New 3D Printable Phase-changing Composites Can Regulate Temperatures Inside Buildings (Material Science)

Changing climate patterns have left millions of people vulnerable to weather extremes. As temperature fluctuations become more commonplace around the world, conventional power-guzzling cooling and heating systems need a more innovative, energy-efficient alternative, and in turn, lessen the burden on already struggling power grids. 

In a new study, researchers at Texas A&M University have created novel 3D printable phase-change material (PCM) composites that can regulate ambient temperatures inside buildings using a simpler and cost-effective manufacturing process. Furthermore, these composites can be added to building materials, like paint, or 3D printed as decorative home accents to seamlessly integrate into different indoor environments.

“The ability to integrate phase-change materials into building materials using a scalable method opens opportunities to produce more passive temperature regulation in both new builds and already existing structures,” said Dr. Emily Pentzer, associate professor in the Department of Materials Science and Engineering and the Department of Chemistry. 

This study was published in the June issue of the journal Matter. 

Heating, ventilation and air conditioning (HVAC) systems are the most commonly used methods to regulate temperatures in residential and commercial establishments. However, these systems guzzle a lot of energy. Furthermore, they use greenhouse materials, called refrigerants, for generating cool, dry air. These ongoing issues with HVAC systems have triggered research into alternative materials and technologies that require less energy to function and can regulate temperature commensurate to HVAC systems.

One of the materials that has gained a lot of interest for temperature regulation is phase-change materials. As the name suggests, these compounds change their physical state depending on the temperature in the environment. So, when phase-change materials store heat, they convert from solid to liquid upon absorbing heat and vice versa when they release heat. Thus, unlike HVAC systems that rely solely on external power to heat and cool, these materials are passive components, requiring no external electricity to regulate temperature. 

The traditional approach to manufacturing PCM building materials requires forming a separate shell around each PCM particle, like a cup to hold water, then adding these newly encased PCMs to building materials. However, finding building materials compatible with both the PCM and its shell has been a challenge. In addition, this conventional method also decreases the number of PCM particles that can be incorporated into building materials.

“Imagine filling a pot with eggs and water,” said Ciera Cipriani, NASA Space Technology Graduate Research Fellow in the Department of Materials Science and Engineering. “If each egg has to be placed in an individual container to be hard-boiled, fewer eggs will fit in the pot. By removing the plastic containers, the veritable shell in our research, more eggs, or PCMs, can occupy a greater volume by packing closer together within the water/resin.”

To overcome these challenges, past studies have shown that when using phase-changing paraffin wax mixed with liquid resin, the resin acts as both the shell and building material. This method locks the PCM particles inside their individual pockets, allowing them to safely undergo a phase change and manage thermal energy without leakage.

Similarly, Pentzer and her team first combined light-sensitive liquid resins with a phase-changing paraffin wax powder to create a new 3D printable ink composite, enhancing the production process for building materials containing PCMs and eliminating several steps, including encapsulation. 

The resin/PCM mixture is soft, paste-like, and malleable, making it ideal for 3D printing but not for building structures. Hence, by using a light-sensitive resin, they cured it with an ultraviolet light to solidify the 3D printable paste, making it suitable for real-world applications. 

Additionally, they found that the phase-changing wax embedded within the resin was not affected by the ultraviolet light and made up 70% of the printed structure. This is a higher percentage when compared to most currently available materials being used in industry. 

Next, they tested the thermoregulation of their phase-changing composites by 3D printing a small-scale house-shaped model and measuring the temperature inside the house when it was placed in an oven. Their analysis showed that the model’s temperature differed by 40% compared to outside temperatures for both heating and cooling thermal cycles when compared to models made from traditional materials.

In the future, the researchers will experiment with different phase-change materials apart from paraffin wax so that these composites can operate at broader temperature ranges and manage more thermal energy during a given cycle.

“We’re excited about the potential of our material to keep buildings comfortable while reducing energy consumption,” said Dr. Peiran Wei, research scientist in the Department of Materials Science and Engineering and the Soft Matter Facility. “We can combine multiple PCMs with different melting temperatures and precisely distribute them into various areas of a single printed object to function throughout all four seasons and across the globe.”

This study was funded by the National Science Foundation’s Division of Materials Research Career Award.

Featured image: New phase-change material composites can regulate ambient temperatures inside buildings. | Image: Dharmesh Patel


Reference: Peiran Wei et al., “Thermal energy regulation with 3D printed polymer-phase change material composites”, Matter, 4(6), pp. 1975-1989, April 12, 2021. DOI: https://doi.org/10.1016/j.matt.2021.03.019


Provided by Texas A&M University

Commonalities Found Between COVID-19 & Rheumatoid Arthritis Could Help Development Of New Treatment Strategies For Long Covid (Medicine)

Severe COVID-19 and Rheumatoid Arthritis (RA) share some common pathogenic mechanisms, according to a new study.

