Scientists Discover Roles For A Cellular Motor in Cancer (Oncology / Medicine)

Utah scientists have discovered new functions of a key cellular machine that regulates gene packaging and is mutated in 20% of human cancers. The study was published in print today in the journal Molecular Cell.

©Clapier et al.

Genes are segments of cellular DNA, and gene packaging is called chromatin. Genes are tightly packaged when they are not activated and then unpackaged by chromatin remodeling machines when genes need to be turned on. Mutations in chromatin regulating machines are a significant driver of cancer and other human diseases, as the mutant chromatin regulators improperly unpackage and express genes, which disrupts normal cell growth, identity, and development.

Chromatin remodeling machines have been a longstanding focus of Brad Cairns, PhD, study lead author, who discovered the first chromatin remodeling machine in 1996. Cairns is a scientist at Huntsman Cancer Institute (HCI) and professor and chair of oncological sciences at the University of Utah (U of U). The Cairns Lab works to understand how chromatin impacts gene expression in humans and other organisms and provides instructions for cell growth, identity, and development. An important aspect of this work is better understanding the role of chromatin in cancer and other diseases.

The major component of chromatin is nucleosomes, which are similar to beads upon which DNA is wrapped like a string, explaining why chromosomes look like beads on a string under a powerful microscope. Cairns and colleagues wanted to know how these beads are moved along or removed from the DNA to unpackage and expose genes. Previous work showed that chromatin remodeling machines have a motor-like component that drives the machine along the DNA, disrupting the nucleosome beads. The fuel for the cellular motor is called ATP, a chemical produced in cells. When properly regulated, the motor ensures that the right genes are properly unpackaged. However, when the motor is misregulated, the wrong genes are unpackaged–and cancer or improper development results.

Cairns’s team wanted to understand how the motor of the machine is regulated. “These really are machines: they contain a ‘gas pedal’ and a ‘clutch’ that together control whether and how the motor moves the machine along the DNA. This new paper shows the gas pedal and clutch sit right on the motor, and the cancer-causing mutations localize to the clutch and gas pedal itself, making the motor hyperactive and unpackaging genes when it should not.” The work reveals how factors in the cell can activate the machine to do its work at the right place and time.

Cairns and his colleagues used data on mutations in human tumors from the COSMIC cancer database, the largest cancer genomics database in the world, in order to study the human chromatin remodeling machine called BAF/PBAF. BAF/PBAF is mutated in 20% of all human tumors, including pancreatic cancer, gastric cancer, and melanoma. They studied these human mutations using yeast as a model system. This analysis revealed a structural hub that tells the motor when to engage (the clutch) and how fast to run along the DNA (the gas pedal), move nucleosomes, and open up genes for their activation. Notably, the team found a series of cancer mutations in an area of the hub that regulates the motor activity and thus ensures proper movement or removal of nucleosomes and proper gene expression. These mutations in the regulatory hub of the motor created a hyperactive and dysregulated motor that improperly opens up chromatin. The team’s findings shed light on a key regulatory behavior of healthy cells and explain how a set of cancer-causing mutations promote cancer.

References: Cedric R. Clapier, Naveen Verma, Timothy J. Parnell, Bradley R. Cairns, “Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub”, Molecular Cell, VOLUME 80, ISSUE 4, P712-725.E5, NOVEMBER 19, 2020.

Provided by Huntsman Cancer Institute

CLCN6 Identified as Disease Gene For a Severe Form of Lysosomal Neurodegenerative Disease (Neuroscience)

A mutation in the CLCN6 gene is associated with a novel, particularly severe neurodegenerative disorder. Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Max Delbrück Center für Molekulare Medizin (MDC), together with an international team of researchers, have now analyzed the effect of a point mutation that was found in three unrelated affected children. ClC-6 is one of nine members of the CLCN gene family of chloride channels and chloride/proton exchangers and, apart from ClC-3, was the only one that could not yet be associated with any human disease. The results have just been published in the American Journal of Human Genetics.

This leads to the appearance of large vesicles that are positive for the lysosomal marker protein LAMP-1 (shown in green). Vesicles with high levels of both proteins appear yellow. ©Carlo Barbini

The term “lysosomal storage disease” summarizes a number of genetically determined metabolic diseases that are due to incorrect or insufficient function of lysosomes. These cellular organelles are important both as “cellular waste disposal” and for the regulation of cellular metabolism. If lysosomal function is compromised, substances that normally would be degraded may accumulate in the affected cells. This may impair their function and may eventually lead to cell death. In the central nervous system, which is often affected because adult neurons are unable to regenerate, this can lead to neurodegeneration.

Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Max-Delbrück-Centrum für Molekulare Medizin (MDC), in close collaboration with colleagues from Rome, Hamburg and the USA, have now found and characterized the gene defect underlying a novel severe form of neurodegenerative disease: A mutation in the CLCN6 gene in three unrelated children from Italy, Germany and the USA, leads to severe developmental delay, intellectual disability, hypotonia severely affecting muscle tone, respiratory insufficiency, visual impairment, and early-onset brain atrophy.

Ion transporter ClC-6 is a member of the chloride channel family

Human geneticists, including the study’s co-leader Marco Tartaglia from Rome and Kerstin Kutsche from Hamburg, independently discovered the same point mutation in their young patients and asked Prof. Thomas Jentsch and his team to examine possible effects of the mutation on the transport properties of ClC-6 and its cellular functions. Jentsch, the discoverer of the CLC chloride channel family, had already found or characterized different disease-causing mutations in almost all nine CLC genes. These are associated with a broad spectrum of different pathologies. Only the genes encoding the ion transporters ClC-3 and ClC-6 had not yet been found to be mutated in human disease. “About fifteen years ago, we had generated a ClC-6 knockout mouse and found that it displayed mild neuronal lysosomal storage. However, our search for patients with similar loss function mutations in ClC-6 was unsuccessful,” explains Prof. Jentsch. “Now we have identified a different type of ClC-6 mutation in a much more severe human disease.”

The presence of exactly the same mutation in three independent patients displaying the same disease pattern already indicated a causal role of the mutation. But only the functional analysis in cell culture brought final certainty and led to the classification as lysosomal disease. “Our cell cultures experiments clearly show that increased ion transport by the mutated ClC-6 affects lysosomes and thereby prove the deleterious effect of the mutation. Based on these results, and taking into account our previous mouse model, we assume that the novel disease can be classified as lysosomal storage disease,” explains Thomas Jentsch. However, definitive proof of this classification would require post-mortem examination of brain slices from patients or a novel mouse model carrying the same mutation.

More chloride uptake leads to abnormally large, lysosome-like vesicles

Unlike the chloride channels ClC-1, -2, -3 and -K, the chloride/proton exchangers ClC-3, -4, -5, -6, and -7 are not located on the plasma membrane but in intracellular membranes, mainly on endosomes and lysosomes. In previous studies, Jentsch and coworkers identified mutations of ClC-7 as the cause of a form of lysosomal storage disease associated with osteopetrosis, and mutations of ClC-4 lead to intellectual deficits. While ClC-7 is found on lysosomes, ClC-6 is predominantly located on late endosomes, kind of lysosome precursors.

The Berlin team found that the patients’ mutation, in contrast to the loss of ClC-6 in their previous knock-out mouse model, caused a hyperactive ClC-6: The transport of chloride and protons was highly increased and was no longer modulated by pH. Normally acidic pH, as gradually achieved in the transition from endosomes to lysosomes, inhibits the transporter. This regulation is missing in the disease-causing mutant. The increased, unregulated ion transport – a pathological gain of function – resulted in drastically enlarged, lysosome-like vesicles in cells that were made to produce the mutated ClC-6. According to Jentsch, this pathological gain of function can explain the children’s disease. “Vesicles carrying the mutated ClC-6 in their membrane are pathologically enlarged by an increased uptake of chloride, which is later followed by water. This uptake is driven by the ClC-6-mediated exchange for protons which are abundantly present in the acidic interior of vesicles. This severely impairs the function of lysosomes and, in the long run, probably leads to lysosomal storage in neurons, cells that are unable to proliferate. The tissue distribution of ClC-6, which is found almost exclusively in neurons, contributes to the predominantly neurological disease “.

“The present work highlights the importance of ion transport for the endosomal-lysosomal pathway,” says Jentsch. “We see a broad spectrum of genetic diseases that are caused by mutations in vesicular CLCs or in different intracellular channels.” Very different organs can be affected: For example, mutations in the endosomal ClC-5 lead to kidney stones and protein loss into the urine, as Jentsch’s team showed a long time ago.

Jentsch is confident that also the ClC-3 exchanger will soon be linked to a genetic disease – a KO mouse previously published by the group shows dramatic neurodegeneration. Together with the current finding, this would link all nine CLCN genes to human genetic disease. “The gap is closing”, says Jentsch, “and we can see very clearly how important basic research – we had cloned the first CLC from an electric fish – is for the diagnosis and understanding of human disease”.

