Scientists Identify Mechanism Linking Traumatic Brain Injury to Neurodegenerative Disease (Neuroscience)

Study reveals that brain injuries can cause intracellular transport defects that can potentially lead to protein build-up and neurodegenerative disease.

Scientists have revealed a potential mechanism for how traumatic brain injury leads to neurodegenerative diseases, according to a study in fruit flies, and rat and human brain tissue, published today in eLife.

The results could aid the development of treatments that halt the progression of cell damage after brain injury, which can otherwise lead to neurological diseases such as amyotrophic lateral sclerosis (ALS), and Alzheimer’s and Parkinson’s disease.

Repeated head trauma is linked to a progressive neurodegenerative syndrome called chronic traumatic encephalopathy (CTE). Postmortem tissues from patients with CTE show dysfunctional levels of a molecule called TDP-43, which is also found in ALS, Alzheimer’s disease and frontotemporal dementia.

“Although TDP-43 is a known indicator of neurodegeneration, it was not clear how repeated trauma promotes the build-up of TDP-43 in the brain,” explains first author Eric Anderson, Postdoctoral Research Associate at the Department of Pediatrics at the University of Pittsburgh, Pennsylvania, US. “We have shown that repetitive brain trauma in fruit flies leads to a build-up of TDP-43. In this study we measured the changes of proteins in the fruit fly brain post injury to identify the molecular pathways that cause this.”

From an analysis of 2,000 proteins, the team identified 361 that significantly changed in response to injury. These included components of the nuclear pore complex (NPC) involved in nucleocytoplasmic transport – the shuttling of important cargoes between the cell nucleus and the rest of the cell.

They found that a family of molecules that make up the NPC called nucleoporins (Nups) were increased in both larval and adult flies after injury. When they looked at the distribution pattern of Nups around the edge of the nucleus in fruit fly nerve cord cells, they found it was altered after brain trauma: there were gaps in the nuclear membrane and clumps of Nups. They also found changes in a key enzyme involved in transporting molecules in and out of the nucleus in injured brains. As a result, the transport of fluorescently labelled cargo in and out of the nucleus was impaired.

Having established that brain injury impairs the transport machinery between the nucleus and the rest of the cell, the team looked at whether the build-up of Nups leads to the aggregation of TDP-43 seen in neurodegenerative diseases. They created fruit flies that produce excess Nup protein and then stained the brain cells for the fruit fly version of TDP-43, called Tbph. They found a significant increase in the number of Tbph deposits in brains that had too much Nup compared with normal brains. Moreover, these high levels of Nups were also toxic to the flies, causing decreased motor function and reducing the distance they could climb in a certain timeframe. When the level of Nups was reduced in cells after injury, this improved the flies’ climbing ability and lifespan, highlighting an avenue to explore for new treatments.

Finally, the team looked at whether the increased build-up of a Nup molecule (Nup62) was also seen in human brain tissue after injury. They examined postmortem brain tissue from patients with mild and severe CTE matched to healthy tissue from people of the same age. All mild and severe patients were involved in sports, while healthier cases were not. They found that Nup62 was present in large amounts in the wrong place in patients with mild and severe disease, but not in the healthy group, and the degree of Nup62 aggregation increased with the severity of disease. They also saw similar changes in the distribution of Nup62 in a rat model of traumatic brain injury.

“Our study reveals that traumatic brain injury can disrupt nuclear transport machinery of the cells, which plays an essential role in normal cell functions such as communication,” concludes senior author Udai Pandey, associate professor of pediatrics, human genetics and neurology at the University of Pittsburgh School of Medicine. “This suggests that the accumulation of neurodegenerative hallmark proteins caused by injury begins with these nuclear transport defects, and that targeting these defects could be a strategy for preventing trauma-induced neurological disorders.”

Other authors of this study include: Sukhleen Kour, PhD, Nandini Ramesh, PhD, Amanda Gleixner, PhD, Christopher Donnelly, PhD, Jeffrey Cheng, Anthony Kline, PhD, and Julia Kofler, MD, from the University of Pittsburgh; Andrés Morera and Jacob Schwartz, PhD, from the University of Arizona; Jonathan Cherry, PhD, and Thor Stein, MD, PhD, from Boston University School of Medicine; and Christopher Ebmeier, PhD, and William Old, PhD, from the University of Colorado.

This work was supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, US.

Featured image: Proteomic analysis of Drosophila brains identifies novel components of the nucleocytoplasmic transport machinery that are disrupted in response to TBI. © Anderson et al.


Reference: Eric N Anderson et al., “Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology”, elife, 2021. Link to paper


Provided by Elife

Direct Action of SARS-CoV-2 On Several Organs May Cause Exacerbated Immune Response in Children (Medicine)

Besides common symptoms such as fever, cough and respiratory distress, some children have an atypical form of COVID-19 known as multisystem inflammatory syndrome in children (MIS-C), characterized by persistent fever and inflammation of several organs, such as the heart and intestines, as well as the lungs to a lesser extent. Reports of MIS-C have been increasingly associated with severe cases and deaths in several countries including Brazil since the onset of the pandemic.

Researchers affiliated with the University of São Paulo’s Medical School (FM-USP) and Adolfo Lutz Institute in Brazil performed the largest series of autopsies to date on children who died from COVID-19. Their findings show that the ability of SARS-CoV-2 to invade and damage several organs is one of the factors leading to MIS-C, producing a wide array of clinical manifestations that include abdominal pain, heart failure and seizures, as well as persistent fever.