The observations from the study – published in JCI Insight and led by the University of Glasgow’s Research into Inflammatory Arthritis Centre (RACE) in collaboration with the Fondazione A.Gemelli IRCCS in Italy – could help development of new treatment strategies for severe COVID-19 and post-COVID-19 syndrome, or Long Covid.

The researchers observed that some rheumatoid arthritis patients who became infected with SARS-CoV-2 had ‘flares’ of joint pain and inflammation, which hinted at similarities between COVID-19 and rheumatoid arthritis.

In the study, researchers identified a specific pathogenic macrophage cluster (a group of specialised cells) within the lungs of patients with severe COVID-19 and in the joints of rheumatoid arthritis (RA) patients. Macrophages are immune-cells that are responsible for engulfing and destroying pathogens and dying cells, but when over-activated, they induce pathologies in the tissues.

Detailed molecular studies showed that these specialised cells produce a mediator called SPP1. Blood levels of this mediator are high in COVID-19 patients, and particularly high levels are predictive of patient transfer to intensive care.

By investigating the mechanisms of SPP1, the study found that this mediator drives multiple features of pathogenic inflammatory response that characterise severe COVID-19.

The study also provides some insight into the mechanisms of post-COVID-19 syndrome, or Long Covid. The authors found that some COVID-19 patients who recovered and were virus negative, but with persistent symptoms, still had abnormally high blood levels of SPP1, despite normalised levels of other pro-inflammatory mediators.

Dr Mariola Kurowska-Stolarska, from the University of Glasgow, said: “Our investigation is promising, because understanding these mechanisms which drives features of COVID-19 can help open the prospect for new treatment strategies for severe COVID-19.

“Our study findings also suggest that SPP1 pathogenic function might contribute to long COVID-19, and if so, this identifies SPP1 as a potential therapeutic target for this increasingly common syndrome.”

Lucy MacDonald, RACE PhD student and one of the first lead authors of the study, said: “We were curious about the most likely common link between joint inflammation and severe response to SARS-CoV-2 infection, which then became the focus of our investigation.

“By understanding this commonality, we have now identified SPP1 as a potential therapeutic target. Our goal now is to identify how SPP1-positive macrophages and their mediators may be involved in the long-COVID-19 symptom spectrum, for example musculoskeletal pain. Our goal is to improve the treatment for patients with COVID-19 and post-COVID-19 as well as for our RA patients.”

Dr Caroline Aylott, Head of Research Delivery at Versus Arthritis, says: “In both rheumatoid arthritis and COVID-19, the immune system attacks the body’s own tissues, causing inflammation and damage. This research is a step forward in understanding why inflammation continues in both rheumatoid arthritis and COVID-19 and may provide a potential target for the future treatments for both conditions.

“Understanding our immune system is key to helping the 18 million people who experience the pain and fatigue linked to arthritis. Versus Arthritis research funding may be unlocking the prospects of future treatment not only for arthritis but also for long COVID.”

The study, ‘COVID-19 and RA share SPP1 myeloid pathway that drives PD-L1pos neutrophils and CD14pos monocytes,’ is published in JCI Insight. The study was funded by the Medical Research Council, Versus Arthritis UK and the Italian Ministry of Health. 


Provided by University of Glasgow

Rare Meteorite Could Hold Secrets To Life On Earth (Planetary Science)

Scientists are set to uncover the secrets of a rare meteorite and possibly the origins of oceans and life on Earth, thanks to Science and Technology Facilities Council (STFC) funding.

Research carried out on the meteorite, which fell in the UK earlier this year, suggests that the space rock dates back to the beginning of the Solar System, 4.5 billion years ago.

The meteorite has now been officially classified, thanks in part to the STFC-funded studies on the sample.

The Winchcombe meteorite, aptly named after the Gloucestershire town where it landed, is an extremely rare type called a carbonaceous chondrite. It is a stony meteorite, rich in water and organic matter, which has retained its chemistry from the formation of the solar system. Initial analyses showing Winchcombe to be a member of the CM (“Mighei-like”) group of carbonaceous chondrites have now been formally approved by the Meteoritical Society.

STFC provided an urgency grant in order to help fund the work of planetary scientists across the UK. The funding has enabled the Natural History Museum to invest in state-of-the-art curation facilities to preserve the meteorite, and also supported time-sensitive mineralogical and organic analyses in specialist laboratories at several leading UK institutions.

