Microscopic CCTV Reveals Secrets of Malaria Invasion (Medicine)

State-of-the-art video microscopy has enabled WEHI researchers to see the molecular details of how malaria parasites invade red blood cells – a key step in the disease.

The researchers used a custom-built lattice light sheet microscope – the first in Australia – to capture high-resolution videos of individual parasites invading red blood cells, and visualise the molecular and cellular changes that occur throughout this process. The research has provided critical new information about malaria parasite biology that may have applications for the development of much-needed new antimalarial medicines.

The research, which was published today in Nature Communications, was led by Ms Cindy EvelynDr Niall GeogheganDr Lachlan WhiteheadProfessor Alan Cowman and Dr Kelly Rogers.

At a glance

  • An advanced microscopy platform, called lattice light sheet microscopy, has been used to obtain detailed, real-time videos of the malaria parasite invading red blood cells.
  • The research has revealed key steps in the parasite invasion process, which is a critical point of the malaria life-cycle and underpins many symptoms of malaria.
  • The team’s discoveries could advance the development of much-needed new antimalarial medicines.

Focusing on a deadly parasite

Malaria is a mosquito-borne disease that kills around 400,000 people globally each year. Many of the serious symptoms of malaria occur because of the invasion and growth of the Plasmodium parasite in an infected person’s red blood cells, said Dr Rogers, who is the head of WEHI’s Centre for Dynamic Imaging.

“Understanding in better detail exactly how the parasite invades red blood cells may reveal new ways to stop this stage of the parasite life cycle, potentially leading to much-needed new therapies,” she said.

“We used microscopy – specifically a state-of-the-art approach, lattice light sheet microscopy (LLSM) – to follow the intricate cellular and molecular changes that occur when the malaria parasite invades red blood cells. We captured the first ever high-resolution, real time and dynamic views of the parasite in action.”

Ms Evelyn, who began the research as an Honours student, said the research revealed many previously unrecognised aspects of parasite invasion.

Lattice light sheet microscopy has been used to reveal the details of how malaria parasites invade red blood cells – a key step in the deadly disease. © WEHI, Australia

“The videos we recorded showed the ‘push and pull’ interactions as the parasite landed on the red blood cell, and then entered the cell in an enclosed chamber – called a vacuole – where it grew and multiplied.There has long been contention in the field about whether the vacuole is derived from the parasite or the host cell. Our research resolved this question, revealing it was created from the red blood cell’s membrane,” she said.

Most antimalarial therapies and vaccines target the initial binding of malaria to red blood cells.

“By visualising these processes in more detail, our research may contribute in several ways to the development of new antimalarial therapies. For example, now that we know that the parasite vacuole relies on components of the red blood cell membrane, it might be possible to target these components with medicines to disrupt the parasite life cycle. This host-directed approach could be one way to bypass the malaria parasite’s propensity to rapidly develop drug resistance,” Dr Rogers said.

“LLSM may also have applications for observing the specific steps of parasite invasion that are blocked by potential new drugs – an area we are now very interested in pursuing.” 

New views of cells

Researchers with instrument
Dr Geoghegan (left) and Dr Whitehead (right) with the lattice light sheet microscope © WEHI

LLSM is an advanced imaging technology that enables researchers to visualise cells and organs in unprecedented detail and in real time. Dr Geoghegan said LLSM had changed how cells could be studied.

“In the past, the choice of microscope for an experiment had to be a compromise between capturing a lower resolution video, which revealed dynamic processes like shape changes or movement, and capturing much higher-definition still images, which provided much more detail about how the cells and molecules are functioning,” he said.

“LLSM allows us to obtain high-resolution videos of cells, which has been a game-changer for many fields of biological research. We custom built a LLSM at WEHI – the first version of this technology in Australia. This groundbreaking microscopy has enabled us to progress multiple areas of research, including this malaria study. To achieve this, we brought together a multidisciplinary team with expertise in physics, engineering and biology – and the results of this current study have vindicated our approach.”
The research was supported by the Australian National Health and Medical Research Council, an EMBO Long Term Fellowship, a Sir Henry Wellcome Fellowship and the Victorian Government.

