The Data-driven Future of Extreme Physics (Physics)

By applying modern machine learning and data science methods to “extreme” plasma physics, researchers can gain insight into our universe and find clues about creating a limitless amount of energy.

In a recent perspective published in NatureLawrence Livermore National Laboratory (LLNL) scientists and international collaborators outline key challenges and future directions in using machine learning (ML) and other data-driven techniques to better understand these extreme conditions that potentially pave the pathway to nuclear fusion as an industrial power source, as well as helping to improve our understanding of the universe.

Extreme plasma is described as the physics of matter at extreme densities, temperatures and pressures like those found in the interior of stars and planets.

“Extreme plasma physics experiments historically had a very low data rate, but future planned laser facilities will have a very high shot rate, with the potential to produce huge amounts of data,” said LLNL physicist Gemma Anderson, one of the lead authors of the paper. “This in turn will move the field into the big-data regime and create a corresponding need to leverage modern data science methods to a much greater extent.”

The newest generation of extreme physics facilities can perform experiments multiple times a second (as opposed to almost daily) – moving away from human-based control toward automatic control. To make the most of the emerging opportunities, the team proposed a playbook for using ML in high energy density science through research design, training, best practices and support for synthetic diagnostics and data analysis.

The study of plasma physics under extreme temperatures, densities and electromagnetic field strength is important to understand astrophysics, nuclear fusion and fundamental physics. These systems are highly non-linear and are very difficult to understand theoretically or demonstrate experimentally.

Anderson and colleagues have suggested that machine learning models and data-driven methods could be the answer by reshaping exploration of these extreme systems that have proven far too complex for human researchers to do on their own. Interpreting the data from the experiments of these systems, such as the National Ignition Facility, requires simultaneously comprehending large amounts of complex multi-modal data from multiple different sources. The image above shows a potential workflow that fully integrates data-driven and machine-learning methods to achieve this goal. Optimizing extreme physics systems requires fine-tuning over large numbers of (often highly correlated) parameters. Artificial intelligence methods have proved highly successful at teasing out correlations in large datasets and can be crucial to understand and optimize systems that up to now have been difficult to understand.

The paper was a result of a workshop organized by Anderson, her LLNL colleauge Jim Gaffney and Peter Hatfield from the University of Oxford, held at the Lorentz Center in The Netherlands in January 2020. A key goal of the meeting was to write a white paper detailing the conclusions of the meeting: what standards the community should adopt, what machine learning can do for the field and what the future may hold.

Anderson said the paper will be circulated to key funding bodies and policy makers in research councils and national labs.

Lead authors of the paper were Hatfield, Gaffney and Anderson. Co-authors include Suzanne Ali, Bogdan Kustowski, Michael MacDonald, Derek Mariscal, Madison Martin and Luc Peterson from LLNL, and others from the University of York, Heslington, UK; Nikhef, National Institute for Subatomic Physics, Netherlands; DIFFER – Dutch Institute for Fundamental Energy Research, Netherlands; Instituto de Plasmas e Fusão Nuclear, Instituto Superior Técnico, Portugal; Sandia National Laboratories; Imperial College London, UK; Queen’s University Belfast, Ireland; University of Rochester; Dutch National Center for Mathematics and Computer Science, Netherlands; and AWE Plc, UK.

The workshop and paper were funded by the Laboratory Directed Research and Development program.

Featured image: The LLNL understanding of inertial confinement fusion implosion physics is based on a combination of high-volume, lower-fidelity simulation ensembles; sparse, difficult-to-diagnose experiments; and best-physics simulations that push the limits of high-performance computing technology. Creating and synthesizing these data into an improved understanding of the physics will require multiple complementary techniques from data science, uncertainty quantification and artificial intelligence. Inset images are courtesy of Damien Jemison/LLNL.