Dr Ashley King, a UK Research and Innovation (UKRI) Future Leaders Fellow in the Department of Earth Sciences at the Natural History Museum, said: “We are grateful for the funding STFC has provided. Winchcombe is the first meteorite fall to be recovered in the UK for 30 years and the first ever carbonaceous chondrite to be recovered in our country. STFC’s funding is aiding us with this unique opportunity to discover the origins of water and life on Earth. Through the funding, we have been able to invest in state-of-the-art equipment that has contributed to our analysis and research into the Winchcombe meteorite.”

The meteorite was tracked using images and video footage from the UK Fireball Alliance (UKFAll), a collaboration between the UK’s meteor camera networks that includes the UK Fireball Network, which is funded by STFC. Fragments were then quickly located and recovered. Since the discovery, UK scientists have been studying Winchcombe to understand its mineralogy and chemistry to learn about how the Solar System formed.

Dr Luke Daly from the University of Glasgow and co-lead of the UK Fireball Network, said: “Being able to investigate Winchcombe is a dream come true. Many of us have spent our entire careers studying this type of rare meteorite. We are also involved in JAXA’s Hayabusa2 and NASA’s OSIRIS-REx missions, which aim to return pristine samples of carbonaceous asteroids to the Earth. For a carbonaceous chondrite meteorite to fall in the UK, and for it to be recovered so quickly and have a known orbit, is a really special event and a fantastic opportunity for the UK planetary science community.”

Funding from STFC enabled scientists to quickly begin the search for signs of water and organics in Winchcombe before it could be contaminated by the terrestrial environment.

Dr Queenie Chan from Royal Holloway, University of London added: “The teams preliminary analyses confirm that Winchcombe contains a wide range of organic material! Studying the meteorite only weeks after the fall, before any significant terrestrial contamination, means that we really are peering back in time at the ingredients present at the birth of the solar system, and learning about how they came together to make planets like the Earth.”

A piece of the Winchcombe meteorite that was recovered during an organised search by the UK planetary science community is now on public display at London’s Natural History Museum. 


Additional Information

Institutions involved include:

  • STFC – urgency grant is funding Natural History Museum and other STFC-funded planetary science groups.
  • Natural History Museum (Curation and Minerals)
  • Imperial College (Organics)
  • Open University (Volatiles)
  • Royal Holloway (Organics)
  • University of Glasgow (Minerals and Organics)
  • University of Plymouth (Minerals)

For more information on the classification of the Winchcombe meteorite click on the following website link.  

Featured image: An image of one of the fragments of the Winchcombe meteorite. CREDIT Trustee of the Natural History Museum


Provided by University of Glasgow

Biosynthesis Pathway of A New DNA Nucleobase Elucidated (Biology)

DNA is composed of nucleobases represented by the letters A, T, G and C. They form the basis of the genetic code and are present in all living beings. But in a bacteriophage, another base, represented by the letter Z, exists. This exception, the only one observed to date, has long remained a mystery. Scientists from the Institut Pasteur and the CNRS, in collaboration with the CEA, have now elucidated the biosynthesis pathway of this base. This work has been published in the April 30th, 2021 issue of Science.

DNA, or deoxyribonucleic acid, is a molecule that serves as the medium for storing genetic information in all living organisms. It is a double helix characterized by alternating purine nucleobases (adenine and guanine) and pyrimidine nucleobases (cytidine and deoxycytidine). The bases of each DNA strand are located at the center of the helix and are bonded together, thereby linking the two DNA strands: adenine forms two hydrogen bonds with thymine (A–T), and guanine forms three hydrogen bonds with cytosine (G–C). This applies to all living beings, with one exception.

Cyanophage S-2L, an exception to conventional genetics.

Cyanophage S-2L is a bacteriophage, in other words a virus that infects bacteria. In this phage, adenine is completely replaced by another base, 2-aminoadenine (represented by the letter Z). The latter forms three hydrogen bonds with thymine (Z–T), instead of the usual two bonds between adenine and thymine. This higher number of bonds increases the stability of the DNA at high temperatures and changes its conformation, meaning that the DNA is less well recognized by proteins and small molecules

2-aminoadenine biosynthesis pathway elucidated

Since it was discovered in 1977, cyanophage S-2L has been the only known exception, and the biosynthesis pathway of 2-aminoadenine has remained unknown. Scientists from the Institut Pasteur and the CNRS, in collaboration with the CEA, recently elucidated this biosynthesis pathway and demonstrated its enzymatic origins. They achieved this by identifying a homolog of the known enzyme succinoadenylate synthase (PurA) in the genome of cyanophage S-2L. A phylogenetic analysis of this enzyme family revealed a link between the homolog, known as PurZ, and the PurA enzyme in archaea. This indicates that the homolog is an ancient enzyme that probably conferred an evolutionary advantage. The research was carried out using the Institut Pasteur’s Crystallography Platform.