WEHI Authors: Dr Niall Geoghegan, Ms Cindy Evelyn, Dr Lachlan Whitehead, Dr Michal Pasternak, Ms Phoebe McDonald, Mr Tony Triglia, Dr Danushka Marapana, Ms Jennifer Thompson, Dr Michael Mlodzianoski, Dr Julie Healer, Professor Alan Cowman, Dr Kelly Rogers

Featured image: Imaging researchers (from left) Ms Cindy Evelyn, 
Dr Niall Geoghegan, Dr Kelly Rogers and
Dr Lachlan Whitehead © WEHI

Reference: Geoghegan, N.D., Evelyn, C., Whitehead, L.W. et al. 4D analysis of malaria parasite invasion offers insights into erythrocyte membrane remodeling and parasitophorous vacuole formation. Nat Commun 12, 3620 (2021). https://doi.org/10.1038/s41467-021-23626-7

Provided by WEHI

Brain Cell Membranes Lipids May Play Big Role in Alzheimer’s Progression (Neuroscience)

Lipids have been largely overlooked for Alzheimer’s disease therapeutics

Alzheimer’s disease is predominant in elderly people, but the way age-related changes to lipid composition affect the regulation of biological processes is still not well understood. Links between lipid imbalance and disease have been established, in which lipid changes increase the formation of amyloid plaques, a hallmark of Alzheimer’s disease.

This imbalance inspired researchers from Aarhus University in Denmark to explore the role of lipids comprising the cellular membranes of brain cells.

In Biointerphases, by AIP Publishing, the researchers report on the significant role lipids may play in regulating C99, a protein within the amyloid pathway, and disease progression. Lipids have been mostly overlooked from a therapeutic standpoint, likely because their influence in biological function is not yet fully understood.

Toxic amyloid plaques are formed within the brain when a series of enzymes cleave the protein APP, which sits within the neuronal cell membrane, to form C99, which in turn is cleaved to release the amyloid-beta peptide that can form plaques.

Both C99 and APP are able to protect themselves from cleavage by forming homodimers, a protein composed of two polypeptide chains that are identical. The interaction between C99 molecules is regulated by lipids that make up the membrane in which the protein sits.

“We showed that a change in the cholesterol content of the neuronal cell membrane can change how the C99 dimerizes,” said Amanda Dyrholm Stange, one of the authors. “Our work suggests age-related changes to cholesterol content in the membrane weakens the C99-C99 interaction, which consequently decreases the ‘protective’ effect of the dimerization process, leading to the hypothesis of why more toxic amyloid-beta peptides are released in the elderly.”

Therapeutics for Alzheimer’s disease currently “have a very high failure rate, with no therapeutics developed for a very long period of time, so a novel strategy is desperately needed,” said co-author Nils Anton Berlund. “Attempting to modulate the composition of the lipid membrane would be an entirely new class of Alzheimer’s disease therapeutics but also immensely challenging without side effects.”

The researchers postulate shifting the strategy away from targeting proteins to instead targeting the lipid concentration of membranes may be worthwhile.

“We hope our work will lead the pharmaceutical/biotechnology sector to choose lipid modulation as a means for targeting in drug development, because these changes in lipid composition are linked not just to Alzheimer’s but a large host of diseases — from diabetes to cardiovascular disease,” said co-author Birgit Schiøtt. “We also hope it will lead to more research and funding toward understanding the fundamental science behind the possible regulatory roles of lipids.”

The article “The effect of cholesterol on the dimerization of C99–a molecular modeling perspective” is authored by Amanda Dyrholm Stange, Jenny Pin-Chia Hsu, Lisbeth Ravnkilde Kjølbye, Nils Anton Berglund, and Birgit Schiøtt. The article will appear in Biointerphases on June 15, 2021 (DOI: 10.1116/6.0000985). After that date, it can be accessed at https://aip.scitation.org/doi/10.1116/6.0000985.