Reference: Hatfield, P.W., Gaffney, J.A., Anderson, G.J. et al. The data-driven future of high-energy-density physics. Nature 593, 351–361 (2021). https://doi.org/10.1038/s41586-021-03382-w


Provided by LLNL

What Leads To Pair Production Process In Pulsar’s Magnetospheres? (Cosmology)

Zaza Osmanov and his collaborators studied the possibility of efficient pair production in a pulsar’s magnetosphere. They showed that, the electrostatic field exponentially amplifies, by means of the relativistic centrifugal force. As a result, the field approaches to Schwinger limit¹, leading to pair creation process in the light cylinder (LC) area². Their study recently appeared in Arxiv.

In 1969, Thomas Gold suggested that, since pulsars are rotating neutron stars, centrifugal effects might be very important. This is because, these can energise the pulsar’s magnetospheric particles to energies enough for producing high energy electromagnetic radiation.

Later, it has been shown by Z. Osmanov and colleagues that the centrifugal force in the LC area is different for different species of particles (magnetospheric electrons and positrons). This in turn, might lead to charge separation creating the Langmuir waves. On the other hand, since the centrifugal force is time dependent, it acts as a parameter, amplifying the electrostatic field, and after it inevitably reach the Schwinger limit, it results in a pair production process.

Now, Z. Osmanov and his collaborators, studied this completely new mechanism of pair creation in the pulsar magnetosphere.

“We consider the normal period pulsars and study the possibility of pair production by means of the centrifugally driven electrostatic fields.”, told Z. Osmanov, professor at Free University of Tbilisi and lead author of the study.

Considering the typical pulsar parameters they showed that the electric field exponentially increases and gradually reaches the Schwinger limit, when efficient pair creation might occur.

They also analysed constraints imposed on the process and found that the process is so efficient that the number density of electron-positron pairs exceeds the Goldreich-Julian density by five orders of magnitude.

In addition, it has been shown that, this novel mechanism of pair production not only changes the number density of electron-positron plasmas in pulsar’s magnetospheres but also, it significantly influences the physical processes there. In particular, it is evident that the processes of particle acceleration strongly depends on the plasma density.

Finally, they showed that, the emission spectral pattern will be influenced as well by the efficient pair creation. This in turn, might give rise to coherent radio emission, which seems to be quite promising in the light of modern enigma – fast radio bursts.

“Since all these problems are beyond the intended scope of the paper we are going to consider them very soon.”, concluded authors of the study.


Note:
1) Schwinger limit is a scale above which the electrostatic field is expected to become nonlinear.
2) Light Cylinder area is a hypothetical area where the linear velocity of rotation coincides with the speed of light.


Reference: Z. Osmanov, G. Machabeli, N. Chkheidze, “The novel mechanism of pair creation in pulsar magnetospheres”, Arxiv, pp. 1-5, 2021. https://arxiv.org/abs/2105.09351


Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article

Milky Way Not Unusual, Astronomers Find (Cosmology)

Detailed cross-section of another galaxy reveals surprising similarities to our home

The first detailed cross-section of a galaxy broadly similar to the Milky Way, published today, reveals that our galaxy evolved gradually, instead of being the result of a violent mash-up. The finding throws the origin story of our home into doubt.

The galaxy, dubbed UGC 10738, turns out to have distinct ‘thick’ and ‘thin’ discs similar to those of the Milky Way. This suggests, contrary to previous theories, that such structures are not the result of a rare long-ago collision with a smaller galaxy. They appear to be the product of more peaceful change.

And that is a game-changer. It means that our spiral galaxy home isn’t the product of a freak accident. Instead, it is typical.

The finding was made by a team led by Nicholas Scott and Jesse van de Sande, from Australia’s ARC Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D) and the University of Sydney.

“Our observations indicate that the Milky Way’s thin and thick discs didn’t come about because of a gigantic mash-up, but a sort-of ‘default’ path of galaxy formation and evolution,” said Dr Scott.

“From these results we think galaxies with the Milky Way’s particular structures and properties could be described as the ‘normal’ ones.”

This conclusion – published in The Astrophysical Journal Letters– has two profound implications.

“It was thought that the Milky Way’s thin and thick discs formed after a rare violent merger, and so probably wouldn’t be found in other spiral galaxies,” said Dr Scott.

“Our research shows that’s probably wrong, and it evolved ‘naturally’ without catastrophic interventions. This means Milky Way-type galaxies are probably very common.