The new Z–T base pair and the discovery of the biosynthesis pathway show that new bases can be enzymatically incorporated into genetic material. This increases the number of coding bases in DNA, paving the way for the development of synthetic genetic biopolymers.

Featured image: A : T, G : C and Z : T bonds © Dona Sleiman et al.


Source

A third purine biosynthetic pathway encoded by aminoadenine-based viral DNA genomes, ScienceApril 30, 2021  


Provided by Institut Pasteur

Dying Cells Protect Their Neighbors To Maintain Tissue Integrity (Biology)

To enable tissue renewal, human tissues constantly eliminate millions of cells, without jeopardizing tissue integrity, form and connectivity. The mechanisms involved in maintaining this integrity remain unknown. Scientists from the Institut Pasteur and the CNRS today revealed a new process which allows eliminated cells to temporarily protect their neighbors from cell death, thereby maintaining tissue integrity. This protective mechanism is vital, and if disrupted can lead to a temporary loss of connectivity. The scientists observed that when the mechanism is deactivated, the simultaneous elimination of several neighboring cells compromises tissue integrity. This lack of integrity could be responsible for chronic inflammation. The results of the research were published in the journal Developmental Cell on June 2, 2021.


Human epithelia are tissues found in several parts of the body (such as the epidermis and internal mucosa). They are composed of layers of contiguous cells that serve as a physical and chemical barrier. This role is constantly being put to the test by both the outside environment and their own renewal. Tissue renewal involves the formation of new cells by cell division and the elimination of dead cells. The mechanisms that regulate the ability of epithelia to maintain their integrity in contexts involving large numbers of eliminated cells remain poorly understood, despite the fact that this situation occurs regularly during embryogenesis or the maintenance of adult tissues. For example, more than ten billion cells can be eliminated every day in an adult intestine. How are these eliminations orchestrated to maintain tissue integrity and connectivity?

Scientists from the Institut Pasteur and the CNRS set out to identify the mechanisms involved in epithelial integrity and the conditions that can affect epithelial connectivity by using Drosophila (or vinegar flies), an organism studied in the laboratory with a similar epithelial architecture to humans.

Using protein-sensitive fluorescent markers, the research team revealed that when a cell dies, the EGFR-ERK pathway – a cell activation signaling pathway known for its involvement in the regulation of cell survival – is temporarily activated in the neighboring cells. The scientists observed that the activation of the EGFR-ERK pathway protected neighboring cells from cell death for approximately one hour, thereby preventing the simultaneous elimination of a group of cells. “We already knew that this pathway plays a key role in regulating cell survival in epithelial tissue, but we were surprised to observe such protective dynamics between cells,” comments Romain Levayer, Head of the Cell Death and Epithelial Homeostasis Unit at the Institut Pasteur and last author of the study.
 

The scientists’ research also shows that inhibiting this protective mechanism has a drastic effect on epithelial tissue: cell elimination becomes random and neighboring cells can be eliminated simultaneously, leading to repeated losses of connectivity. The elimination of groups of neighboring cells is never observed in epithelial tissue in normal conditions, when the EGFR-ERK pathway is not deliberately inhibited, even if a large number of cells are eliminated.

Artistic rendering of dying cells protecting their neighbors to maintain tissue integrity. Holes in epithelium created by uncoordinated cell death are shown in purple. © Institut Pasteur / Leo Valon et Romain Levayer

By using a new optogenetic tool that can control cell death in time and space and bypass the protective mechanism, the scientists confirmed that epithelial integrity was compromised when neighboring cells were eliminated simultaneously. “Surprisingly, epithelial tissue is highly sensitive to the spatial distribution of eliminated cells. Although it can withstand the elimination of a large number of cells, epithelial integrity is affected if just three neighboring cells are eliminated simultaneously,” explains Léo Valon, a scientist in the Cell Death and Epithelial Homeostasis Unit at the Institut Pasteur and first author of the study.

The scientists’ observations confirm that tissues need to develop mechanisms preventing the elimination of neighboring groups of cells. “These observations are important as they illustrate the incredible self-organizing ability of biological tissues, a property that enables them to withstand stressful conditions. So there is no need for a conductor to orchestrate where and when the cells should die; everything is based on highly local communications between neighboring cells,” adds Romain Levayer.