References: Polovitskaya M., Barbini C., Martinelli D., Harms F., Cole S., Calligari P.,Bocchinfuso G., Stella L., Ciolfi A., Niceta M., Rizza T., Shinawi M., Sisco K., Johannsen J., Denecke J., Carrozzo R., Wegner D., Kutsche K., Tartaglia M., Jentsch T.J.,
A recurrent gain-of-function mutation in CLCN6, encoding the ClC-6 Cl-/H+-exchanger, causes early-onset neurodegeneration,
American J. Human Genetics, 107, 2020.

Provided by FV Berlin

Taking Out the Trash is Essential for Brain Health (Neuroscience)

A research team at Tokyo Medical and Dental University (TMDU) find that Wipi3, a protein involved in cellular waste disposal, is crucial for neuronal health.

A little mess never killed anyone, right? Wrong. Researchers at Tokyo Medical and Dental University (TMDU) have recently shown that a build-up of cellular “trash” in the brain can actually cause neurodegeneration, and even death.

Abnormal motor performance in Wipi3cKO mice at 10 weeks of age. In (a), the limb-clasping reflex is observed in Wipi3cKO mice. In (b), the footprint assay indicated a motor deficit in Wipi3cKO mice. ©Department of Pathological Cell Biology,TMDU

Reporting their findings in Nature Communications, the researchers describe how defects in a cellular waste disposal mechanism, called “alternative autophagy”, can lead to a lethal build-up of iron and protein in brain cells.

“Cells are constantly clearing out dysfunctional or unnecessary components, which are then degraded and recycled,” explains study lead author Hirofumi Yamaguchi. “Autophagy is the process whereby unwanted cellular components and proteins are contained within a spherical doubled-membraned vesicle called an autophagosome, which fuses with an enzyme-filled lysosome to form an autolysosome. The waste material is then broken down and reused by the cell.”

This common form of autophagy, called “canonical autophagy”, is well characterized and involves a suite of autophagy-related proteins, such as Atg5 and Atg7. More recently though, several Atg5-independent alternative autophagy pathways have also been described, the biological roles of which remain unclear.

Cryosections of the cerebellum from Wipi3cKO mice and WT mice were stained with Prussian blue (a) and were immunostained with anti-ceruloplasmin (green) and anti-calbindin (red) antibodies (b). Blue puncta indicate iron deposition in (a). ©Department of Pathological Cell Biology,TMDU

After identifying alternative autophagy-related proteins in yeast, the team at TMDU focused on a mammalian ortholog called “Wipi3”, which had previously been implicated in canonical autophagy. “When we deleted Wipi3 in a mouse cell line and induced alternative autophagy, we no longer observed the formation of double-membraned autophagosomes or single-membraned autolysosomes, confirming that Wipi3 is essential for alternative autophagy,” says Yamaguchi.

Mice containing a brain-specific deletion of Wipi3 demonstrated growth and motor defects most commonly seen in patients with neurodegeneration, with the researchers also noting an accumulation of iron and the iron-metabolizing protein ceruloplasmin in the brain cells of affected mice.

“Iron deposition has been flagged as a possible trigger in various neurodegenerative disorders, and is usually associated with the abnormal accumulation of iron-binding proteins,” explains study senior author Shigeomi Shimizu. “Our findings are strong evidence that alternative autophagy, and Wipi3 specifically, may be essential for preventing this toxic build-up of iron.”

Wipi3 is translocated from the cytosol to the trans-Golgi, and manipulates the trans-Golgi membrane to generate autophagic vacuoles. In vivo, Wipi3-dependent alternative autophagy degrades excess ceruloplasmin, and prevents abnormal iron deposition in brain cells. ©Department of Pathological Cell Biology,TMDU

Interestingly, although Wipi3-deficient and Atg7 (canonical autophagy)-deficient mice showed similar motor defects, they exhibited very different sub-cellular changes, suggesting that alternative autophagy and canonical autophagy act independently to protect neurons. Supporting this, deletion of both Wipi3 and Atg7 in mice was almost always fatal.

The researchers are hopeful that this research could lead to the development of neuroprotective drugs. Preliminary tests indicate that over-expression of Dram1, another alternative autophagy-associated protein, can reverse the effects of Wipi3 deletion, and may form the basis of future therapies for various neurodegenerative diseases. The article, “Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration,” was published in Nature Communications (DOI: 10.1038/s41467-020-18892-w).

References: Yamaguchi, H., Honda, S., Torii, S. et al. Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration. Nat Commun 11, 5311 (2020).

Provided by Tokyo Medical and Dental University

Gut Microbiome Link to Deadly Lung Disease (Medicine)

Research led by the Centenary Institute, the University of Technology Sydney and the University of Queensland has shown for the first time a link between chronic obstructive pulmonary disease (COPD), an often fatal lung condition, and the gut microbiome.