“It also means we can use existing very detailed observations of the Milky Way as tools to better analyse much more distant galaxies which, for obvious reasons, we can’t see as well.”

The research shows that UGC 10738, like the Milky Way, has a thick disc consisting mainly of ancient stars – identified by their low ratio of iron to hydrogen and helium. Its thin disc stars are more recent and contain more metal.

(The Sun is a thin disc star and comprises about 1.5% elements heavier than helium. Thick disc stars have three to 10 times less.)

Although such discs have been previously observed in other galaxies, it was impossible to tell whether they hosted the same type of star distribution – and therefore similar origins. Scott, van de Sande and colleagues solved this problem by using the European Southern Observatory’s Very Large Telescope in Chile to observe UGC 10738, situated 320 million light years away.

The galaxy is angled “edge on”, so looking at it offered effectively a cross-section of its structure.

“Using an instrument called the multi-unit spectroscopic explorer, or MUSE, we were able to assess the metal ratios of the stars in its thick and thin discs,” explained Dr van de Sande.

“They were pretty much the same as those in the Milky Way – ancient stars in the thick disc, younger stars in the thin one. We’re looking at some other galaxies to make sure, but that’s pretty strong evidence that the two galaxies evolved in the same way.”

Dr Scott said UGC 10738’s edge-on orientation meant it was simple to see which type of stars were in each disc.

“It’s a bit like telling apart short people from tall people,” he said. “It you try to do it from overhead it’s impossible, but it if you look from the side it’s relatively easy.”

Co-author Professor Ken Freeman from the Australian National University said, “This is an important step forward in understanding how disk galaxies assembled long ago. We know a lot about how the Milky Way formed, but there was always the worry that the Milky Way is not a typical spiral galaxy. Now we can see that the Milky Way’s formation is fairly typical of how other disk galaxies were assembled”.

ASTRO 3D director, Professor Lisa Kewley, added: “This work shows how the Milky Way fits into the much bigger puzzle of how spiral galaxies formed across 13 billion years of cosmic time.”

Other co-authors are based at Macquarie University in Australia and Germany’s Max-Planck-Institut fur Extraterrestrische Physik.

Featured image: Galaxy UGC 10738, seen edge-on through the European Southern Observatory’s Very Large Telescope in Chile, revealing distinct thick and thin discs. © Jesse van de Sande/European Southern Observatory


Reference: Nicholas Scott, Jesse van de Sande et al., “Identification of an [α/Fe]—Enhanced Thick Disk Component in an Edge-on Milky Way Analog”, The Astrophysical Journal Letters, 913(1), 2021. Link to paper


Provided by ASTRO-3D

Vaccination Against Mutated Protein Tested in Brain Tumor Patients For The First Time (Medicine)

Tumor vaccines can help the body fight cancer. Mutations in the tumor genome often lead to protein changes that are typical of cancer. A vaccine can alert the patients’ immune system to these mutated proteins. For the first time, physicians and cancer researchers from Heidelberg and Mannheim have now carried out a clinical trial to test a mutation-specific vaccine against malignant brain tumors. The vaccine proved to be safe and triggered the desired immune response in the tumor tissue, as the team now reports in the journal Nature.

Diffuse gliomas are usually incurable brain tumors that spread in the brain and are difficult to remove completely by surgery. Chemotherapy and radiotherapy often only have a limited effect too. In many cases, diffuse gliomas share a common feature: in more than 70 percent of patients, the tumor cells have the same gene mutation. An identical error in the DNA causes a single, specific protein building block to be exchanged in the IDH1* enzyme. This creates a novel protein structure, known as a neo-epitope, which can be recognized as foreign by the patient’s immune system.

“Our idea was to support patients’ immune system and to use a vaccine as a targeted way of alerting it to the tumor-specific neo-epitope,” explained study director Michael Platten, Medical Director of the Department of Neurology of University Medicine Mannheim and Head of Division at the German Cancer Research Center (DKFZ). The IDH1 mutation is a particularly suitable candidate here, as it is highly specific to the gliomas and does not occur in healthy tissue. Moreover, the IDH1 mutation is responsible for the development of these gliomas: “That means that a vaccine against the mutated protein allows us to tackle the problem at the root,” Platten added.