This process seems to have been conserved during evolution. The same protective mechanism based on local EGFR-ERK activation was discovered independently in human cell lines by the research group led by Olivier Pertz at the University of Bern in Switzerland (the results are published in the same journal2). The results of the other study suggest that the protective mechanism is conserved between species separated by hundreds of millions of years, indicating that it is a relatively universal mechanism.

Future research will reveal whether disruption to this cell death coordination mechanism and repeated loss of connectivity in epithelial tissue could be one of the roots of chronic inflammation, a phenomenon responsible for various diseases that are currently among the leading causes of death worldwide.

Distribution of cell deaths in a Drosophila epithelium:

Development of the Drosophila pupa epithelium showing the location of all cell deaths (colored dots). The cell contours are shown in gray.
© Institut Pasteur / Léo Valon et Romain Levayer

Activation of the EGFR-ERK pathway in neighboring cells:

Activation of the EGFR-ERK pathway in the neighbors of a cell extruded from the tissue. The reporter on the left is excluded from the nucleus when the pathway is activated (the eliminated cell is circled in green). Activation can also be viewed by other pathway sensors (the FRET sensor – red for strong activation
© Institut Pasteur  / Romain Levayer et Léo Valon

This research project was supported by the European Research Council (ERC), a Marie Skłodowska-Curie post-doctoral fellowship, the Fondation pour la Recherche Médicale (FRM) et the Cercle Fondation Schlumberger pour l’Education et la Recherche (FSER), R.Levayer 2019 laureate.
 

Featured image: A Drosophila pupa epithelium showing cell contours (gray) and the reporter of the EGFR-ERK pathway (yellow/purple gradient).
© Institut Pasteur / Romain Levayer et Léo Valon


Source

1. Robustness of epithelial sealing is an emerging property of local ERK feedback driven by cell elimination, Developmental Cell2 juin 2021


Provided by Institut Pasteur

Powerhouse Of The Cell Has Self-preservation Mechanism (Biology)

Mitochondria, the powerhouse of the cell, convert sustenance into energy, fueling the cell’s activities. In addition to power, mitochondria also produce reactive oxygen species, byproduct molecules primed to help facilitate communication among the other units in the cells. But when produced too abundantly, they damage DNA and render some cellular components dysfunctional. Now, an international research team has revealed how mitochondria keep their reactive oxygen species production in check.

They published their results on June 30 in Frontiers in Cell and Developmental Biology.

“Excessive generation of reactive oxygen species in mitochondria damages mitochondria and reduces cell function, so the mechanism by which mitochondria maintain production of reactive oxygen species is crucial for cells,” said lead paper author Yoshihiro Ohta, associate professor in the Department of Biotechnology and Life Science at Tokyo University of Agriculture and Technology in Japan. “In this study, we found that mitochondria have a mechanism to spontaneously avoid the production of excess reactive oxygen species.”

Mitochondria are double membraned, with genetic information and functional units contained within its internal matrix. Mitochondria convert chemical energy into power for the cell by moving protons from outside to inside the matrix with the help of an enzyme responsible for energy conversion. But mitochondria also appear to impulsively and temporarily take up protons through another protein through a process called spontaneous transient depolarization.

“Spontaneous fluctuations in mitochondrial membrane potential are physiological phenomena observed in a wide range of cells from plants to mammals,” said Ohta. “In this study, we investigated how this spontaneous fluctuation occurs and what it is useful for.”

In a video, mitochondria in rat cardiomyocytes (H9c2) are shown. Mitochondria (white strings) pump out protons and have an internal negative membrane potential. In the yellow ring, the membrane potential of the mitochondria is rapidly lost and then recovered, suppressing the generation of reactive oxygen species. The phenomenon is demonstrated in this video of rodent heart cells. © Yoshihiro Ohta/ TUAT

The researchers found that increasing the pH of the matrix from neutral to basic significantly increased reactive oxygen species production. They also found that inhibition of the spontaneous fluctuation, or depolarization, increased both the matrix pH and presence of reactive oxygen species.

“Spontaneous transient depolarization may decrease reactive oxygen species production in the mitochondria by inhibiting sustained matrix pH elevation,” Ohta said. “This is the first study suggesting the relationship between spontaneous transient depolarization and reactive oxygen species production.”

While the researchers have not fully elucidated the mechanism by which mitochondria control their reactive oxygen species production, they did propose a model suggesting that spontaneous transient depolarization occurs when increased matrix pH facilitates moving more protons from outside the matrix into the matrix.

