Daily Archives: 12 Feb 2021

Material science

Scientists Manipulate Magnets At the Atomic Scale (Physics)

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Fast and energy-efficient future data processing technologies are on the horizon after an international team of scientists successfully manipulated magnets at the atomic level.

Physicist Dr Rostislav Mikhaylovskiy from Lancaster University said: “With stalling efficiency trends of current technology, new scientific approaches are especially valuable. Our discovery of the atomically-driven ultrafast control of magnetism opens broad avenues for fast and energy-efficient future data processing technologies essential to keep up with our data hunger.”

Magnetic materials are heavily used in modern life with applications ranging from fridge magnets to Google and Amazon’s data centers used to store digital information.

These materials host trillions of mutually aligned elementary magnetic moments or “spins”, whose alignment is largely governed by the arrangement of the atoms in the crystal lattice.

The spin can be seen as an elementary “needle of a compass”, typically depicted as an arrow showing the direction from North to South poles. In magnets all spins are aligned along the same direction by the force called exchange interaction. The exchange interaction is one of the strongest quantum effects which is responsible for the very existence of magnetic materials.

The ever-growing demand for efficient magnetic data processing calls for novel means to manipulate the magnetic state and manipulating the exchange interaction would be the most efficient and ultimately fastest way to control magnetism.

To achieve this result, the researchers used the fastest and the strongest stimulus available: ultrashort laser pulse excitation. They used light to optically stimulate specific atomic vibrations of the magnet’s crystal lattice which extensively disturbed and distorted the structure of the material.

The results of this study are published in the prestigious journal Nature Materials by the international team from Lancaster, Delft, Nijmegen, Liege and Kiev.

PhD student Jorrit Hortensius from the Technical University of Delft said: “We optically shake the lattice of a magnet that is made up of alternating up and down small magnetic moments and therefore does not have a net magnetization, unlike the familiar fridge magnets.”

After shaking the crystal for a very short period of time, the researchers measured how the magnetic properties evolve directly in time. Following the shaking, the magnetic system of the antiferromagnet changes, such that a net magnetization appears: for a fraction of time the material becomes similar to the everyday fridge magnets.

This all occurs within an unprecedentedly short time of less than a few picoseconds (millionth of a millionth of a second). This time is not only orders of magnitude shorter than the recording time in modern computer hard drives, but also exactly matches the fundamental limit for the magnetization switching.

Dr Rostislav Mikhaylovskiy from Lancaster University explains: “It has long been thought that the control of magnetism by atomic vibrations is restricted to acoustic excitations (sound waves) and cannot be faster than nanoseconds. We have reduced the magnetic switching time by 1000 times that is a major milestone in itself.”

Dr Dmytro Afanasiev from the Technical University of Delft adds: “We believe that our findings will stimulate further research into exploring and understanding the exact mechanisms governing the ultrafast lattice control of the magnetic state.” 

Featured image: Researchers used ultrashort laser pulse excitation to optically stimulate specific atomic vibrations of the magnet’s crystal lattice © Ella Maru Studio and Caviglia Lab (TU Delft)

Reference: Afanasiev, D., Hortensius, J.R., Ivanov, B.A. et al. Ultrafast control of magnetic interactions via light-driven phonons. Nat. Mater. (2021). https://doi.org/10.1038/s41563-021-00922-7

Provided by University of Lancaster

Medicine

Antitumoral Effects of LXR Activation ( Medicine)

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Macrophages that boost tumor growth

Tumor cells are able to avoid the attack of the immune system through several mechanisms. For instance, these can secrete factors that turn macrophages -cells in the immune system- into dual action agents that contribute to the tumor progress and will protect it from immune body defences: these become, thus, the tumor-associated macrophages (TAMs).

An article published in the journal Cancer Research describes a new molecular mechanism that counteracts the immunosupressive action of these macrophaes to boost tumor growth, and brings knowledge of potential interest for the design of future therapeutical options against cancer. The preclinical study is led by the tenure-track 2 lecturer Annabel Valledor, from the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB).

Among the participants are also the researchers of the Faculty of Pharmacy and Food Sciences of the UB, the Josep Carreras Leukaemia Research Institute, the Sant Pau Institute of Biomedical Research, the University of Las Palmas de Gran Canaria, University College London, and the Free University of Brussels, among others.