Featured image: Links between lipid imbalance and disease have been established, in which lipid changes increase the formation of amyloid plaques, a hallmark of Alzheimer’s disease. This imbalance inspired researchers to explore the role of lipids comprising the cellular membranes of brain cells. In Biointerphases, the researchers report on the significant role lipids may play in regulating C99, a protein within the amyloid pathway, and disease progression. © Amanda Dyrholm Stange, Jenny Pin-Chia Hsu, Lisbeth Ravnkilde, Nils Berglund, and Birgit Schiøtt

Provided by American Institute of Physics

Fuel Flow, Heat Fluctuations Drive Dangerous Oscillations in Rocket Engines (Physics)

Power source clusters near rocket engine fuel injectors could create combustion oscillations

Combustion engines can develop high frequency oscillations, leading to structural damage to the engines and unsafe operating conditions. A detailed understanding of the physical mechanism that causes these oscillations is required but has been lacking until now.

In Physics of Fluids, by AIP Publishing, research from the Tokyo University of Science and the Japan Aerospace Exploration Agency clarifies the feedback processes that give rise to these oscillations in rocket engines.

The investigators studied simulated combustion events in a computational model of a rocket combustor. Their analysis involved sophisticated techniques, including symbolic dynamics and the use of complex networks to understand the transition into oscillatory behavior.

The symbolic dynamics techniques allowed the scientists to determine similarities in behavior between two variables that characterize the combustion event. They found a relationship between fluctuations in the flow velocity of the fuel injector and fluctuations in the heat release rate of the combustor.

A rocket engine uses injectors to deliver a fuel, typically hydrogen gas, H2, and an oxidizer, oxygen gas, O2, to a combustion chamber where ignition and subsequent combustion of the fuel occurs.

“Periodic contact of the unburnt H2/O2 mixture with high-temperature products of the H2 [and] air flame gives rise to significant fluctuations in the ignition location,” said author Hiroshi Gotoda.

Fluctuations in the ignition location produce fluctuations in the heat release rate, which affects pressure fluctuations in the combustor.

“We found that the heat release fluctuations and pressure fluctuations synchronize to each other,” said Gotoda.

The product of the pressure and the heat release rate fluctuations in the combustor is an important physical quantity for understanding the origin of combustion oscillations. Regions where this product is greater than zero correspond to acoustic power sources that drive the oscillations.

The investigators discovered power sources in the shear layer near the injector rim. These power sources would suddenly collapse and reemerge upstream in a periodic fashion, leading to oscillations in combustion.

“The repetition of the formation and collapse of thermoacoustic source clusters in the hydrodynamic shear layer region between the inner oxidizer and outer fuel jets plays an important role in driving combustion oscillations,” said Gotoda.

The investigators believe their analysis method will lead to a better understanding of the dangerous oscillations that sometimes arise in rocket engines and other combustors.

The article “Formation mechanism of high-frequency combustion oscillations in a model rocket engine combustor” is authored by Satomi Shima, Kosuke Nakamura, Hiroshi Gotoda, Yuya Ohmichi, and Shingo Matsuyama. The article will appear in Physics of Fluids on June 8, 2021 (DOI: 10.1063/5.0048785). After that date, it can be accessed at https://aip.scitation.org/doi/full/10.1063/5.0048785.

Featured image: Combustion chamber during combustion oscillations in a model rocket engine. © Hiroshi Gotoda

Provided by American Institute of Physics

CNIO Researchers Discover A Protein That Facilitates DNA Repair May Potentiate Chemotherapy (Biology)

The PrimPol protein helps the cell to survive the damage caused by chemotherapy; the researchers want to make tumor cells more sensitive to cancer treatments by repressing PrimPol

Chemotherapy kills tumour cells by causing damage to them. One of the most effective ways of causing damage is to prevent the two DNA strands from separating so that the cellular machinery cannot read the instructions written in the genes. But sometimes, the cell manages to repair the damage and survive, evading the effect of chemotherapy. CNIO researchers have found out how the cell does that and plan to use this knowledge to enhance cancer treatments.