The study was supported by FAPESP and reported in an article in EClinicalMedicine, a Lancet group journal.

“The direct action of the virus on the tissue of various organs is one of the reasons why children with this syndrome have an exacerbated and altered inflammatory response to infection,” Marisa Dolhnikoff, last author of the article, told Agência FAPESP. Dolhnikoff is a professor at FM-USP.

The researchers performed autopsies on five children who died from COVID-19 in São Paulo: one boy and four girls aged between 7 months and 15 years. Two were seriously ill before being infected by SARS-CoV-2, one with cancer and the other with a congenital genetic disorder. The other three were previously healthy and developed MIS-C with different clinical manifestations. One had myocarditis (inflammation of the heart muscle), another had colitis (inflammation of the bowel), and a third had acute encephalopathy (brain damage) with seizures.

A minimally invasive technique, ultrasound-guided with coaxial and punch needles, was used to collect tissue samples from all major organs. The presence of SARS-CoV-2 in the samples was determined by real-time reverse transcription polymerase chain reaction (RT-PCR, the technique also used to diagnose COVID-19) and by immunohistochemistry, in which antibodies were deployed to detect the viral nucleocapsid protein (N) and one of the spike proteins (S2).

Histopathological analysis showed that both children with severe pre-existing disease had “classic” severe COVID-19, characterized by acute respiratory distress due to extensive damage to the lung alveoli caused by SARS-CoV-2. The virus was also detected in other organs.

The three previously healthy children were found to have inflammatory lesions outside the lungs, such as myocarditis and colitis. The virus was detected in heart endothelial and muscle cells from the patient with myocarditis, in intestinal tissue from the child with acute colitis, and in brain tissue from the patient with acute encephalopathy.

“We found that SARS-CoV-2 had spread throughout the body via the blood vessels, infecting various types of cell and tissue in these children. The clinical manifestations varied according to the organ targeted,” Dolhnikoff said. “It’s important for pediatricians to watch out for these possible differences in the clinical manifestations of COVID-19 in children of all ages so that the infection is diagnosed and MIS-C can be treated early on.”

MIS-C may occur a few days or weeks after infection by SARS-CoV-2. The runaway inflammatory reaction was thought to occur whether or not the virus was still in the organism, as a result of the immune response, but the study found evidence that the manifestations of MIS-C are also triggered by the direct action of the virus on the cells of infected organs.

“We’re not saying everything described to date about pediatric multisystem inflammatory syndrome is wrong. We’re merely adding the observation that the damage done to tissues by the virus is associated with this exacerbated inflammatory response in children, and is very probably a key component in its induction,” Dolhnikoff said.

Why some children respond to infection by SARS-CoV-2 with the exacerbated inflammation that characterizes MIS-C is unknown, but the answer may include a genetic component.

Endothelial cells targeted

The researchers found that the virus’s main targets included endothelial cells, which line blood vessels of all sizes and regulate exchanges between the bloodstream and the surrounding tissues. “One hypothesis is that when an endothelial cell is infected it activates bloodstream mediators that trigger an inflammatory cascade and the other reactions observed in children with MIS-C, such as persistent fever, colitis, myocarditis and encephalitis,” said Amaro Nunes Duarte Neto, first author of the article. Duarte Neto is an infectious disease specialist and pathologist at FM-USP and Adolfo Lutz Institute.

“The virus induces these reactions in the cells, but it’s the immune system that produces a response with adverse effects on the patient,” he said. “It’s not an autoimmune response, however, like what we see in lupus, psoriasis or inflammatory arthritis, which also involve damage to blood vessels. In MIS-C, the virus is involved directly.”

Electron microscopy analysis by Elia Caldini, a professor at FM-USP, supported these conclusions. Electron microscopes magnify viral particles more than 50,000 times directly, without the use of reagents. The technique enabled the researchers to describe alterations in cell cytoplasm associated with the presence of the virus.

“To confirm our identification of the virus unequivocally, we were the first to use immunolabeling of SARS-CoV-2 in conjunction with electron microscopy,” Caldini said. “We coupled colloidal gold particles to the specific antibodies used in light microscopy against structural viral proteins.”

The researchers also detected microthrombi (small blood clots) for the first time in children. This had already been observed and reported in adults. “Phenomena relating to blood clotting should always be considered in COVID-19. Our electron microscopy analysis showed that capillary blood vessels in all organs were obstructed by accumulated red and white blood cells, cellular debris, and fibrin, with disruption of the endothelial wall,” Caldini said.