Macrophages that boost tumor growth

Macrophages are cells in the immune system that unfold several functions (they kill invasive pathogens, remove cells or damaged tissue, etc.). However, in the tumoral microenvironment, tumor-associated macrophages can become an enemy to patients with cancer. Therefore, a field of study of great outreach in biomedicine is the one finding strategies to activate TAMs and help the immune system fight tumors, as well as improve the effects of anticancer therapies.

From left to right, the experts José María Carbó, Annabel Valledor, Joan Font-Díaz and Theresa E. León. © University of Barcelona

The article published in Cancer Research describes how the action of a compound known as TO901317 limits the ability of TAMs to protect the tumor in laboratory animals. According to the results, the TO901317 compound can inhibit the synthesis of molecules that serve to attract regulatory T lymphocytes (Treg) to the tumor.

“In a healthy person, the most important function of Treg is to maintain the balance of the immune system and avoid unwanted responses towards the own body. However, in a tumor, Treg stop the antitumoral activity of other types of lymphocytes. Actually, several studies show that a high number of Treg in the tumoral microenvironment suggests a worse prognosis”, notes lecturer Annabel Valledor, from the Department of Cell Biology, Physiology and Immunology and IBUB.

Antitumoral effects of LXR activation

In particular, the TO901317 compound acts on the liver X receptor (LXR), a transcription factor of the family of nuclear receptors that regulates the gene expression with a key role in the activity of macrophages and the metabolism.

As stated in the article, the activation of LXR by the antagonist TO901317 inhibits the expression of the transcription factor IRF4 in macrophages. Specifically, the IRF4 factor is necessary so that chemokines Ccl17 and Ccl22 are expressed as a response to signals such as interleukin IL-4 or the GM-CSF factor. As a result, the action of the TO901317 compound inhibits the production of chemokines Ccl17 and Ccl22, which are important for the recruitment of regulatory T lymphocytes to the tumoral microenvironment.

“Once the LXR is activated, tumor-associated macrophages undergo important changes in their gene expression profile, and as a result, their ability to produce molecules with an immunopressive function in the tumoral microenvironment decreases”, notes researcher Joan Font Díaz, from the Faculty of Biology and IBUB.

This action is correlated to a decrease in the number of Treg in the tumor and a slower tumor growth, as stated by the authors of the study.

Featured image: The new study describes how the activation of the nuclear receptor LXR limits the activity of tumor-associated macrophages to protect the tumor. © University of Barcelona

Reference: José M. Carbó, Theresa E. León, Joan Font-Díaz, Juan Vladimir De la Rosa, Antonio Castrillo, Felix R. Picard, Daniel Staudenraus, Magdalena Huber, Lídia Cedó, Joan Carles Escolà-Gil, Lucía Campos, Latifa Bakiri, Erwin F. Wagner, Carme Caelles, Thomas Stratmann, Jo A. Van Ginderachter and Annabel F. Valledor, “Pharmacological activation of LXR alters the expression profile of tumor-associated macrophages and the abundance of regulatory T cells in the tumor microenvironment”, Cancer Res December 23 2020 DOI: 10.1158/0008-5472.CAN-19-3360

Provided by University of Barcelona

Medicine

New Insight Into Protein Structures That Could Treat Huntington’s Disease (Medicine)

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Our cells have specialized waste disposal systems to keep our body free from clumps of defective proteins. To fight diseases like Huntington’s, where protein clumps damage and ultimately kill brain cells, it is necessary to know how these disposal systems – which are themselves made up of proteins – work. Scientists studied a disposal system that protects against clumps like those in Huntington’s disease. As these disposal proteins themselves also form ‘good’ clumps, it was difficult to discover their exact structure. Using special techniques, the scientists discovered that, under normal circumstances, two regions of these proteins are folded onto themselves. However, when they encounter the clumps, these two parts release each other and are then free to attach to another protein that dissolves the clumps. In the distant future, this insight may lead to drugs that stimulate the prevention of these harmful protein clumps.