Promising preclinical results

Platten’s team had already generated an artificial version of the segment of the IDH1 protein with the characteristic mutation several years ago. This mutation-specific peptide vaccine was able to halt the growth of IDH1-mutated cancer cells in mice. In 2019, Platten was awarded the German Cancer Prize for this discovery.

Encouraged by these results, Platten and a team of physicians decided to test the mutation-specific vaccine for the first time in a phase I study** in patients newly diagnosed with a IDH1-mutated glioma (WHO grades III and IV astrocytomas). A total of 33 patients at several different centers in Germany were enrolled in the study, which was supported by the National Center for Tumor Diseases (NCT) Heidelberg and the Neurooncology Working Group (NOA) of the German Cancer Society. In addition to the standard treatment, they received the peptide vaccine produced by Michael Schmitt, Head of Cellular Immunotherapy, Department of Hematology, Oncology and Rheumatology at Heidelberg University Hospital, and Stefan Stevanović, Professor of Molecular Immunology at the Department of Immunology, University of Tübingen. The immune response was able to be evaluated in 30 patients.

The physicians did not observe any serious side effects in any of the patients who were vaccinated. In 93 percent of the patients, the immune system showed a specific response to the vaccine peptide and did so regardless of the patient’s genetic background, which determines the immune system’s important presentation molecules, the HLA proteins.

In a large proportion of the vaccinated patients, the physicians observed “pseudoprogression”, swelling of the tumor caused by a host of invading immune cells. These patients had a particularly large number of T helper cells in their blood with immune receptors that responded specifically to the vaccine peptide, as single cell sequencing revealed. “We were also able to demonstrate that the activated mutation-specific immune cells had invaded the brain tumor tissue,” reported Theresa Bunse from DKFZ, who coordinated the immunological analyses for these studies.

The three-year survival rate after treatment was 84 percent in the fully vaccinated patients, and in 63 percent of patients tumor growth had not progressed within this period. Among the patients whose immune system showed a specific response to the vaccines, a total of 82 percent had no tumor progression within the three-year period.

Vaccine concept being pursued

“We cannot draw any further conclusions about the vaccine efficacy from this early study without a control group,” remarked Michael Platten. “The safety and immunogenicity of the vaccine were so convincing that we continued to pursue the vaccine concept in a further phase I study.” In this follow-on study, the researchers are combining the IDH1 vaccine with checkpoint inhibitor immunotherapy. “Checkpoint inhibitors act as an immune boost. We believe there is a good chance that they can activate the immune cells against the gliomas to an even greater extent.” The study is being implemented in cooperation with other centers in Germany and with support from the German Cancer Consortium (DKTK).

The researchers are also preparing a phase II study to examine for the first time whether the IDH1 vaccine leads to better treatment results than the standard treatment alone. “Gliomas are diagnosed in around 5,000 people in Germany every year, of which about 1,200 are diffuse gliomas with an IDH1 mutation. Up to now, we have usually had only limited success in halting tumor progression in these patients. We believe that the IDH1 vaccine offers the potential for developing a treatment that can suppress these tumors more effectively and on a long-term basis,” commented study co-director Wolfgang Wick, Medical Director of the Neurological Clinic of Heidelberg University Hospital and Head of Division at DKFZ.

* Isocitrate dehydrogenase 1

** Neurooncology Working Group of the German Cancer Society (NOA) trial 16, ClinicalTrials.gov Identifier NCT02454634

Michael Platten, Lukas Bunse, Antje Wick, Theresa Bunse, Lucian Le Cornet, Inga Harting, Felix Sahm, Khwab Sanghvi, Chin Leng Tan, Isabel Poschke, Edward Green, Sune Justesen, Geoffrey A. Behrens, Michael Breckwoldt, Angelika Freitag, Lisa-Marie Rother, Anita Schmitt, Oliver Schnell, Jörg Hense, Martin Misch, Dietmar Krex, Stefan Stevanović, Ghazaleh Tabatabai, Joachim P. Steinbach, Martin Bendszus, Andreas von Deimling, Michael Schmitt, and Wolfgang Wick: A vaccine targeting mutant IDH1 in newly diagnosed glioma

Nature 2021, DOI: https://dx.doi.org/10.1038/s41586-021-03363-z 

Featured image: MRI image of diffuse glioma (top). © Universitätsmedizin Mannheim


Provided by DKFZ

Step-closer to Nasal Spray Drug Delivery For Parkinson’s Disease (Medicine)

Scientists at the University of York have made significant progress in the development of a nasal spray treatment for patients with Parkinson’s disease.