The EClinicalMedicine article “An autopsy study of the spectrum of severe COVID-19 in children: from SARS to different phenotypes of MIS-C” (doi: 10.1016/j.eclinm.2021.100850)  by Amaro Nunes Duarte-Neto , Elia Garcia Caldini, Michele Soares Gomes-Gouvêa, Cristina Takami Kanamura, Renata Aparecida de Almeida Monteiro, Juliana Ferreira Ferranti, Andrea Maria Cordeiro Ventura, Fabina Aliotti Regalio, Maria Augusta Bento Cicaroni Gibelli, Werther Brunow de Carvalho, Gabriela Nunes Leal, João Renato Rebello Pinho, Artur Figueiredo Delgado, Magda Carneiro-Sampaio, Thais Mauad, Luiz Fernando Ferraz da Silva, Paulo Hilario Nascimento Saldiva and Marisa Dolhnikoff is at: www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00130-9/fulltext

Featured image: Electron micrograph of the brain of a child with MIS-C associated with COVID-19 and encephalopathy: immunohistochemical detection of SARS-CoV-2 nucleocapsid antigen in brain endothelial cells, with cytoplasm stained red (image: researchers’ archive)


Provided by FAPESP

Harmonious Electronic Structure Leads to Enhanced Quantum Materials (Material Science)

The electronic structure of metallic materials determines the behavior of electron transport. Magnetic Weyl semimetals have a unique topological electronic structure – the electron’s motion is dynamically linked to its spin. These Weyl semimetals have come to be the most exciting quantum materials that allow for dissipationless transport, low power operation, and exotic topological fields that can accelerate the motion of the electrons in new directions. The compounds Co3Sn2S2 and Co2MnGa [1-4], recently discovered by the Felser group, have shown some of the most prominent effects due to a set of two topological bands.

Researchers at the Max Planck Institute for Chemical Physics of Solids in Dresden, the University of South Florida in the USA, and co-workers have discovered a new mechanism in magnetic compounds that couples multiple topological bands. The coupling can significantly enhance the effects of quantum phenomena. One such effect is the anomalous Hall effect that arises with spontaneous symmetry breaking time-reversal fields that cause a transverse acceleration to electron currents. The effects observed and predicted in single crystals of Co3Sn2S2 and Co2MnGa display a sizable increase compared to conventional magnets.

In the current publication, we explored the compounds XPt3, where we predicted an anomalous Hall effect nearly twice the size of the previous compounds. The large effect is due to sets of entangled topological bands with the same chirality that synergistically accelerates charged particles. Interestingly, the chirality of the bands couple to the magnetization direction and determine the direction of the acceleration of the charged particles. This chirality can be altered by chemical substitution. Our theoretical results of CrPt3 show the maximum effect, where MnPt3 significantly reduced the effect due to the change in the order of the chiral bands.

Advanced thins films of the CrPt3 were grown at the Max Planck Institute. We found in various films a pristine anomalous Hall effect, robust against disorder and variation of temperature. The result is a strong indication that the topological character dominates even at finite temperatures. The results show to be near twice as large as any intrinsic effect measured in thin films. The advantage of thin films is the ease of integration into quantum devices with an interplay of other freedoms, such as charge, spin, and heat.  XPt3 films show possible utilization for Hall sensors, charge-to-spin conversion in electronic devices, and charge-to-heat conversion in thermoelectric devices with such a strong response.

Featured image: Schematic of a single set of band interactions, where E is the band energy and EF the Fermi energy. A change in chirality or magnetization would cause a change in the anomalous Hall conductivity.  Schematic of multiple sets of band interactions, where E is the band energy and EF the Fermi energy. Comparison of off stoichiometric CrPt3 with elemental metals and magnetic Weyl Semimetals. © MPI CPfS


References: [1] Enke Liu et al., Nat. Phys. 14, 1125 (2018).
[2] Kaustuv Manna et al., Phys. Rev. X 8, 041045 (2018).
[3] D. F. Liu, et al. Science 365, 1282–1285 (2019).
[4] Noam Morali et al. Science 365, 1286–1291 (2019).
[5] Anastasios Markou et al., Hard magnet topological semimetals in XPt3 compounds with the harmony of Berry curvature, Communications Physics 4, 104 (2021) DOI: https://doi.org/10.1038/s42005-021-00608-1


Provided by MPI CPfS

What Allows Bat Coronavirus RaTG13 To Use Human ACE2 Receptor? (Biology)

Since its first occurence in Wuhan, SARS-CoV-2 has infected more than 170 million people by June 2021, with more than 3.55 million confirmed deaths attributed to COVID-19, making it one of the deadliest pandemics in history.

In 2013, bat virus RaTG13 sampled from a Rhinolophus affinis horseshoe bat in Yunnan has been identified as the closest relative of SARS-CoV-2 showing approximately 96% sequence identity throughout the genome. Thus, SARS-CoV-2 most likely originated from horseshoe bats, although it has been proposed that cross-species transmission to humans may have involved pangolins as secondary intermediate host.

But, though the RaTG13 spike (S) protein is highly similar to the SARS-CoV-2 S it does not interact efficiently with the human ACE2 receptor, suggesting that this bat virus would most likely not be able to directly infect humans. But, Fabian Zech and colleagues now showed that mutation of T403R strongly enhances the ability of the bat RaTG13 spike protein to utilize ACE2 for infection of human cells and intestinal organoids.

“Our results demonstrate that a single amino acid change of T403R allows RaTG13, the closest known bat relative of SARS-CoV-2, to utilize human ACE2 for viral entry.”

They also suggested that, the strong enhancing effect of the T403R, likely came from a positively charged amino acid at position 403 in the spike protein, which was most likely a prerequisite for efficient zoonotic transmission and pandemic spread of SARS-CoV-2.