In Huntington’s disease, a faulty protein aggregates in brain cells and eventually kills them. Such protein aggregates could, in principle, be prevented with a heat shock protein. However, it is not well known how these proteins interact with the Huntington’s disease protein. New research by Patrick van der Wel (University of Groningen, the Netherlands) and colleagues at the University of Texas has partially resolved the structure of heat shock proteins that bind to such aggregating proteins, helping us to understand how they work. The results were published on 11 February in the journal Nature Communications.

Heat shock proteins (Hsp) are produced by cells that are exposed to stressful conditions. The Hsp family is diverse, and quite a few of the proteins function as chaperone. This means that they help other proteins to fold (or re-fold after being damaged) in the correct way. “These proteins can assist in folding thousands of different proteins. To this end, they use co-chaperones with specific binding abilities,” explains Patrick van der Wel, Associate Professor of Solid State NMR Spectroscopy at the University of Groningen.

Ordered

One class of heat shock proteins, Hsp40, helps to suppress protein aggregates like those that appear in Huntington’s disease. These Hsp40 proteins come in different kinds, and some of them will bind specifically to aggregating proteins with a lot of repeated glutamine amino acids, like the faulty protein found in Huntington’s disease. One of these Hsp40 proteins is called DnaJB8, and this was the protein studied by Van der Wel and his colleagues.

“In order to understand the action of DnaJB8, we need to know what it looks like,” says Van der Wel. However, it is difficult to resolve the structure of this type of protein. “It appears as a dimer or an oligomer, so a number of these protein units work together, but their structure is not really ordered,” he continues. This makes it impossible to use standard techniques, which all require ordered structures.

Carbon atoms

Van der Wel was asked by colleagues at the University of Texas to help tackle this problem. Van der Wel is specialized in solid state NMR spectroscopy, a technology that can measure how atoms are connected to each other. In simple terms, the NMR signals of two connected carbon atoms in DnaJB8 depend on how they interact with other atoms in the molecule. Therefore, the measured spectrum of the carbon atoms can show in which amino acid they are located. Such information can be used to get an idea of the protein’s structure, even if it is not well ordered.

Solid-state NMR spectroscopy (top right) highlights how DnaJB8 chaperone protein blocks itself. In the displayed NMR data each signal comes from an amino acid in a key part of the chaperone protein: its J-domain. Based on the shape and steepness of the contour lines, we know that this domain is trapped by the chaperone itself, keeping it from doing its job. Fortunately it is also shown how this inactivated state can be disrupted, revealing an intricate orchestration in how chaperone proteins work together to fight and prevent diseases such as Huntington’s disease.

The DnaJB8 protein is made up of different domains, with different functions. Through a series of experiments, Van der Wel was able to determine which domains are stuck inside the DnaJB8 protein, and which are available on the outside. The experiments suggested that the so-called ‘J domain’ of DnaJB8 was able to switch between being stuck and being accessible. This is important because this part of the DnaJB8 protein is responsible for turning on the Hsp70 protein, which can prevent the protein aggregates from forming. In other words, there seems to be a ‘switch’ in DnaJB8 that controls this interaction with Hsp70. Interestingly, this switch was found to be located in a domain of DnaJB8 whose exact role was previously unclear.

Hypothesis

“Thus, our hypothesis based on the structure was that the DnaJB8 is inactive until it binds to the faulty proteins, and that it then attracts Hsp70,” says Van der Wel. A series of simulations and experiments at the University of Texas confirmed this idea and yielded a detailed model of how these proteins work together.

DnaJB8 is a protein that is mainly found in the testes. However, a very similar protein called DnaJB6 is present in the brain, where Huntington’s disease strikes. It seems more than likely that this protein acts similarly, when it protects against glutamine-rich proteins that aggregate in the brain cells of patients. “It may take many more years, but now that we understand how this process works, it could help us to find a way to enhance the activity of DnaJB6, which could reduce the protein aggregates that cause the disease,” concludes Van der Wel.

