inflammation and also act as catalysts for excess formation of reactive oxygen species, which are known to cause oxidative stress and eventual death of neurons. Critically, the brainstems of age- and gender- matched controls who lived in lower-pollution areas have not shown the neurodegenerative pathology seen in the young Mexico City residents.

These new findings show that pollution-derived, metal-rich nanoparticles can reach the brainstem whether by inhalation or swallowing, and that they are associated with damage to key components of nerve cells in the brainstem, including the substantia nigra.

Even in these young Mexico City residents, the type of neurological damage associated with Alzheimer's, Parkinson's and motor neurone diseases is already evident. These data indicate the potential for a pandemic of neurological disease in high-pollution cities around the world as people experience longer lifespans, and full symptoms of earlier, chronic neurological damage develop.

Professor Barbara Maher said: "It's critical to understand the links between the nanoparticles you're breathing in or swallowing and the impacts those metal-rich particles are then having on the different areas of your brain.

"Different people will have different levels of vulnerability to such particulate exposure but our new findings indicate that what air pollutants you are exposed to, what you are inhaling and swallowing, are really significant in development of neurological damage.

"With this in mind, control of nanoparticulate sources of air pollution becomes critical and urgent."



Reference: 

Calderón-Garcidueñasa L, González-Maciel A, Reynoso-Robles R, et al. Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal. Environ. Res. 2020;191.doi: 10.1016/j.envres.2020.110139