(article continues below image)

Fig 1: SARS-CoV-2 S and T403R RaTG13 S allow entry with human but not bat ACE2. (a) HEK293T cells expressing indicated ACE2 (Human ACE2 or Rhinolophus affinis ACE2) constructs or (b) , Tb 1 Lu, Tadarida brasiliensis derived lung epithelial and Ri 1 Lu huACE2 Rhinolophus affinis derived lung epithelial cells expressing human ACE2 were infected with VSVΔG-GFP pseudotyped with SARS-CoV-2, RaTG13 or indicated mutant S. Quantification by automatic counting of GFP positive cells. n=3 (biological replicates) ± SEM. P values are 457 indicated (student’s t test). © Zech et al.

Finally, they found that a positively charged residue at the corresponding position is present in the spike proteins of the great majority of RaTG13-related bat coronaviruses (as shown in Fig. 2) raising the possibility that many bat sarbecoviruses, including the 148 unknown precursor of SARS-CoV-2, are fitter for zoonotic transmission than RaTG13.

Fig 2: Conservation of the RGD motif in bat Coronavirus Spike proteins. (a) Sequence logo of the alignment of 137 different bat Coronavirus Spike RBD sequences. The 493 RGD motif is highlighted by a red box. (b) Primary sequence alignment of selected bat 494 coronaviruses, human coronaviruses and SARS-CoV-2 strains. The RGD motif is highlighted 495 in bold. © Zech et al.

Reference: Fabian Zech, Daniel Schniertshauer, Christoph Jung, Alexandra Herrmann, Qinya Xie, Rayhane Nchioua, Caterina Prelli Bozzo, Meta Volcic, Lennart Koepke, Jana Krueger, Sandra Heller, Alexander Kleger, Timo Jacob, Karl-Klaus Conzelmann, Armin Ensser, Konstantin Maria Johannes Sparrer, Frank Kirchhoff, “Spike mutation T403R allows bat coronavirus RaTG13 to use human ACE2”, bioRxiv 2021.05.31.446386; doi: https://doi.org/10.1101/2021.05.31.446386


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

Turbulence in Interstellar Gas Clouds Reveals Multi-fractal Structures (Astronomy)

The German-French Cooperation Programme GENESIS describes the complex structure of the interstellar medium using a new mathematical method / The dispersion of interstellar turbulence in gas clouds before star formation unfolds in a cosmically small space

In interstellar dust clouds, turbulence must first dissipate before a star can form through gravity. A German-French research team has now discovered that the kinetic energy of the turbulence comes to rest in a space that is very small on cosmic scales, ranging from one to several light-years in extent. The group also arrived at new results in the mathematical method: Previously, the turbulent structure of the interstellar medium was described as self-similar – or fractal. The researchers found that it is not enough to describe the structure mathematically as a single fractal, a self-similar structure as known from the Mandelbrot set. Instead, they added several different fractals, so-called multifractals. The new methods can thus be used to resolve and represent structural changes in astronomical images in detail. Applications in other scientific fields such as atmospheric research is also possible.

The German-French programme GENESIS (Generation of Structures in the Interstellar Medium) is a cooperation between the University of Cologne’s Institute for Astrophysics, LAB at the University of Bordeaux and Geostat/INRIA Institute Bordeaux. In a highlight publication of the journal Astronomy & Astrophysics, the research team presents the new mathematical methods to characterize turbulence using the example of the Musca molecular cloud in the constellation of Musca.

Stars form in huge interstellar clouds composed mainly of molecular hydrogen – the energy reservoir of all stars. This material has a low density, only a few thousand to several tens of thousands of particles per cubic centimetre, but a very complex structure with condensations in the form of ‘clumps’ and ‘filaments’, and eventually ‘cores’ from which stars form by gravitational collapse of the matter. 

The spatial structure of the gas in and around clouds is determined by many physical processes, one of the most important of which is interstellar turbulence. This arises when energy is transferred from large scales, such as galactic density waves or supernova explosions, to smaller scales. Turbulence is known from flows in which a liquid or gas is ‘stirred’, but can also form vortices and exhibit brief periods of chaotic behaviour, called intermittency. However, for a star to form, the gas must come to rest, i.e., the kinetic energy must dissipate. After that, gravity can exert enough force to pull the hydrogen clouds together and form a star. Thus, it is important to understand and mathematically describe the energy cascade and the associated structural change.

Publication:
www.aanda.org/2021-highlights/2182


Provided by University of Cologne

Novel Nano-encapsulation Approach For Efficient Dopamine Delivery in Parkinson’s Treatment (Neuroscience)

Parkinson’s disease (PD) is a common neurodegenerative disorder caused by the death of dopaminergic neurons in a part of the brain (known as substantia nigra pars compacta), which leads to a deficit of dopamine (DA), one of the main neurotransmitters active in the central nervous system. Symptomatic treatment focuses on increasing the concentration of dopamine into the brain.

However, dopamine is not directly administered, because it is unable to cross the so called blood-brain barrier, which prevents some of the substances circulating in the blood to penetrate into the nervous system. Thus, DA precursor levodopa (L-DOPA) -an amino-acid which participates in the synthesis of dopamine- is used, due to its better ability to cross such barrier. Nevertheless, long-term and intermittent administration of this drug is associated with important disabling complications, such as motor disorders and involuntary muscle movements.