Featured image: Patrick van der Wel | Photo Sylvia Germes

Reference: Bryan D. Ryder, Irina Matlahov, Sofia Bali, Jaime Vaquer-Alicea, Patrick C. A. van der Wel, & Lukasz A. Joachimiak: Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone. Nature Communications, 11 February 2021

Provided by University of Groningen

Biology

Scientists Identify How Harmless Gut Bacteria “Turn Bad” (Biology)

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Scientists have determined how harmless E. coli gut bacteria in chickens can easily pick up the genes required to evolve to cause a life-threatening infection.

An international team of scientists has determined how harmless E. coli gut bacteria in chickens can easily pick up the genes required to evolve to cause a life-threatening infection. Their study, published in Nature Communications, warns that such infections not only affect the poultry industry but could also potentially cross over to infect humans.

E. coli is a common bacterium that lives in the intestines of most animals, including humans. It is usually harmless when it stays in the gut, however it can become very dangerous if it invades the bloodstream, causing a systemic infection that can even lead to death.

Avian pathogenic E.coli (APEC) is most common infection in chickens reared for meat or eggs. It can lead to death in up to 20 per cent of cases and causes multi-million pound losses in the poultry industry. The problem is made worse by increasing antibiotic resistance and infections also pose a risk of causing disease in humans.

The team of scientists, led by the Milner Centre for Evolution at the University of Bath, sequenced and analysed the whole genomes of E. coli bacteria found in healthy and infected chickens bred at commercial poultry farms to better understand why and how these normally innocuous bugs can turn deadly.

They found there was no single gene responsible for switching a harmless bacterium into a pathogenic one, but rather that it could be caused by several combinations of a diverse group of genes.

Their results indicate that all bacteria in chicken intestines have the potential to pick up the genes they need to turn into a dangerous infection, through a process called horizontal gene transfer.

Horizontal gene transfer enables bacteria to acquire new genetic material from other bacteria nearby. This can happen by scavenging DNA molecules from dead bacteria; by exchanging strands of DNA by having ‘bacterial sex’ or by getting infected by viruses which transfer DNA from one bacterium to another.

Professor Sam Sheppard, from the Milner Centre for Evolution at the University of Bath, led the study. He said: “Previously we thought that E. coli became pathogenic by acquiring specific genes from other bugs, often packaged in mobile elements called plasmids.

“But our study compared the genomes of disease-causing and harmless E. coli in chickens and found that they can ‘turn bad’ simply by picking up genes from their environment.

“Bacteria do this all the time inside the guts of chicken, but most of the time the scavenged genes are detrimental to the bacteria so it becomes an evolutionary dead end.

“However, there are 26 billion chickens worldwide, representing around 70 per cent of all bird biomass on earth.

“That increases the likelihood of bacteria picking up genes that could help the bacteria survive and turn infectious, or even jump species to infect humans.”

The study authors stress the need to monitor strains that are most likely to become pathogenic so can treat them before they become dangerous.

Professor Sheppard said: “We were surprised to find that it’s not just a single strain that causes APEC, but any strain can potentially acquire the ‘monster combination’ of genes needed to turn bad.”

Strains with the potential to turn pathogenic could be identified using a similar method to that used to detect variant strains of Covid19. After whole genome sequencing, rapid PCR tests can be used to probe for specific genes that could lead to an APEC infection.

Professor Sheppard said: “We identified around 20 genes that are common in pathogenic bugs and if we can look out for these key genes in a flock of birds, that would help farmers target those carriers before they cause a problem.”

Featured image: Professor Sam Sheppard from the Milner Centre for Evolution at the University of Bath led the study. © University of Bath

Reference: Mageiros, L., Méric, G., Bayliss, S.C. et al. Genome evolution and the emergence of pathogenicity in avian Escherichia coli. Nat Commun 12, 765 (2021). https://doi.org/10.1038/s41467-021-20988-w

Provided by University of Bath

Medicine

Going The Distance–Insights Into How Cancer Cells Spread (Medicine)

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Most tumors consist of a heterogenous mix of cells. Genetic mutations found only in some of these cells are known to aid with the spread and progression of cancer. However, oncologists often find that when tumors metastasize to distant organs, they retain this heterogenous nature–a phenomenon termed “polyclonal metastasis”. The mechanism by which non-metastatic cells accompany the metastatic cells is ambiguous. Now, Masanobu Oshima and his research team have used mouse models to explain how non-metastatic cells begin their long commute.