The researchers plan to further investigate the mechanism to understand not only how mitochondria can prevent overproduction of reactive oxygen species, but also if detecting the spontaneous fluctuation in mitochondria could indicate the oxidative stress state — and damage — of cells.

###

Other contributors include Jannatul Aklima, Takumi Onojima, Sawako Kimura, Kanji Umiuchi, Takahiro Shibata, Yusho Kuraoka, Yoshiki Oie and Youshiki Suganuma, Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology. Aklima is also affiliated with the Department of Biochemistry & Molecular Biology, University of Chittagong, Bangladesh.

The Program on Open Innovation Platform with Enterprises, Research Institute and Academia (OPERA) from Japan Science and Technology Agency (JST) and Luca Science Inc. supported this research in part.

Featured image: When the balance of proton influx and efflux is lost and theproton inside the mitochondria is insufficient, the amount of ROS generated increases. Proton deficiency inside the mitochondria induces proton influx from the emergency route. Once the proton shortage inside the mitochondria is resolved, the emergency route is closed. © Yoshihiro Ohta/ TUAT


Original Paper:

  • Aklima J, Onojima T, Kimura S, Umiuchi K, Shibata T, Kuraoka Y, Oie Y, Suganuma Y and Ohta Y (2021) Effects of Matrix pH on Spontaneous Transient Depolarization and Reactive Oxygen Species Production in Mitochondria.
  • Front. Cell Dev. Biol. 9:692776.
  • doi: 10.3389/fcell.2021.692776

Provided by TUAT

Anti-tumor Agent From The Intestine (Medicine)

Certain metabolites of bacteria from the intestine make immune cells more aggressive as a new study conducted by scientists from Würzburg and Marburg reveals. The findings could help improve cancer therapies.

It is believed to be involved in the development of chronic inflammatory intestinal diseases, to trigger diabetes, to be responsible for obesity, even neurological diseases such as multiple sclerosis and Parkinson’s could have their causes here – not to mention depressions and autistic disorders. We are talking about the microbiome – the vast collection of bacteria in the human gut. It is estimated that each person carries around 100 trillion bacterial cells in their digestive tract, belonging to several thousand species.

The microbiome has been the focus of research for 20 years – ever since a new technique made it possible to analyse these bacteria quickly and precisely: high-throughput sequencing. Since then, there has been an increasing body of findings that the microbiome, which is sometimes also referred to as the second human genome, is not only of central importance for digestion, but also influences, if not controls, at least a large number of body functions. The immune system is mentioned particularly frequently.

The microbiome influences the immune system

Scientists at the Universities of Würzburg and Marburg have now succeeded for the first time in experimentally demonstrating that bacterial metabolites are able to increase the cytotoxic activity of certain immune cells and thus positively influence the efficiency of tumour therapies. Ideally, the composition of the bacterial species in the microbiome could be used to control its influence on the success of the therapy.

The research team published the results of its study in the journal Nature Communications. Dr. Maik Luu, postdoc in the laboratory of Professor Michael Hudecek at the Medical Clinic and Polyclinic II of the University Hospital of Würzburg, was responsible for the finding. Another participant was Professor Alexander Visekruna from the Institute of Medical Microbiology and Hygiene at the Philipps University in Marburg, where Luu did research before moving to Würzburg.

Fatty acids increase the activity of killer cells

“We were able to show that the short-chain fatty acids butyrate and, in particular, pentanoate are able to increase the cytotoxic activity of CD8 T cells,” Maik Luu describes the central result of the now published study. CD8 T cells are sometimes also called killer cells. As part of the immune system, it is their task to specifically kill cells that are harmful to the organism.

Short-chain fatty acids, in turn, belong to the most dominant class of metabolites of the gut microbiome. On the one hand, they can boost the metabolism of T cells by inducing central regulators of energy metabolism. On the other hand, they can inhibit specific enzymes that regulate the accessibility to the genetic material and thus the gene expression in the T cells. In doing so, they induce epigenetic changes.

Solid tumor models are combated more effectively

“When short-chain fatty acids reprogram CD8 T cells, one of the results is increased production of pro-inflammatory and cytotoxic molecules,” Luu explains. In the experiment, treatment with the fatty acid pentanoate increased the ability of tumor-specific T cells to fight solid tumor models. “We were able to observe the same effect when fighting tumor cells with so-called CAR-T cells,” says the scientist.