In a paper recently published in ACS Nano, synthetic melanin-like nanoparticles are used to overcome these limitations. This research was coordinated by Dr Daniel Ruiz-Molina, leader of the ICN2 Nanostructured Functional Materials Group, and Dr Julia Lorenzo, leader of the Protein Engineering Group at the Institute of Biotehcnology and Biomedicine (IBB) of the Universitat Autònoma de Barcelona (UAB), and was developed in collaboration with the Neurodegenerative Diseases group of Vall d’Hebron Research Institute (VHIR), led by Prof. Miquel Vila.

The main objective of this work was to obtain a “nanoplatform” -which is a biocompatible nano-structure including the substance to be delivered- able to reach the brain through a noninvasive route and generate a slow and controlled release of dopamine. A tailor-made nanoscale coordination polymer (NCP), characterized by the reversible incorporation of DA as its principal component, was tested in vitro and in vivo in rats. Intranasal administration of these nanoparticles, called DA-NCPs, showed a relevant biocompatibility, non-toxicity and a fast and efficient distribution of dopamine in the central nervous system of the animals (avoiding the blood-brain barrier).

As reported by the researchers, the proposed method is effective in delivering dopamine to the brain and, thus, in reversing Parkinson’s symptoms. In addition, the synthetic methodology used is simple, cheap and exhibited a satisfactory yield (with a DA loading efficiency up to 60%).

These findings establish nanoscale coordination polymers as promising future candidates for efficient nasal delivery of drugs to the central nervous system, and thus for the symptomatic treatment of people affected by Parkinson’s and other neurodegenerative disorders. This type of nano-formulation and administration route may also pave the way to the development of other platforms able to deliver a wide range of drugs into the brain in a controlled manner, for the treatment of various brain diseases (such as brain tumours, Alzheimer’s, Epilepsy).

Featured image: Nanoencapsulation of dopamine © ICN2/IBB-UAB


Reference: Javier García-Pardo, Fernando Novio, Fabiana Nador, Ivana Cavaliere, Salvio Suárez-García, Silvia Lope-Piedrafita, Ana Paula Candiota, Jordi Romero-Gimenez, Beatriz Rodríguez-Galván, Jordi Bové, Miquel Vila, Julia Lorenzo, and Daniel Ruiz-Molina, “Bioinspired Theranostic Coordination Polymer Nanoparticles for Intranasal Dopamine Replacement in Parkinson’s Disease”, ACS Nano 2021, 15, 5, 8592–8609.
https://doi.org/10.1021/acsnano.1c00453


Provided by UAB

Researchers Discover How Cells Survive in High Salt Concentrations (Biology)

Researchers from IRB Barcelona and UPF have identified a chloride channel involved in cell volume recovery under osmotic stress.

The results have been published in the journal PNAS.

Cells have to constantly adapt to their surroundings in order to survive. A sudden increase in the environmental levels of an osmolyte, such as salt, causes cells to lose water and shrink. In a matter of seconds, they activate a mechanism that allows them to recover their initial water volume and avoid dying.

Finding out which genes are involved in surviving osmotic stress was the subject of a study led by the laboratories of Dr. Posas and Dr. de Nadal at the Institute for Research in Biomedicine (IRB Barcelona) and Dr. Valverde at Pompeu Fabra University (UPF), in collaboration with a group led by Dr. Moffat from the University of Toronto (Canada). wide-genome genetic screening, the scientists discovered the central role of a gene known as LRRC8A in cellular ability to survive osmotic shock.

This gene codes for a protein that forms channels in the membrane and that allow chloride ions to leave the cell. “Using a human epithelial cell model, as well as other human and mouse cell types, we have been able to demonstrate that this channel opens shortly after the cells are exposed to a high concentration of sodium chloride (NaCl),” explains Dr. De Nadal, who, together with Dr. Francesc Posas, heads the Cell Signalling laboratory at IRB Barcelona. The authors have also identified the molecular mechanism that causes this rapid opening. The chloride channel phosphorylates, which means a phosphate group is added to a specific amino acid in its sequence, thus activating the channel.

Fluorescence microscopic image showing the changes in chloride concentration in two cells over time, using a pseudo colour scale © IRB Barcelona

“This has been a very complex project, and it has taken us years to see the light,” explains Dr. Miguel Ángel Valverde, head of UPF’s Laboratory of Molecular Physiology. “We have also shown how vital it is for this channel to become activated and remove chloride in order to start the volume recovery process and for cells to survive over time,” he adds.

The use of a violet dye that stains only living cells has allowed the researchers to observe that cell death increases by approximately 50% when the activity of this chloride channel is blocked with a particular compound.

A journey through time to answer old questions

In the ’90s, various landmark scientific papers on cell volume regulation described the process by which cells regulate their volume to survive. It was known that the proteins responsible for volume recovery under salt stress require low intracellular concentrations in order to become activated, but it was not known how this occurred under such adverse conditions. With this discovery, the authors have answered a question posed by researchers years ago: how does chloride exit the cell to start the whole process? In the words of the paper’s main co-author, Dr. Selma Serra (UPF): “Now we have the answer to that question. It is the LRRC8A channel that brings down the chloride levels in a cell. Until now we had a good understanding of the role played by this channel in cell adpatation to environments with very low salt concentrations. The big challenge was to find out how the same chloride channel could be crucial in the opposite mechanism. At the beginning of the project, it seemed to go against any kind of scientific logic that a channel used to shrink cells could also swell them.”

Using electrophysiological and fluorescence microscopy techniques in living cells to ascertain intracellular chloride levels, the researchers have demonstrated the involvement of the LRRC8A chloride channel in responses to high-salt stimuli.