The team has previously developed various cancerous mutants of mice and analyzed them closely to reveal which cancer cells inherently spread and which do not. It was found that cells with four mutations, colloquially termed AKTP, were the most fatal. When these cells were transplanted into the spleens of mice, they migrated to and formed colonies in the livers within 3 days. In contrast, cells with two mutations, AK and AP, could not traverse this distance. To replicate polyclonal metastasis, AP cells were then co-transplanted with AKTP cells, and voila, both cell types indeed moved into the livers. Instead, when AP cells were injected into the blood (without prior exposure to the AKTP cells) they could not metastasize. Certain processes seemed to be at play when the cells were incubated together.

Next, AKTP cells within the liver tumors were killed to see how closely that affected the AP cells. The AP cells continued thriving and grew into larger tumors suggesting they did not need the AKTP cells anymore. Thus, at some point in the journey from the spleen to the liver the AP cells turned dangerous. To identify this point, the researchers traced back the chain of events. Within a day after transplantation, AKTP clusters were found in the sinusoid vessel, a major blood vessel supplying the liver. By 14 days, this cluster transformed into a mass termed as a “fibrotic niche”. The same mass was observed with a mix of AP and AKTP cells, but not with AP cells alone. What’s more, within this mass AKTP cells were activating hepatic stellate cells (HSCs). HSCs are responsible for scarring of liver tissue. Activated HSCs then set up the perfect environment for AP cells to proliferate infinitely. Harboring the AP cells within the fibrotic environment was, therefore, a key step.

Organoid transplantation experiments. (a) Fluorescence-labeled organoids (top), and liver tissues (macro images) of organoid-transplanted mice under fluorescent microscope (bottom). (b) Liver tissues (macro images) of chimeric organoid-transplanted mice under fluorescent microscope (top), and fluorescent immunohistochemistry of metastatic lesions. © Kanazawa University

“These results indicate that non-metastatic cells can metastasize via the polyclonal metastasis mechanism using the fibrotic niche induced by malignant cells,” conclude the researchers. Targeting this fibrotic niche might be a promising strategy to keep the spread of solid tumors in check.

Background

Polyclonal metastasis: Solid tumors such as breast and colorectal cancer are famous for spreading notoriously. These tumor cells break off from the point of origin and migrate via the bloodstream into distant organs to set up shop. It is often found that such metastatic tumors are genetically diverse in nature. However, the role of cancer mutations in conferring tumors metastatic is still unclear. Older theories have suggested that genetic alterations are the sole key to turning cells metastatic. However, the study depicted here shows that other mechanisms are also at play.

Hepatic stellate cells (HSCs) and the fibrotic niche: HSCs are specialized cells of the liver responsible for scarring and wound healing mechanisms when activated. Upon activation, (after events such as liver damage) HSCs start proliferating and induce fibrotic tissue within the liver. Thus, their activation by AKTP cells resulted in development of the fibrotic niche, an environment particularly favorable for tumor proliferation.

Featured image: Schematic drawing of polyclonal metastasis. Metastatic cells generate metastatic niche by activation of hepatic stellate cells (HSCs). Non-metastatic cells can survive and proliferate with the presence of such metastatic niche, resulting in polyclonal metastasis development. © Kanazawa University

Reference: Kok, S.Y., Oshima, H., Takahashi, K. et al. Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation. Nat Commun 12, 863 (2021). https://doi.org/10.1038/s41467-021-21160-0

Provided by Kanazawa University

Medicine

Instant Death From Heart Attack More Common in People Who Do Not Exercise (Medicine)

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An active lifestyle is linked with a lower chance of dying immediately from a heart attack, according to a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

Heart disease is the leading cause of death globally and prevention is a major public health priority. The beneficial impact of physical activity in stopping heart disease and sudden death on a population level is well documented. This study focused on the effect of an active versus sedentary lifestyle on the immediate course of a heart attack – an area with little information.

The researchers used data from 10 European observational cohorts including healthy participants with a baseline assessment of physical activity who had a heart attack during follow-up – a total of 28,140 individuals. Participants were categorised according to their weekly level of leisure-time physical activity as sedentary, low, moderate, or high.