The key lies in a peculiar protein called PrimPol, as explained in a publication in The EMBO Journal by the CNIO’s DNA Replication Group, led by Juan Méndez.

The DNA molecule harbours the genes that direct the life of the cell and, by extension, the life of the whole organism. It consists of two intertwined strands, the famous double helix. For the instructions written in the genes to be read by the cellular machinery, the two strands of DNA must be pulled apart and put back together again, like a zipper that opens and closes. If this does not happen, the cell cannot function and, of course, cannot replicate.

That is why lesions that prevent DNA strands from separating are among the most serious that a cell can suffer. They are called interstrand cross-links (ICLs). ICL lesions can appear naturally, as a result of cell metabolism, or as a consequence of certain toxins, such as chemotherapeutic drugs. Cisplatin, used in the treatment of among others ovarian and lung cancers, kills tumour cells by inducing ICL lesions.

A ‘staple’ that holds the double helix together

As Méndez explains, “The ICL is a chemical bond between the two strands, a kind of staple that prevents them from separating. If the cell tries to divide, the chromosomes end up breaking.”

The cell, however, knows how to repair these lesions, which in fact only become lethal when their frequency is very high. In the paper now published in The EMBO Journal, the CNIO group reveals that the cell achieves this in part thanks to PrimPol.

Binding of PrimPol to ICL lesions in DNA. PrimPol protein (red) is distributed between the nucleus (blue) and cytoplasm of osteosarcoma cells (left). In the presence of ICL lesions, PrimPol quickly binds to damaged DNA to facilitate its repair (right). © CNIO

PrimPol belongs to a family of proteins called “primases” that appeared very early in the evolution of life and is still present today in a great many species, which indicates its importance for the functioning of organisms. In 2013, Juan Méndez and Luis Blanco, from the Centro de Biología Molecular Severo Ochoa (CSIC), discovered why PrimPol is so important: it allows the cellular machinery to use the instructions written in the DNA even when it contains an error. In other words, PrimPol makes the cell more resilient by helping it to survive when its DNA is damaged.

PrimPol helps to keep reading the DNA

Usually, DNA-copying proteins are blocked when they detect defects in the double helix, and if the blockage persists for too long, the cell will die. But PrimPol enables the reading of the DNA to continue after the error, like keeping on reading a text after skipping a misspelt or misunderstood word. “PrimPol,” explains Méndez “offers ‘an immediate solution’ to bypass the blockage, giving the cell a chance to repair the error in the DNA at a later time.”

The new study focuses on PrimPol’s function when the error is an ICL lesion. The researchers found that PrimPol is required for the DNA copying phase that precedes the repair of the staple in the DNA strands. Thanks to the intervention of this enzyme, the cell not only survives ICL lesions but also mobilises the machinery responsible for repairing them.

Repressing PrimPol to potentiate chemotherapy

It is a basic finding, but “with very interesting clinical implications,” says Méndez, because “by facilitating the repair of ICLs, PrimPol is interfering with the effectiveness of chemotherapy.”

That suggests that if PrimPol were absent, the tumour cell would be more sensitive to chemotherapy. The authors, therefore, believe that the new results “open the possibility of targeting PrimPol to enhance the therapeutic effects of molecules that produce ICL lesions,” they write in The EMBO Journal.

In another recent study in which Méndez participated together with researchers from Washington University (St Louis, USA), it was found that ovarian tumour cells produce more PrimPol to tolerate DNA damage caused by cisplatin-based chemotherapy.

“If we can repress PrimPol function in these cells, we could improve the efficiency of chemotherapy,” Méndez points out. To this end, his team is working together with CNIO’s Experimental Therapeutics Programme to identify specific PrimPol inhibitors.