CAR-T cells are written out as “chimeric antigen receptor T cells”. While normal T cells are largely “blind” to tumor cells, CAR T cells are able to recognize specific target antigens on the tumor surface and destroy the cancer cells thanks to a genetic modification. Michael Hudecek is one of the leading experts in the field of CAR-T cell research.

Targeted control via the composition of the microbiome

“The results are an example of how metabolites of intestinal bacteria can change the metabolism and gene regulation of our cells and thus positively influence the efficiency of tumor therapies,” says Maik Luu. In particular, the use of CAR-T cells against solid tumors could benefit from this.

In these cases, therapy with genetically modified cells has so far been much less effective than the treatment of haematological tumours such as leukaemia. This could change if the CAR-T cells were treated with pentanoate or other short-chain fatty acids before being used in patients, the scientists hope.

This effect might specifically be exploited via the composition of the bacterial intestinal colonisation – especially since Luu and the others involved in the study were also able to identify the essential pentanoate producer of the intestinal flora: the bacterium Megasphaera massiliensis.

A long way to clinical applications

However, there is still a long way to go before the new findings will lead to new therapies for cancer patients. In a next step, the research team will initially expand the spectrum of tumour diseases investigated and, in addition to other solid tumours, also look at haematological tumour diseases such as multiple myeloma. In addition, it wants to investigate the functioning of short-chain fatty acids more intensively in order to identify starting points for targeted genetic modifications.

The study was financially supported by the P. E. Kempkes Foundation, the Von Behring-Röntgen Foundation, the German Cancer Aid, the Fazit Foundation and the German Research Foundation.

Featured image: The bacterium Megasphaera massiliensis produces the short-chain fatty acid pentanoate in the human digestive tract. It is capable of altering certain cells of the immune system so that they can fight tumours more effectively. This also applies to CAR-T cells. (Image: Maik Luu)


Original publication

Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Maik Luu, Zeno Riester, Adrian Baldrich, Nicole Reichardt, Samantha Yuille, Alessandro Busetti, Matthias Klein, Anne Wempe, Hanna Leister, Hartmann Raifer, Felix Picard, Khalid Muhammad, Kim Ohl, Rossana Romero, Florence Fischer, Christian A. Bauer, Magdalena Huber, Thomas M. Gress, Matthias Lauth, Sophia Danhof, Tobias Bopp, Thomas Nerreter, Imke E. Mulder, Ulrich Steinhoff, Michael Hudecek & Alexander Visekruna. Nature Communications, https://doi.org/10.1038/s41467-021-24331-1


Provided by University of Wurzburg

Tetanus Toxin Fragment May Treat Depression, Parkinson’s Disease and ALS (Neuroscience)

Depression has been treated traditionally with inhibitors of serotonin reuptake in the central nervous system. These drugs do not come without side effects, such as lack of immediate therapeutic action, the need for daily doses and the danger of becoming addicted to some of these drugs. That is why scientists continue to work on new therapies to treat depression.

In 2019, an international group of researchers co-led by Dr Yousef Tizabe from the Howard University College of Medicine in Washington, D.C., and Professor José Aguilera from the Department of Biochemistry and Molecular Biology and the Institut de Neurociències at the Universitat Autònoma de Barcelona (UAB), observed that a non-toxic derivative of the tetanus neurotoxin (which causes tetanus infections) improved depression symptoms in rat animal models. “One intramuscular dosis of Hc-TeTx made depression symptoms disappear in less than 24 hours, and its effects lasted two weeks”, explains Aguilera. Based on these findings, scientists began to work on discovering the mechanism through which this substance produces these effects.

In a recent study coordinated by Professor Aguilera and conducted in collaboration with the research group led by Dr Thomas Scior of the Benemérita Universidad Autónoma de Puebla (BUAP) in Mexico, researchers demonstrated that Hc-TeTx is capable of inhibiting the transport of serotonin within the central nervous system, by binding to neurotrophin receptors, proteins that induce the survival of neurons. These results, published in the journal Molecules, suggest that the drug may not only serve in treating depression, but also be useful in treating neurodegenerative diseases, such as Parkinson’s disease or amyotrophic lateral sclerosis (ALS).

According to researchers, the advantages of introducing Hc-TeTx as a new drug are evident. A biweekly or monthly dosis would allow medical professionals to control the progress. Since it is a recombinant product, there would be no problems with drug safety, production or high costs. Furthermore, in neurodegenerative cases, Hc-TeTx would stop the development of the pathology and at the same time eliminate any disease-related depressions.