A major technical and conceptual challenge

Studying this process at the molecular level has posed a considerable challenge for the team involved in this project. Because it is very complicated to conduct in vivo studies of cells while they undergo osmotic shock and shrink.  “Imagine you’re looking at a juicy grape, and suddenly it looks like a raisin, that makes things very complicated for us,” say the authors.

Another high-impact factor is that, under these stress conditions, the mechanism for activating the chloride channel is very different to what has been described so far in the literature. The article’s lead co-author, Predrag Stojakovic, says, “It came as a big surprise to find out that the signalling pathways in response to stress, the MAP kinase, proteins we’ve been studying in the lab for months, are directly responsible for activating this channel”. MAP kinases are a group of signalling proteins that add phosphate groups to other proteins, thus activating or deactivating them. Using molecular techniques, the authors have looked throughout the channel’s protein to find the target sequence of these kinase proteins. “We have been able to identify the specific residue of the chloride channel that leads to activation under the control of the MAP kinase channel in response to stress,” says doctoral student Stojakovic.

Future implications

“This new piece of research opens up new possibilities for studying cell adaptation and survival  salt stress. Certain organs of the body, such as the kidneys, are often exposed to high salt concentration, which can threaten their survival. Knowing what molecules control survival under these conditions could be very useful for understanding certain pathologies that entail volume recovery in response to salts,” explains Dr. Posas.

In addition, discovering the role of this channel in these cell regulation processes is highly relevant in many pathologies involving proteins regulated by LRRC8A. This may be significant in situations such as certain kinds of arterial hypertension or cerebral ischemia.

Featured image: Image of a cell “ruptured” by a fire-polished micropipette © UPF – IRB Barcelona


Reference article: Selma A Serra, Predrag Stojakovic, Ramon Amat, Fanny Rubio-Moscardo, Pablo Latorre, Gerhard Seisenbacher, David Canadell, René Böttcher, Michael Aregger, Jason Moffat, Eulàlia de Nadal, Miguel A. Valverde & Francesc Posas, “LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions”, PNAS (2021).


Provided by IRB Barcelona

Why Deep Freezing Iron-based Materials Makes Them Both Magnetic & Superconducting (Physics)

Physicists at Bath have uncovered a new mechanism for enabling magnetism and superconductivity to co-exist in the same material.

Physicists at the University of Bath, in collaboration with researchers from the USA, have uncovered a new mechanism for enabling magnetism and superconductivity to co-exist in the same material. Until now, scientists could only guess how this unusual coexistence might be possible. The discovery could lead to applications in green energy technologies and in the development of superconducting devices, such as next-generation computer hardware.

As a rule, superconductivity (the ability of a material to pass an electrical current with perfect efficiency) and magnetism (seen at work in fridge magnets) make poor bedfellows because the alignment of the tiny electronic magnetic particles in ferromagnets generally leads to the destruction of the electron pairs responsible for superconductivity. Despite this, the Bath researchers have found that the iron-based superconductor RbEuFe4As4, which is superconducting below -236°C, exhibits both superconductivity and magnetism below -258°C.

Physics postgraduate research student David Collomb, who led the research, explained: “There’s a state in some materials where, if you get them really cold – significantly colder than the Antarctic – they become superconducting. But for this superconductivity to be taken to next-level applications, the material needs to show co-existence with magnetic properties. This would allow us to develop devices operating on a magnetic principle, such as magnetic memory and computation using magnetic materials, to also enjoy the benefits of superconductivity.

“The problem is that superconductivity is usually lost when magnetism is turned on. For many decades, scientists have tried to explore a host of materials that have both properties in a single material, and material scientists have recently had some success fabricating a handful of such materials. However, so long as we don’t understand why the coexistence is possible, the hunt for these materials can’t be done with as fine a comb.

“This new research gives us a material that has a wide temperature range where these phenomena co-exist, and this will allow us to study the interaction between magnetism and superconductivity more closely and in great detail. Hopefully, this will result in us being able to identify the mechanism through which this co-existence can occur.”

In a study published in Physical Review Letters, the team investigated the unusual behaviour of RbEuFe4As4 by creating magnetic field maps of a superconducting material as the temperature was dropped. To their surprise, they found the vortices (the points in the superconducting material where the magnetic field penetrates) showed a pronounced broadening near the temperature of -258°C, indicating a strong suppression of superconductivity as the magnetism turned on.

crystals coasted in gold
On the left: a crystal coated in gold – the gold coating allows the magnetic imaging tool to get within nanometers of the material’s surface. On the right: a magnetic picture of a segment of the crystal showing the vortices (dark holes) that were studied. © University of Bath

These observations agree with a theoretical model recently proposed by Dr Alexei Koshelev at Argonne National Laboratory in the USA. This theory describes the suppression of superconductivity by magnetic fluctuations due to the Europium (Eu) atoms in the crystals. Here, the magnetic direction of each Eu atom begins to fluctuate and align with the others, as the material drops below a certain temperature. This causes the material to become magnetic. The Bath researchers conclude that while superconductivity is considerably weakened by the magnetic effect, it is not fully destroyed.

“This suggests that in our material, the magnetism and superconductivity are held apart from each other in their own sub-lattices, which only minimally interact,” said Mr Collomb.