The association between activity level and the risk of death due to a heart attack (instantly and within 28 days) was analysed in each cohort separately and then the results were pooled. The analyses were adjusted for age, sex, diabetes, blood pressure, family history of heart disease, smoking, body mass index, blood cholesterol, alcohol consumption, and socioeconomic status.

A total of 4,976 (17.7%) participants died within 28 days of their heart attack – of these, 3,101 (62.3%) died instantly. Overall, a higher level of physical activity was associated with a lower risk of instant and 28-day fatal heart attack, seemingly in a dose–response-like manner. Patients who had engaged in moderate and high levels of leisure-time physical activity had a 33% and 45% lower risk of instant death compared to sedentary individuals. At 28 days these numbers were 36% and 28%, respectively. The relationship with low activity did not reach statistical significance.

Study author Dr. Kim Wadt Hansen of Bispebjerg Hospital, Copenhagen, Denmark said: “Almost 18% of patients with a heart attack died within 28 days, substantiating the severity of this condition. We found an immediate survival benefit of prior physical activity in the setting of a heart attack, a benefit which seemed preserved at 28 days.”

He noted: “Based on our analyses, even a low amount of leisure-time physical activity may in fact be beneficial against fatal heart attacks, but statistical uncertainty precludes us from drawing any firm conclusions on that point.”

The authors said in the paper: “Our pooled analysis provides strong support for the recommendations on weekly physical activity in healthy adults stated in the 2016 European Guidelines on cardiovascular disease prevention in clinical practice;2 especially as we used cut-off values for physical activity comparable to those used in the guidelines.”

The guidelines recommend that healthy adults of all ages perform at least 150 minutes a week of moderate intensity or 75 minutes a week of vigorous intensity aerobic physical activity or an equivalent combination thereof.

Dr. Hansen concluded: “There are many ways to be physically active at little or no cost. Our study provides yet more evidence for the rewards of exercise.”

The Danish Heart Foundation (18-R124-A8318-22104). The funding source was not involved in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication.

References: (1) Hansen KW, Peytz N, Blokstra A, et al. Association of fatal myocardial infarction with past level of physical activity: a pooled analysis of cohort studies. Eur J Prev Cardiol. 2021. doi: 10.1093/eurjpc/zwaa146. https://academic.oup.com/eurjpc/article-lookup/doi/10.1093/eurjpc/zwaa146 (2) Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2016;37:2315–2381. https://academic.oup.com/eurheartj/article/37/29/2315/1748952

About the European Society of Cardiology

The ESC brings together health care professionals from more than 150 countries, working to advance cardiovascular medicine and help people to live longer, healthier lives.

About the European Journal of Preventive Cardiology

The European Journal of Preventive Cardiology is the world’s leading preventive cardiology journal, playing a pivotal role in reducing the global burden of cardiovascular disease.

Medicine

New Study Identifies the Main Genetic Causes of Autoimmune Addison’s Disease (Medicine)

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Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition.

Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison’s disease, a condition where the body’s immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone.

Groundbreaking study

The rarity of Addison’s disease has until now made scanning of the whole genome for clues to the disease’s genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world’s two largest Addison’s disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator).

AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life.

Knowing what predisposes people to develop Addison’s disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye’s lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future.

Featured image: Professor Eystein Husebye, University of Bergen, Norway © Ingvild F. Melien

Reference: Eriksson, D., Røyrvik, E.C., Aranda-Guillén, M. et al. GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nat Commun 12, 959 (2021). https://doi.org/10.1038/s41467-021-21015-8

Provided by University of Bergen

Maths

UrFU Mathematician’s New Methods For Solving Optimal Control Problem of Objects (Maths)

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Mathematician from Ural Federal University Yurii Averboukh, suggests new methods for solving optimal control problem of a group of objects by implementing the concept of dynamic stability by Krasovski and Subbotin

“We are surrounded by a huge number of systems – biological, technical, economic, which we can influence, which we can control. The task is to do it optimally, for example, reaching the desired point with a minimum of effort, resources, and time, – explains Prof. Yurii Averboukh. – From a mathematical point of view, the task is narrowed down to the theory of optimal control. A classic example of this theory is moon landing: fuel consumption optimization enables to increase cargo volumes transported to the moon”.