Researchers have developed a new gel that can adhere to tissue inside the nose alongside the drug levodopa, helping deliver treatment directly to the brain.

Levodopa is converted to dopamine in the brain, which makes-up for the deficit of dopamine-producing cells in Parkinson’s patients, and helps treat the symptoms of the disease. Over extended periods of time, however, levodopa becomes less effective, and increased doses are needed.

Professor David Smith, from the University of York’s Department of Chemistry, said: “The current drug used for Parkinson’s Disease is effective to a point, but after a long period of use the body starts to breakdown the drug before it gets to the brain where it is most needed.

“This means increased dosage is necessary, and in later stages, sometimes, instead of tablets, the drug has to be injected. Investigations into nasal sprays have long been of interest as a more effective delivery because of its direct route to the brain via the nerves that service the nose, but the challenge here is to find a way of making it adhere to the nasal tissue long enough to release a good dosage of the drug.”

The researchers created a gel, loaded with levodopa, that could flow into the nose as a liquid and then rapidly change to a thin layer of gel inside the nose. The method was tested in animal models by a team at King’s College London, where levodopa was successfully released from the gel into the blood and directly to the brain.

Professor Smith said: “The results indicated that the gel gave the drug better adhesion inside the nose, which allowed for better levels of uptake into both the blood and brain.”

The team are now working to incorporate these materials in nasal spray devices to progress to clinical trials in humans. The approach may also be relevant to other neurodegenerative diseases such as Alzheimer’s.

Khuloud Al-Jamal, Professor of Drug Delivery and Nanomedicine from King’s College London, said: “Not only did the gel perform better than a simple solution, but the brain uptake was better than that achieved using intravenous injection of the drug. This suggests that nasal delivery of Parkinson’s drugs using this type of gel may have clinical relevance.”

The research, part of the Centre for Future Health, and funded by the The Wellcome Trust, is published in the journal Advanced Science.


Reference: Wang, J. T.-W., Rodrigo, A. C., Patterson, A. K., Hawkins, K., Aly, M. M. S., Sun, J., Al, K. T., Smith, D. K., Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self-Healing Supramolecular Gel. Adv. Sci. 2021, 2101058. https://doi.org/10.1002/advs.202101058


Provided by University of York

How “Paralyzed” Immune Cells Can Be Reactivated Against Brain Tumors? (Medicine)

Brain tumor cells with a certain common mutation reprogram invading immune cells. This leads to the paralysis of the body’s immune defense against the tumor in the brain. Researchers from Heidelberg, Mannheim, and Freiburg discovered this mechanism and at the same time identified a way of reactivating the paralyzed immune system to fight the tumor. These results confirm that therapeutic vaccines or immunotherapies are more effective against brain tumors if active substances are simultaneously used to promote the suppressed immune system.

Diffuse gliomas are usually incurable brain tumors that spread in the brain and are difficult to completely remove by surgery. Chemotherapy and radiotherapy often only have a limited effect too. Oncologists are thus urgently trying to find innovative treatment approaches to fight the gliomas using the immune system – by means of therapeutic vaccines or immunotherapies.

Gliomas do not consist entirely of cancer cells: up to 50% of the tumor mass is made up of microglia cells – the brain’s own phagocytes – and of macrophages that enter the tumor through the blood vessels. Macrophages are also scavenger cells, but they are not effective in fighting tumor cells.