“This work significantly advances our understanding of these rare coexisting phenomena and could lead to possible applications in the superconducting devices of the future. It will spawn a deeper hunt into materials that display both superconductivity and magnetism. We hope it will also encourage researchers in more applied fields to take some of these materials and make the next-generation computing devices out of them.

“Hopefully, the scientific community will gradually enter an era where we move from blue-sky research to making devices from these materials. In a decade or so, we could be seeing prototype devices using this technology that do a real job.”

The American collaborators for this project were the Argonne National Laboratory, Hofstra University and Northwestern University.

Featured image: Magnetism can be generated simply by passing a current through a wire, but how it interacts with other physical phenomena (such as superconductivity) is shrouded in mystery. © University of Bath


Reference: D. Collomb, S. J. Bending, A. E. Koshelev, M. P. Smylie, L. Farrar, J.-K. Bao, D. Y. Chung, M. G. Kanatzidis, W.-K. Kwok, and U. Welp, “Observing the Suppression of Superconductivity in RbEuFe4As4 by Correlated Magnetic Fluctuations”, Phys. Rev. Lett. 126, 157001 – Published 14 April 2021. DOI: https://doi.org/10.1103/PhysRevLett.126.157001


Provided by University of Bath

With Mavis Images Three Times Sharper Than Hubble (Astronomy)

Interview with Giovanni Cresci (Inaf) on the new instrument just approved by Eso for the Vlt, Mavis. It will cost about 12 million euros (8 already funded), will make adaptive optics in the visible and will allow the telescope to reach the sensitivity and resolution of the next generation giant telescopes, remaining at the forefront of astronomical research.

With the signing of the agreement with Ex (announced today , Tuesday, June 1), the project Mavis – a new innovative tool designed for the VLT – enters the so-called Phase B . The design of the instrument then begins in view of the next stage, the Preliminary Design Review . What characteristics must an instrument have to be considered worthy of being included in a system that – between the individual Vlt telescopes and the Vlti network – already boasts at least fifteen others? Media Inaf went to ask Giovanni Cresci , co-project scientist of Mavis and researcher of INAF of Arcetri.

With the start of Phase B , it starts to get serious. However, there are still many steps to be taken. What are the timelines?

«I would say that the most important date to keep in mind is when the instrument will have to be operational at the telescope: this is what interests astronomers and also those who want to see the results in terms of the instrument’s performance. We are talking about 2028, date in line – among other things – with the implementation of the first instruments of the Extremely large telescope ( Elt ), the 30-meter ESO telescope that will soon be built in Chile ».

Why does he emphasize this alignment?

«It is an interesting combination because on the one hand we will have Mavis, which will obtain images with very high angular resolution in the visible, and on the other Elt, which will reach the same resolution in the infrared. A unique synergy can be established between the two ».

About seven years to go from concept to realization. Is it likely as a time frame?

«Our schedule foresees that it is, even if unexpected events and delays can always happen. Until now, however, despite the pandemic – which has greatly limited the possibility of interaction and work in the laboratories – we have managed to stay on time and conclude Phase A with excellent results. The Mavis consortium is mainly composed of some INAF offices in Italy and various Australian institutes, plus a contribution from the Laboratoire d’Astrophysique de Marseille (Lam): we work with time differences of ten hours and the fact of not being able to see each other in person he weighed a lot ».

Before looking closely at the division of roles between partners, however, let’s take a step back. What is Mavis?

“Mavis is an instrument that will make multi-conjugated adaptive optics in the visible: it will use 8 laser guide stars and 3 natural guide stars to make a correction of the turbulence introduced by the Earth’s atmosphere on a very large field of 30 × 30 arc seconds – rather than correcting a very small field of view as the tools available today do. Moreover, it will do so at optical wavelengths ».

Which is totally new, right?

“Exact. A few years ago we began to do adaptive optics also to optical wavelengths but limiting ourselves to a small source in the center of the field, while this instrument will allow to do so on a large field. Mavis will allow its imager to obtain images at a resolution three times better than that of the Hubble Space Telescope. In addition, it is also equipped with an integral field spectrograph, which will provide a spectrum with a resolution of approximately 20 milliarcoseconds for each point of a field of 6 × 6 arc seconds. It is a revolutionary instrument which, thanks to its angular resolution and sensitivity, will allow us to do astronomy as we have never done so far ».

Will the full-field spectrograph be better than Muse ?

“It will be different and somewhat complementary to Muse – which is a spectrograph that covers a very large field, 1 × 1 arc minutes. With Mavis we will be able to study the regions at the center of galaxies or globular clusters where the sources have a very high density and cannot be solved individually with Muse ».

What other adaptive optics tools are currently present at the Vlt?

«The adaptive tools in the visible are Sphere and Muse, and they have two main limitations: they work on very small fields and they need a very bright star to guide the adaptive optics system. Mavis will overcome these limits, and will be able to see about an order of magnitude more sources than those currently observable in the visible. For example, at the Galactic Pole , where there are fewer stars, Muse can only see 5 percent of the sources. With Mavis, on the other hand, we will be able to reach 50 percent ».

What are the main risks and the main technological challenges in making Mavis?

«As I said before, this is the first time that multi-conjugated adaptive optics have been done in the visible – usually in infrared. This is our great technological challenge. However, we think that the techniques developed up to now in the infrared are mature enough to allow such an extension. It is difficult, but we can also count on what the Vlt already offers us ».