Fanconi anaemia

The new study is also of interest for Fanconi anaemia, a rare and severe disease. The CNIO researchers show that PrimPol facilitates the repair of ICL lesions by a family of proteins called FANC. And genetic defects that reduce the activity of these proteins cause Fanconi anaemia.

“Patients with Fanconi anaemia have very few therapeutic options, but very promising results are beginning to be obtained with gene therapy,” says Méndez. “Any advances that lead to a better understanding of the ICL repair pathways may prove useful in the near future.”

The experimental work was carried out by three PhD students supervised by Méndez: Daniel González, Elena Blanco and Patricia Ubieto. Luis Blanco, a CSIC scientist, Massimo Lopes, a scientist at the University of Zurich (Switzerland), and the CNIO Proteomics Core Unit also participated.

The research has been funded by the Spanish Ministry of Science and Innovation, the National Institute of Health Carlos III, the European Regional Development Fund., the Swiss National Science Foundation and the European Research Council.

The study, “PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks”, EMBO J (2021)e106355. https://doi.org/10.15252/embj.2020106355

Featured image: The director of the study, Juan Méndez, in the center, together with the researchers Elena Blanco-Romero, on the left, and Patricia Ubieto-Capella, on the right. © CNIO

Provided by CNIO

Researchers Identify Why COVID-19 Patients Develop Life-threatening Clots (Medicine)

New insights could lead to new therapies for COVID-19

Scientists have identified how and why some Covid-19 patients can develop life-threatening clots, which could lead to targeted therapies that prevent this from happening.

The work, led by researchers from RCSI University of Medicine and Health Sciences, is published in the Journal of Thrombosis and Haemostasis.

Previous research has established that blood clotting is a significant cause of death in patients with Covid-19. To understand why that clotting happens, the researchers analysed blood samples that were taken from patients with Covid-19 in the Beaumont Hospital Intensive Care Unit in Dublin.

They found that the balance between a molecule that causes clotting, called von Willebrand Factor (VWF), and its regulator, called ADAMTS13, is severely disrupted in patients with severe Covid-19.

When compared to control groups, the blood of Covid-19 patients had higher levels of the pro-clotting VWF molecules and lower levels of the anti-clotting ADAMTS13. Furthermore, the researchers identified other changes in proteins that caused the reduction of ADAMTS13.

“Our research helps provide insights into the mechanisms that cause severe blood clots in patients with Covid-19, which is critical to developing more effective treatments,” said Dr Jamie O’Sullivan, the study’s corresponding author and research lecturer within the Irish Centre for Vascular Biology at RCSI.

“While more research is needed to determine whether targets aimed at correcting the levels of ADAMTS13 and VWF may be a successful therapeutic intervention, it is important that we continue to develop therapies for patients with Covid-19. Covid-19 vaccines will continue to be unavailable to many people throughout the world, and it is important that we provide effective treatments to them and to those with breakthrough infections.”

This work was funded by Irish COVID-19 Vasculopathy Study (ICVS) through the Health Research Board COVID-19 Rapid Response award as well as a philanthropic grant from the 3M Foundation to RCSI University of Medicine and Health Sciences in support of COVID-19 research.

Featured image: Dr Jamie O’Sullivan, the study’s corresponding author and research lecturer within the Irish Centre for Vascular Biology at RCSI. © RCSI

Reference: Ward, S.E., Fogarty, H., Karampini, E., Lavin, M., Schneppenheim, S., Dittmer, R., Morrin, H., Glavey, S., Ni Cheallaigh, C., Bergin, C., Martin-Loeches, I., Mallon, P.W., Curley, G.F., Baker, R.I., Budde, U., O’Sullivan, J.M., O’ Donnell, J.S. and (2021), ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. J Thromb Haemost. Accepted Author Manuscript. https://doi.org/10.1111/jth.15409

Provided by RCSI

New Discovery Of A Rare Superconductor May be Vital For the Future of Quantum Computing (Quantum)

Research led by the University of Kent and the STFC Rutherford Appleton Laboratory has resulted in the discovery of a new rare topological superconductor, LaPt3P. This discovery may be of huge importance to the future operations of quantum computers.