A special section of optimal control theory is the theory of differential games. It studies the control of one, several, or many objects in a conflict situation and based on current information about the behavior of the players – both leading (fleeing) and followers (catching up). Like the whole theory of optimal control, the theory of differential games is closely related to the theory of differential equations in partial derivative.

A strong connection between the theory of partial differential equations and differential games was established in the 1970s-1980s by the most prominent representatives of the Ural mathematical school, academicians Nikolai Krasovski, who developed the concept of stability, and Andrei Subbotin, who expressed the stability condition in the form of partial differential equations.

“The stability function is a function of the minimum guaranteed result of the «controlling» player. According to the Krasovski’s theory, we “force” our “fleeing” opponent, be it a person, a technical device, or forces of nature, to “tell” us about their managerial intentions. Based on this data and calculating the number of this player’s gains as a result of the game, you can estimate your own final gains. The situation when at the end of the game we do not make our results worse, corresponds to the stability condition – says Yurii Averboukh. – Since we understand what we will get in the end, the situation gets completely predictable. That is, the calculation of the stability function allows you to foresee and predict the result of the development of the situation and, consequently, to build a strategy for managing it.”

“The genius of the approach of Academicians Krasovski and Subbotin is that having developed the so-called strategy of extreme shift, they showed how, knowing the” intentions “of the opposing player, in this case, the wind, who is ready to” tell “about his plans to control the plane (let’s call such a player “Stupid”, “dummy”), play against the “smart”, “malicious”, that is, the real wind. Thus, to fulfill the stability condition, it is enough to play against the “dummy” wind, and to play against the “smart” player, the real wind, you need to calculate the stability function by solving the partial differential equations,” continues Prof. Yurii Averboukh.

The scientist, in turn, wondered: is the Krasovski-Subbotin’s concept of stability applicable to the situation of managing a large number of similar objects. In his article published in the Journal of Mathematical Analysis and Applications, Prof. Averboukh substantiated a positive answer to this question. He showed how the solution looks in the form of partial differential equations.

“The matter turned out to be not easy: after all, we are dealing with many agents, assuming that their number is infinite, like the number of molecules in the air. To ensure that all the objects act in a consistent manner, each of them needs to be shown how to manage it. At the same time, we assume that a separate object acts without “recognizing” the others separately, but perceiving them as an “impersonal” mass, that is, in the so-called “middle field,” says Yurii Averboukh. “The use of the description language of measures (shares) that gives an idea of the density of objects within the boundaries of a certain area, allowed us to cope with this problem”.

The most obvious practical application of the research results of Yurii Averboukh today is the control of squadrons of unmanned aerial vehicles.

“Let’s imagine that the drones are tasked to divide themselves across the field at a given time and treating it from pests. In this case, the wind affects the drones. Having determined their density in a particular zone at the start from the ground (for example, it turns out that 20% of drones are concentrated in one area, and 80% in another) and calculating the stability function, we can, firstly, give the drones a command to distribute more uniformly, and, secondly, confidently predict that at a certain moment the error in their uniform distribution will be, say, 10%, after some time – 9%, and so on, and at the end – 5%, which will be an acceptable minimum value. That is, the solution to the stability function will show how to move the drones to take the optimal position over the field at the right time, “explains Yurii Averboukh.

In this case, the “dummy” we are playing against in PDEs is the “dumb” wind that “tells” how it will affect the drones. Knowing this and according to the Krasovsky-Subbotin extreme shift strategy, one can calculate how the “smart and evil” wind will act, that is, what effect it will have on drones in reality and, therefore, how they need to move in order not to worsen the result, but if possible improve it.

In the future, according to Yurii Averboukh, the same principles can be applied in the management of nanoparticles, for example, to transport drugs to a certain part of the body.