Four laser lights currently in operation on the Vlt, in Paranal. Credits: Eso / F. Kamphues

Or?

“The idea is to use an infrastructure already present in one of the four telescopes, which has a deformable secondary mirror with 1170 actuators and four laser guide stars working for Muse.”

The four stars, however, are not enough, according to what he told me before.

“No, we need eight stars. Our solution is to divide the laser beam of each one in two: instead of having four lasers we will have eight with a reduced power ».

How much money has been allocated for this tool?

“Thus, the workforce is provided by the partners, who will receive approximately 150 nights of guaranteed observation time. Inaf will therefore have about 45 percent of these nights. As for the hardware, Eso will finance us with eight million euros, which however are not enough to complete the tool. We need about 10 million plus two in contingency – for the unexpected. We are working to find the missing sum ».

How do you plan to do?

«First of all, by participating in European and Australian calls for funding and grants , or by identifying a new partner who wants to join the consortium by bringing the money that is missing to be able to implement the instrument. We think we can do it quickly, given that we already have the bulk of the sum ».

What led to the signing of this agreement today?

«We had to pass a first review at the end of the so-called Phase A , in which Eso verified that the design of the instrument met the needs that the institution had for it. Before signing, we also had to negotiate the technical and scientific requirements of Mavis to make explicit the objectives to be achieved ».

How will the work be divided between the partners?

“Most of the effort is shared between INAF and a consortium of Australian institutes. As for Inaf, we will mainly deal with adaptive optics and instrument software, while the Australians will focus on wavefront sensors for lasers and postfocal instrumentation: imager and spectrograph. Lam instead will mainly deal with the postprocessing of raw data, in particular with the reconstruction of the point spread function . Finally, there is Eso, who will take care of inserting the instrument into the telescope and interfacing with the other instruments ».

All these parts, therefore, will be developed separately. In which laboratory will the integration take place?

“In Australia, at the Stromlo Observatory . And finally in Chile for integration with the telescope ».

In Italy, however, in which laboratories will you work?

«In the laboratories of the Inaf headquarters in Padua».

Example of observation of a galaxy az = 5. The first panel shows the simulated galaxy “Athena” by Pallottini et al. (2017). The other panels show how the galaxy would look if observed in the same optical band by Hst, Elt / Micado, Jwst / Nircam and Vlt / Mavis respectively, with an exposure time of 1 hour. MAVIS is capable of obtaining details that are invisible to other instruments at these wavelengths. Credits: Mavis collaboration

If you were to identify an emblematic scientific case to which Mavis will contribute, what would you say?

«So, it is a bit difficult, because this instrument will deal with numerous and very different scientific cases: from the Solar System to the most distant galaxies. Kind of like Hubble did , and in fact Mavis sets out to be a bit of Hubble’s replacement when it can’t work anymore. However, I can mention something particularly interesting: First, we want to create the deepest image ever made of the universe. With 10 hours of integration it will be possible to observe galaxies even fainter than those seen in the Hubble Ultra Deep Field, the deepest picture of the universe we have so far. It will also be possible to investigate the origin of supermassive black holes, whose primordial seeds should reside at the center of low-mass objects such as globular clusters or dwarf galaxies. Before Mavis, we did not have the angular resolution necessary to do astrometry at this level of precision ».

So, if everything goes as it should, will Mavis have nothing to envy to a space telescope like Hubble despite being on Earth?

“Exactly. In fact, it should be more sensitive and be able to see finer details. In fact, with this adaptive optics system, the damaging effect of the Earth’s atmosphere should be overcome. But, above all, it will be interesting that Mavis will be the optical counterpart of what we will do in the infrared with the great telescopes of the future like Elt ».

As if to say that it will give a new life to Vlt allowing it to stay on track alongside the telescopes of the future.

“That’s right.”

Giovanni Cresci, researcher at INAF of Arcetri and co-project scientist of the new instrument for the Vlt Mavis © INAF

What is your role in Mavis?

«As regards the scientific part, we have two project scientists : one for the Australian part and one for Inaf, which is me. I am mainly concerned with ensuring that the characteristics of the instrument are the optimal ones for doing the science that is required. For the scientific part, then, there is also a representative for each site that participates in the construction of the instrument. In the case of Inaf, therefore, the offices of Arcetri, Rome and Padua. In identifying scientific cases for Mavis, Italy played the lion’s share: when there was a call from Eso for the presentation of scientific proposals, more than half of the proposed projects had Italian principal investigators ».

Besides being involved in many projects of telescope instruments, you use them to do science. What do you do?

«I deal with the evolution of galaxies – especially chemical evolution – from the local universe to the more distant one. I am also involved in the co-evolution between the central black hole and the host galaxy. Also for the scientific progress of these two areas Mavis will be a revolutionary tool. As he said, I also deal a lot with instrumentation: I think it is interesting for us scientists to understand what is the whole process that is needed to build and optimize the instruments, and allow them to obtain the results we are looking for from them ».

Does knowing the tools in depth also allow us to think about more adequate scientific cases?

“Of course. And also to better understand what problems can arise in the data and how to solve any oddities or artifacts that can only be understood by knowing the instrument in depth ».

Featured image: Rendering of the Mavis tool. Credits: Eso / Mavis consortium / L. Calçada


Provided by INAF