Superconductors are vital materials able to conduct electricity without any resistance when cooled below a certain temperature, making them highly desirable in a society needing to reduce its energy consumption.

Superconductors manifest quantum properties on the scale of everyday objects, making them highly attractive candidates for building computers which use quantum physics to store data and perform computing operations, and can vastly outperform even the best supercomputers in certain tasks. As a result, there is an increasing demand from leading tech companies like Google, IBM and Microsoft to make quantum computers on an industrial scale using superconductors.

However, the elementary units of quantum computers (qubits) are extremely sensitive and lose their quantum properties due to electromagnetic fields, heat and collisions with air molecules. Protection from these can be achieved by making more resilient qubits using a special class of superconductors called topological superconductors which in addition to being superconductors also host protected metallic states on their boundaries or surfaces.

Topological superconductors, such as LaPt3P, newly discovered through muon spin relaxation experiments and extensive theoretical analysis, are exceptionally rare and are of tremendous value to the future industry of quantum computing.

To ensure its properties are sample and instrument independent, two different sets of samples were prepared in the University of Warwick and in ETH Zurich. Muon experiments were then performed in two different types of muon facilities: in the ISIS Pulsed Neutron and Muon Source in the STFC Rutherford Appleton Laboratory and in PSI, Switzerland.

Dr Sudeep Kumar Ghosh, Leverhulme Early Career Fellow at Kent and Principle Investigator said: ‘This discovery of the topological superconductor LaPt3P has tremendous potential in the field of quantum computing. Discovery of such a rare and desired component demonstrates the importance of muon research for the everyday world around us.’

The paper ‘Chiral singlet superconductivity in the weakly correlated metal LaPt3P’ is published in Nature Communications (University of Kent: Dr. Sudeep K. Ghosh; STFC Rutherford Appleton Laboratory: Dr. Pabitra K. Biswas, Dr. Adrian D. Hillier; University of Warwick – Dr. Geetha Balakrishnan, Dr. Martin R. Lees, Dr. Daniel A. Mayoh; Paul Scherrer Institute: Dr. Charles Baines; Zhejiang University of Technology: Dr. Xiaofeng Xu; ETH Zurich: Dr. Nikolai D. Zhigadlo; Southwest University of Science and Technology: Dr. Jianzhou Zhao). URL: https://www.nature.com/articles/s41467-021-22807-8 DOI: https://doi.org/10.1038/s41467-021-22807-8

Provided by University of Kent

Receptor Location Plays A Key Role in Their Function (Medicine)

Research teams from Würzburg, Munich, Erlangen and the MDC in Berlin have identified, for the first time, where special receptors are located on heart muscle cells. Their findings open up new perspectives for developing therapies for chronic heart failure.

In the heart there are two different subtypes of beta-adrenergic receptors – beta1 and beta2 – which are activated by the stress hormones adrenaline and noradrenaline. They both trigger the strongest stimulation of the heart rate and pumping capacity that we know of. The two subtypes are highly similar biochemically, but differ substantially in terms of their functional and therapeutic relevance.

Both receptor types can stimulate the heart in the short term, yet when the beta1 receptor is activated over a prolonged period of time, it has a range of effects that are not seen with beta2. Beta1 can elicit a number of persistent changes and is endowed with the ability to initiate – oftentimes detrimental – growth of the heart muscle cells by activating various genes.

Recent studies by researchers at the Universities of Würzburg and Erlangen, the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, and the ISAR Bioscience Institute in Munich-Planegg have now shed light on the mechanisms behind these different effects. The research teams have published the results of their work in the current issue of the journal Proceedings of the National Academy of Sciences of the USA.