“If we are to make progress in developing immunotherapies or therapeutic vaccines, we need to understand exactly how the immune environment behaves during tumor development. Moreover, we were interested in whether special genetic features of the gliomas have a particular influence on the function of the glioma-associated immune cells,” explained Michael Platten, Director of the Department of Neurology of University Medicine Mannheim, Head of Division at the German Cancer Research Center (DKFZ), and director of the current study.

Scientists from Platten’s division have now teamed up with Marco Prinz, Medical Director of the Institute of Neuropathology in Freiburg, and his working group to publish a molecular “status analysis” of the glioma-associated immune cells. To do so, they specifically studied the RNA and protein profiles of individual microglia cells and macrophages. Using tumor models in mice, they were also able to demonstrate the development of the immune environment over the course of the disease.

Metabolic product of the glioma cells paralyzes immune cells in the brain

The researchers were particularly interested in tumors with what is known as an IDH mutation, which is found in around 70% of all low-grade gliomas. These tumor cells have an identical mutation that leads to a particular protein building block being exchanged in the IDH* enzyme.

As a result of the IDH mutation, the glioma cells release the cancer-promoting metabolic product (R)-2-HG, which, as the researchers discovered, affects the invading macrophages. These scavenger cells are reprogrammed as it were, blocking an immune response against the tumor: they release messenger substances that suppress the immune system and inhibit T cell activity – researcher refer to this as “immune paralysis”. “Ultimately, the IDH mutation enables the gliomas to protect themselves against the human immune system,” explained Mirco Friedrich, DKFZ researcher and physician at Heidelberg University Hospital, one of the lead authors of the current publication.

The researchers were subsequently able to decipher the molecular mechanism by which (R)-2-HG reprograms the macrophages: the cancer-promoting metabolic product interferes with the amino acid metabolism of the scavenger cells. This leads to activation of a central immune system regulatory molecule, aryl hydrocarbon receptor. The activated receptor causes immunosuppression of the macrophages.

Reactivating the paralyzed immune system

In view of this central role of the aryl hydrocarbon receptor, the researchers decided to specifically deactivate the function of this key molecule. To do so, they used a specific substance co-developed by DKFZ and Bayer. They combined this substance with a special immunotherapy, known as an immune checkpoint inhibitor. This immunotherapy is normally ineffective, but the combination rendered it effective in an animal model and prolonged the lives of the mice with IDH-mutant tumors.

“For the first time, we have thus demonstrated that the ‘paralyzed’ glioma-associated scavenger cells can be specifically reactivated by drugs in IDH-mutant gliomas,” Mirco Friedrich remarked. “The work is a good example of how single cell studies can lead to a treatment mechanism,” added Roman Sankowski from Freiburg University Hospital.

As Lukas Bunse, a physician at DKFZ and Mannheim University Medicine, explained, “We were recently able to prove in an early clinical study that a therapeutic vaccination** against IDH-mutant diffuse gliomas triggers the desired immune response in the study subjects. Our current studies now demonstrate how to sidestep the immunosuppressive environment in the brain and improve the effectiveness of this vaccine even further. This is an encouraging result showing that the immune system can help fight this currently almost incurable disease more effectively.” Clinical studies will now be conducted to reveal whether this treatment strategy is a promising option for glioma patients.


* IDH = isocitrate dehydrogenase

** Michael Platten et al., A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 2021, DOI: https://dx.doi.org/10.1038/s41586-021-03363-z

https://www.dkfz.de/en/presse/pressemitteilungen/2021/dkfz-pm-21-17-Vaccination-against-mutated-protein-tested-in-brain-tumor-patients-for-the-first-time.php

Current publication:

Mirco Friedrich, Roman Sankowski, Lukas Bunse, Michael Kilian, Edward Green, Carina Ramallo Guevara, Stefan Pusch, Gernot Poschet, Khwab Sanghvi, Markus Hahn, Theresa Bunse, Philipp Münch, Hagen M. Gegner, Jana K. Sonner, Anna von Landenberg, Frederik Cichon, Katrin Aslan, Tim Trobisch, Lucas Schirmer, Denis Abu-Sammour, Tobias Kessler, Miriam Ratliff, Daniel Schrimpf, Felix Sahm, Carsten Hopf, Dieter H. Heiland, Oliver Schnell, Jürgen Beck, Chotima Böttcher, Camila Fernandez-Zapata, Josef Priller, Sabine Heiland, Ilona Gutcher, Francisco J. Quintana, Andreas von Deimling, Wolfgang Wick, Marco Prinz and Michael Platten: Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas. Nature Cancer 2021, DOI: https://www.nature.com/articles/s43018-021-00201-z