Researchers recently patented the therapeutic use of Hc-TeTx for the treatment of depression, Parkinson’s disease and amyotrophic lateral sclerosis, and are now looking for investors to be able to conduct clinical trials on humans. “This is an important advance in science, and even more so now when in addition to the high incidence in depression and alterations in behaviours, we see mental alterations as a result of COVID-19 and the negative environments of stress, self-isolation or fear”, Aguilera concludes.

Featured image: Mice neuromuscular junction in a tibialis anterior muscle slice. Microscope images obtained for the research. © UAB


Reference: Candalija, A.; Scior, T.; Rackwitz, H.-R.; Ruiz-Castelan, J.E.; Martinez-Laguna, Y.; Aguilera, J. Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin. Molecules 2021, 26, 3988. https://doi.org/10.3390/molecules26133988


Provided by UAB

UCPH Researchers Prove Powerhouse Malfunction As The Major Cause Of Parkinson’s Disease (Neuroscience)

The major cause of Parkinson’s Disease is a dysregulation of immune genes central for fighting against viruses, a new study reveals. Researchers from the University of Copenhagen show that this dysregulation leads to a malfunction in the cell’s powerhouse, which cannot produce sufficient energy for neurons to stay alive, causing them to gradually die.

12,000 people in Denmark and 7 to 10 million people worldwide suffer from Parkinson’s Disease (PD). It is the second most common neurogenerative disorder of aging and the most common movement disorder, but the cause of the disease is largely unknown.

In a new study, researchers from the University of Copenhagen show that the most common form of the disease, encompassing 90 to 95 percent of all Parkinson’s Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates the nerve cell’s powerhouse, the mitochondria. 

‘Just like when people eat, cells take what they need and get rid of the rest waste products. But if our brain cells have this specific kind of signaling blockage, it means that the powerhouse of the cell – mitochondria – cannot get cleaned up after being damaged’, explains corresponding author and group leader Professor Shohreh Issazadeh-Navikas at the Biotech Research & Innovation Centre.

The blockage leads to an accumulation of high amounts of damaged mitochondria, while not being able to produce enough energy for the cells. It causes neurons to gradually die, which is the reason for the development of Parkinson’s Disease symptoms, and why it leads to dementia.

The blockage is caused by a dysregulation of the immune genes, more specifically a pathway called type 1 interferon, which is normally important for fight against viruses, but now we show that it is also responsible for regulating the energy supply of the nerve cells.

‘Every part of our body needs to be regulated. We get a signal to stop eating, when we are full, and the same thing happens everywhere else in our body. If we get an infection, parts of our body need to fight it and stop it from replicating. But when the infection is cleaned up, the signal should subside. This is the job of a protein called PIAS2. That causes the blockage of the type 1 interferon-pathway, and when the infection is over, the blockage should stop and go back to normal. But that does not seem to be the case in patients with Parkinson’s Disease. We further demonstrate that this dysregulation leads to a defect in the mitochondrial energy supply, as mentioned before’, says Shohreh Issazadeh-Navikas.

These pathways are very important for brain functions, but they are also associated with microbial and virus recognition. For example, they are very important for fighting COVID-19, and a mutation in the related gene has been shown to be linked to a deadly outcome after contracting COVID-19.

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A detail look into what happens in the neurons. Illustration by authors © University of Copenhagen

Combining datasets for a bigger picture

The researchers combined and analyzed four data sets, which studied neurons from brains with Parkinson’s Disease and looked at what type of genes they express.

They then looked at which gene patterns were disturbed in patients with Parkinson’s Disease and especially those who had also developed PD with dementia.

In order to test the results, the major findings of the combined data was tried in three different mouse models using a negative regulator of the type I interferon pathway, PIAS2, which had been identified from the patients study as one of the key proteins linked to the progression of Parkinson’s Disease and dementia.

‘We show that a high accumulation of the PIAS2-protein is what is causing the blockage in the pathway, which should have activated the processes responsible for removing damaged protein and mitochondrial garbage’, says Shohreh Issazadeh-Navikas.

‘The accumulation of damaged mitochondrial mass further leads to increase of other toxic proteins. So when we compare patients to same-aged healthy patients without Parkinson’s Disease, we see that this PIAS2-protein is highly expressed in the neurons, which is why this pathway should be evaluated for potential roles in the other forms of familial Parkinson’s Disease that we have not studied here.’

The researchers hope the study will encourage research to counteract the pathway blockage, which could have a beneficial impact on the disease and towards preventing dementia.

In the next stages, the Shohreh Group will study how the pathway contributes to neuronal homeostasis and survival, as well as how its dysregulation causes neuronal cell death.

Read the full paper ‘PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia’ here.

Featured image credit: Colourbox


Provided by University of Copenhagen