Special ligands and new microscopy methods

“Using a fluorescent ligand synthesized at the University of Erlangen and novel highly sensitive microscopy methods, we were able to show for the first time where these receptors are located on heart muscle cells,” explains Professor Martin Lohse of the Institute of Pharmacology and Toxicology at the Julius Maximilians University of Würzburg (JMU). He is co-lead author of the study along with Dr. Paolo Annibale, who is acting head of the MDC’s Receptor Signaling Lab. “The endogenous receptors are expressed at relatively low levels,” explains Annibale. “To detect their movement, it was necessary to use a form of spectroscopy based on the analysis of the signal’s minute fluorescence fluctuations.”

This revealed that beta1 receptors are found on the entire surface of heart muscle cells, while beta2 receptors are exclusively found in specific structures in these cells called T-tubules. Through invaginations of the cell surface, these tubules create a pipe-like network that runs through the entire interior of heart muscle cells. “One of the research focuses of our team at the MDC is the relationship between receptor function and subcellular localization,” adds Annibale. “So the biophysical environment of T-tubules, which have curved membranes, is of particular interest to us.”

Not all heart muscle cells have beta1 receptors

“The specific cellular location of beta2 receptors explains why they have a much narrower range of functionality than beta1 receptors and why they are limited to direct and short-term stimulation of the heart,” explains Lohse. Such stimulation is mediated by signals that are locally restricted to the cell membrane. In contrast, gene activation and cell growth stimulation occur via more far-reaching signals that can only be triggered at the cell surface, where only beta1 receptors are located.

Another surprising finding of the study is that not all heart muscle cells have these receptors. “There are apparently different types or states of heart muscle cells, so not all cells respond to adrenaline,” Lohse said. Until now, it was assumed that heart muscle cells in the large chambers were all the same.

New target for heart failure therapy

It has been known for many years that in chronic heart failure, too much adrenaline and noradrenaline circulate in the bloodstream and stimulate the heart to such an extent that it causes changes in the heart and its cells to grow. This initially compensates for heart failure, but in the long run the excessive growth damages the heart. Therefore, based in part on earlier findings by the Würzburg team, blocking beta receptors has become the accepted therapy for chronic heart failure.

The new findings now show why beta1 receptors play a much greater role in producing these adverse effects than beta2 receptors. Beta1 receptors are localized on the entire cell surface, enabling them to have a more diverse impact than beta2 receptors. The new knowledge about the differential localization and distinct functional effects of beta1 and beta2 receptors in the heart could possibly be exploited to develop better therapies for chronic heart failure. These would selectively inhibit the harmful effects of beta receptors (such as heart muscle cell growth), while at the same time activating the beneficial effects (such as stimulation of heart function).

Featured image: Beta1- and beta2-adrenergic receptors in heart muscle cells: In the left cell, beta1 receptors are labeled – they are found both on the cell surface (yellow) and in the T-tubules (green). In the right cell, the beta2-receptors are labeled – they appear only in the T-tubules (green), but not on the cell surface (which is therefore not visible in the image). (Image: Marc Bathe-Peters & Horst-Holger Boltz)


Marc Bathe-Peters et al (2021): “Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes,” Proceedings of the National Academy of Sciences of the USA, DOI: 10.1073/pnas.2101119118

Provided by University of Wurzburg

Newly Developed Ion-conducting Membrane Improves Performance of Alkaline-zinc Iron Flow Battery (Chemistry)

Alkaline zinc-iron flow battery (AZIFB) is well suitable for stationary energy storage applications due to its advantages of high open-cell voltage, low cost, and environmental friendliness. However, it surfers from zinc dendrite/accumulation and relatively low operation current density.

Recently, a research group led by Prof. LI Xianfeng from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Science (CAS) developed layered double hydroxide (LDH) membrane with high hydroxide conductivity and ion selectivity for alkaline-zinc iron flow battery.

The study was published in Nature Communications on June 7.