Provided by DKFZ

Scientists Discover A New Feature That Distinguishes Modern Humans From Neanderthals (Biology)

Skoltech scientists and their colleagues from Germany and the United States have analyzed the metabolomes of humans, chimpanzees, and macaques in muscle, kidney, and three different brain regions. The team discovered that the modern human genome undergoes mutation which makes the adenylosuccinate lyase enzyme less stable, leading to a decrease in purine synthesis. This mutation did not occur in Neanderthals, so the scientists believe that it affected metabolism in brain tissues and thereby strongly contributed to modern humans evolving into a separate species. The research was published in the journal eLife.

The predecessors of modern humans split from their closest evolutionary relatives, Neanderthals and Denisovans, about 600,000 years ago, while the evolutionary divergence between our ancestors and those of modern chimpanzees dates as far back as 65 million years ago. Evolutionary biologists are after the particular genetic features that distinguish modern humans from their ancestors and may give a clue as to why humans are what they are.

Researchers from the Skoltech Center for Neurobiology and Brain Restoration (CNBR) led by Professor Philipp Khaitovich and their colleagues from the Max Planck Institutes in Leipzig, Dresden and Cologne and the University of Denver studied metabolic differences in the brain, kidney and muscle of humans, chimpanzees, and macaques.

The research supervisor was a renowned evolutionary biologist, Professor Svante Pääbo, who earlier on had discovered the Denisovan and led the Neanderthal Genome Project.

The team looked at an interesting human mutation that leads to amino acid substitution in adenylosuccinate lyase, an enzyme involved in the synthesis of purine inside DNA. This substitution reduces the enzyme’s activity and stability, which results in a lower concentration of purines in the human brain. The team showed that the new mutation is typical for humans only and does not appear in other primates or Neanderthals. The researchers proved that this mutation is indeed the reason for the metabolic peculiarities in humans by introducing it into the mouse genome. The mice subjected to mutation produced fewer purines, whereas an ancestral gene, when introduced into human cells, led to apparent metabolic changes.

“Although a powerful tool for scientists, the decoded human genome, unfortunately, cannot account for all the phenotypic differences between humans. The study of the metabolic composition of tissues can give clues about why functional changes occur in humans. I am delighted that we have succeeded in predicting the metabolic characteristics of modern humans and validated our hypotheses on mouse and cell models, even though we did not have ‘live Neanderthals’ to work on,” says lead author and Skoltech PhD student Vita Stepanova.

Featured image credit: Pavel Odinev/Skoltech


Provided by Skoltech

To Make Particles Flow More Efficiently, Put An Obstacle in Their Way (Medicine)

Microfluidic chips speed up biological and chemical experiments. Researchers made them more efficient by using cleverly designed ‘traffic circles’ to direct the flow of fluids.

Scientists used to perform experiments by stirring biological and chemical agents into test tubes.

Nowadays, they automate research by using microfluidic chips the size of postage stamps. In these tiny devices, millions of microscopic particles are captured in droplets of water, each droplet serving as the “test tube” for a single experiment. The chip funnels these many droplets, one at a time, through a tiny channel where a laser probes each passing droplet to record thousands of experimental results each second.

These chips are used for such things as testing new antibiotics, screening drug compounds, sequencing the DNA and RNA of single cells, and otherwise speeding up the pace of scientific discovery.

The problem, however, is that droplets racing toward the narrow end of the funnel can become congested and collide, breaking up in a way that can foul experiments, just like shattering test tubes in the old days. “It’s a traffic problem, like several lanes of cars trying to squeeze through a tollbooth,” said Sindy Tang, an associate professor of mechanical engineering at Stanford School of Engineering.