Featured image: Mathematician from Ural Federal University Yurii Averboukh, suggests new methods for solving optimal control problem of a group of objects © Ural Federal University

Reference: Yurii Averboukh, A stability property in mean field type differential games, Journal of Mathematical Analysis and Applications, Volume 498, Issue 1, 2021, 124940, ISSN 0022-247X, https://doi.org/10.1016/j.jmaa.2021.124940. (https://www.sciencedirect.com/science/article/pii/S0022247X21000196)

Provided by Ural Federal University

Chemistry

Detecting Single Molecules And Diagnosing Diseases With a Smartphone (Chemistry)

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LMU researchers show that the light emitted by a single molecule can be detected with a low-cost optical setup. Their prototype could facilitate medical diagnostics.

Biomarkers play a central role in the diagnosis of disease and assessment of its course. Among the markers now in use are genes, proteins, hormones, lipids and other classes of molecules. Biomarkers can be found in the blood, in cerebrospinal fluid, urine and various types of tissues, but most of them have one thing in common: They occur in extremely low concentrations, and are therefore technically challenging to detect and quantify.

Many detection procedures use molecular probes, such as antibodies or short nucleic-acid sequences, which are designed to bind to specific biomarkers. When a probe recognizes and binds to its target, chemical or physical reactions give rise to fluorescence signals. Such methods work well, provided they are sensitive enough to recognize the relevant biomarker in a high percentage of all patients who carry it in their blood. In addition, before such fluorescence-based tests can be used in practice, the biomarkers themselves or their signals must be amplified. The ultimate goal is to enable medical screening to be carried out directly on patients, without having to send the samples to a distant laboratory for analysis.

Molecular antennas amplify fluorescence signals

Philip Tinnefeld, who holds a Chair in Physical Chemistry at LMU, has developed a strategy for determining levels of biomarkers present in low concentrations. He has succeeded in coupling DNA probes to tiny particles of gold or silver. Pairs of particles (‘dimers’) act as nano-antennas that amplify the fluorescence signals. The trick works as follows: Interactions between the nanoparticles and incoming light waves intensify the local electromagnetic fields, and this in turn leads to a massive increase in the amplitude of the fluorescence. In this way, bacteria that contain antibiotic resistance genes and even viruses can be specifically detected.

“DNA-based nano-antennas have been studied for the last few years,” says Kateryna Trofymchuk, joint first author of the study. “But the fabrication of these nanostructures presents challenges.” Philip Tinnefeld’s research group has now succeeded in configuring the components of their nano-antennas more precisely, and in positioning the DNA molecules that serve as capture probes at the site of signal amplification. Together, these modifications enable the fluorescence signal to be more effectively amplified. Furthermore, in the minuscule volume involved, which is on the order of zeptoliters (a zeptoliter equals 10-²¹ of a liter), even more molecules can be captured.

The high degree of positioning control is made possible by DNA nanotechnology, which exploits the structural properties of DNA to guide the assembly of all sorts of nanoscale objects – in extremely large numbers. “In one sample, we can simultaneously produce billions of these nano-antennas, using a procedure that basically consists of pipetting a few solutions together,” says Trofymchuk.

Routine diagnostics on the smartphone

“In the future,” says Viktorija Glembockyte, also joint first author of the publication, “our technology could be utilized for diagnostic tests even in areas in which access to electricity or laboratory equipment is restricted. We have shown that we can directly detect small fragments of DNA in blood serum, using a portable, smartphone-based microscope that runs on a conventional USB power pack to monitor the assay.” Newer smartphones are usually equipped with pretty good cameras. Apart from that, all that’s needed is a laser and a lens – two readily available and cheap components. The LMU researchers used this basic recipe to construct their prototypes.

They went on to demonstrate that DNA fragments that are specific for antibiotic resistance genes in bacteria could be detected by this set-up. But the assay could be easily modified to detect a whole range of interesting target types, such as viruses. Tinnefeld is optimistic: “The past year has shown that there is always a need for new and innovative diagnostic methods, and perhaps our technology can one day contribute to the development of an inexpensive and reliable diagnostic test that can be carried out at home.”

Featured image credit: © Lennart Grabenhorst / Tinnefeld Group

Reference: Trofymchuk, K., Glembockyte, V., Grabenhorst, L. et al. Addressable nanoantennas with cleared hotspots for single-molecule detection on a portable smartphone microscope. Nat Commun 12, 950 (2021). https://doi.org/10.1038/s41467-021-21238-9

Provided by LMU Munich