In order to enhance the operating current density of AZIFB, the researchers added LDHs nano materials into the AZIFB and designed a LDHs-based composite membrane with high performance. High selectivity and superb hydroxide ion conductivity were achieved through the combination of the well-defined interlayer gallery with a strong hydrogen bond network along 2D surfaces.

They identified that surface -OH groups of LDHs layer could assist the conduction of OH by promoting proton transfer away from one water molecule to the original OH.

Because of the high ionic conductivity, the LDHs-based membrane enabled the AZIFB to operate at 200 mA cm-2, along with an energy efficiency of 82.36%.

“This study offers a new insight to design and manufacture high-performance membranes for AZIFB,” said Prof. LI.(Text by YUAN Zhizhang)

Featured image: Selective ions transport and the hydroxide ions transport in LDHs (Image by HU Jing)

Provided by DICP

Main Gland in Hormonal System Ages Due To Process That Can Potentially Be Slowed Down (Biology)

Stem cell biologist Hugo Vankelecom and his colleagues have discovered that the pituitary gland in mice ages as the result of an age-related form of chronic inflammation. It may be possible to slow down this process or even partially repair it. The researchers have published their findings in PNAS.

The pituitary gland is a small, globular gland located underneath the brain that plays a major role in the hormonal system, explains Professor Hugo Vankelecom from the Department of Development and Regeneration at KU Leuven. “My research group discovered that the pituitary gland ages as a result of a form of chronic inflammation that affects tissue and even the organism as a whole. This natural process usually goes unnoticed and is referred to as ‘inflammaging’ — a contraction of inflammation and ageing. Inflammaging has previously been linked to the ageing of other organs.” Due to the central role played by the pituitary, its ageing may contribute to the reduction of hormonal processes and hormone levels in our body – as is the case with menopause, for instance.

The study also provides significant insight into the stem cells in the ageing pituitary gland. In 2012, Vankelecom and his colleagues showed that a prompt reaction of these stem cells to injury in the gland leads to repair of the tissue, even in adult animals. “As a result of this new study, we now know that stem cells in the pituitary do not lose this regenerative capacity when the organism ages. In fact, the stem cells are only unable to do their job because, over time, the pituitary becomes an ‘inflammatory environment’ as a result of the chronic inflammation. But as soon as the stem cells are taken out of this environment, they show the same properties as stem cells from a young pituitary.” 

Chance of recovery?

This insight opens up a number of potential therapeutic avenues: would it be possible to reactivate the pituitary? This wouldn’t just involve slowing down hormonal ageing processes, but also repairing the damage caused by a tumour in the pituitary, for example. “No fewer than one in every 1,000 people is faced with this kind of tumour — which causes damage to the surrounding tissue — at some point. The quality of life of many of these patients would be drastically improved if we could repair this damage. We may be able to do so by activating the stem cells already present — for which our present study also provides new indications — or even by transplanting cells. That said, these new treatment options are not quite around the corner just yet, as the step from fundamental research to an actual therapy can take years to complete. For the time being, our study sets out a potential direction for further research.” 

The study also suggests another interesting avenue: the use of anti-inflammatory drugs to slow down pituitary ageing or rejuvenate an ageing pituitary. “Several studies have shown that anti-inflammatory drugs may have a positive impact on some ageing organs. No research has yet been performed on this effect in relation to the pituitary.” 

From mice to humans

Vankelecom and his colleagues studied the pituitary of mice, so further research is required to demonstrate whether their findings also apply to humans. Vankelecom comments: “Mice have a much greater regeneration capacity than humans. They can repair damaged teeth, for instance, while humans have lost this ability over the course of their evolution. Regardless, there are plenty of signs suggesting that pituitary processes in mice and humans are similar, and we have recent evidence to hand that gene expression in the pituitaries of humans and mice is very similar. As such, it is highly likely that the insights we gained will equally apply to humans.”

Featured image credit: © KU Leuven – Emma Laporte (first co-author of the study). Image created with BioRender.

More information 

Provided by Ku Leuven