But her lab recently showed how it was possible to make microfluidic experiments far more efficient by putting near the base of the funnel tiny “traffic circles” that cause droplets to line up in an orderly fashion so they can zoom through the system with far fewer collisions. (see video).

In a paper published in Proceedings of the National Academy of Sciences that details the finding, she and her team, led by former Stanford Engineering graduate student Alison Bick, noted that droplet breakups occurred a thousand times less frequently in the traffic circle system as compared to today’s congestion-prone microfluidic chips. The researchers found that the location of the traffic circles was the crucial variable. Traffic circles that are too far away from the funnel exit exert no effect on the breakup. Traffic circles that are too close to the exit end up causing more “accidents,” collisions and breakups.

“There’s a sweet spot in the placement of the obstacles that minimizes the reduction in breakups and collisions in the droplet flow,” Tang said. Using properly situated traffic circles could yield a 300% increase in experimental efficiency.

The technology could lead to a faster way to screen drug compounds, as well as numerous other benefits. For instance, it could be useful in 3D printing because some 3D printers work in a similar way: They force drops of plastic or some other emulsion-based material through a fine nozzle at high speed to build structures bit by bit, and layer by layer. In this application, a system to reduce the frequency of collisions could ensure that drops of uniform size exit the nozzle in order to form the structure correctly.

“This discovery has applications that extend beyond research to other systems involving interactions between many similarly sized bodies, from aggregations of biological cells to crowds of people,” Tang said.

Other co-authors include graduate students Jian Wei Khor and Ya Gai.

This work was supported by the National Science Foundation.

Featured image: Tang’s lab showed how it was possible to make microfluidic experiments far more efficient. | Unsplash/Yingchih


Provided by University of Stanford

Link Between Local Oxygen Depletion in the Brain and Alzheimer’s Disease (Neuroscience)

The study, published in the journal Nature Aging and led by the laboratories of Dr. Alberto Pascual (CSIC), from the Neuronal Maintenance Mechanisms Group, and Prof. Javier Vitorica (University of Seville/CIBERNED) of the Physiopathology of Alzheimer’s Disease Group at IBiS, demonstrates for the first time that low oxygen levels in the so-called senile plaques in the brain reduces the immune system’s defensive capacity against the disease.

The study also suggests that this lack of oxygen in the brain enhances the action of disorders associated with Alzheimer’s disease that are characterised by low systemic oxygen levels, such as atherosclerosis and other cardiovascular diseases.

What happens in the brain?

A characteristic feature of Alzheimer’s patients is the accumulation of highly toxic substances in their brains, known as senile plaques. The brain has an immune system whose main component are the microglial cells, which were first described and named 100 years ago by Pío del Río Hortega, a disciple of Ramón y Cajal. In the absence of damage, these cells facilitate the neurons’ function. In response to Alzheimer’s disease, microglia defend neurons by surrounding senile plaques, preventing their spread in the brain and decreasing damage (Image, centre).

Alzheimer’s disease is aggravated by other pathologies, such as cardiovascular diseases, which cause a decrease in oxygen levels in the body. This study has revealed reduced oxygen levels around senile plaques, compromising microglial activity (Image, centre). When this is compounded by reduced oxygen supply to the brain due to other systemic pathologies, the microglia are unable to provide protection and there is an increase in the pathology associated with the disease (Image, right).

Relevance

Alzheimer’s disease is the leading cause of dementia in Spain and around the world. In Spain, its incidence is increasing dramatically as the population ages. Unfortunately, the origin of the disease remains unknown.

The mechanism proposed in this study is mediated by the expression of the HIF1 molecule, whose discoverers received the Nobel Prize in Physiology or Medicine in 2019. Increased HIF1 levels compromise the mitochondrial activity of microglial cells and limit their protective capacity against disease.

This study opens new lines of research to improve the metabolic capacity of microglia, which would enable a sustained response over time against the disease. Indirectly, the study supports previous work highlighting the importance of maintaining good cardiovascular health for healthy ageing.


Reference: March-Diaz, R., Lara-Ureña, N., Romero-Molina, C. et al. Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1. Nat Aging 1, 385–399 (2021). https://doi.org/10.1038/s43587-021-00054-2


Provided by University of Seville