Professor Phil Hansbro – Director of the Centenary UTS Centre for Inflammation. ©Centenary Institute

The findings, published in the high impact science journal ‘Nature Communications’, suggests that the gut may be helpful in diagnosing COPD and may also be a potential source of new therapeutic targets to help treat the chronic respiratory disorder.

“It’s already known that the lung microbiome is a contributing factor in COPD,” said Professor Phil Hansbro, senior author of the study and Director of the Centenary UTS Centre for Inflammation.

“We wanted to see if the gut environment was also somehow involved-to determine whether the gut could act as a reliable indicator of COPD or if it was connected in some way to the development of the disease.”

In the study, the researchers compared the microbiome and metabolite profiles of stool samples from COPD patients with healthy individuals. Revealed were significant differences between the two groups.

COPD patients exhibited increased levels of the bacteria Streptococcus and Lachnospiraceae in their stool samples. Also identified in individuals with COPD was a unique metabolite signature-formed by the chemical by-products of the metabolic process.

“Our research indicates that the gut of COPD patients is notably different from healthy individuals,” said first author on the paper Dr Kate Bowerman, University of Queensland.

“This suggests that stool sampling and analysis could be used to non-invasively diagnose and monitor for COPD,” she said.

The study’s researchers believe that the altered gut microbiome found in COPD patients could also support the gut as a potential target for new treatments.

“The ‘gut-lung axis’ describes the common immune system of the lung and gastrointestinal tract. This means that activity in the gut can impact activity in the lung. Our COPD findings suggest that the gut microbiome should now also be considered when looking for new therapeutic targets to help treat lung disease,” said Professor Hansbro.

COPD, a life threatening inflammatory disorder of the lungs, is the third most common cause of death globally. More than 3 million lives are lost every year to COPD.

References: Bowerman, K.L., Rehman, S.F., Vaughan, A. et al. Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease. Nat Commun 11, 5886 (2020).

Provided by Centenary Institute

New Process Narrows the Gap Between Natural and Synthetic Materials (Engineering)

Natural materials like skin, cartilage and tendons are tough enough to support our bodyweight and movements, yet flexible enough that they don’t crack easily. Although we take these properties for granted, replicating this unique combination in synthetic materials is much harder than it sounds. Now, scientists at EPFL have developed a new way of making strong, supple composite polymers that more closely mimic materials found in the natural world. Their breakthrough, described in a paper appearing in Advanced Functional Materials, could have applications in fields such as soft robotics and cartilage prosthetic implants.

The research team showed that a tube measuring just 3 mm across can withstand a tensile load of up to 10 kg and a compressive load of as much as 80 kg with no damage to its structural integrity. ©EPFL

Normally, synthetic hydrogels fall into two very different material categories. The first type, which includes window glass and some polymers, are hard and load-bearing but notoriously poor at absorbing energy: even the slightest crack can spread through the structure. Materials in the second group are better able to resist cracking, but there’s a trade-off: they’re extremely soft – so soft, in fact, that they can’t bear heavy loads. Yet some natural composites – made from a combination of biological materials and proteins, including collagen – are both strong and crack-resistant. They owe these properties to their highly precise structure, from the nano to the millimeter scales: for example, woven fibers are organized into larger structures, which in turn arrange to form other structures, and so on.

“We’re still a long way from being able to control the structure of synthetic materials at so many different scales,” says Esther Amstad, an assistant professor at EPFL’s Soft Materials Laboratory and the paper’s lead author. Yet Matteo Hirsch and Alvaro Charlet – two doctoral assistants working under Amstad’s guidance – have devised a new approach to building synthetic composites, taking their cues from the natural world. “In nature, basic building blocks are encapsulated in compartments, which are then released in a highly localized way,” explains Amstad. “This process provides greater control over a material’s final structure and local composition. We took a similar approach, arranging our own building blocks into compartments then assembling them into a superstructure.”

First, the scientists encapsulated monomers in droplets of a water-and-oil emulsion, which serve as the compartments. Inside the droplets, the monomers bind together to form a network of polymers. At this point, the microparticles are stable but the interactions between them are weak, meaning the material doesn’t hold together well. Next, the microparticles – which are highly porous like sponges – were soaked in another type of monomer before the material was reduced to form a kind of paste. Its appearance, as Alvaro Charlet puts it, is “a bit like wet sand that can be shaped into a sandcastle”.

The scientists then 3D-printed the paste and exposed it to UV radiation. This caused the monomers added at the second step to polymerize. These new polymers intertwined with the ones formed earlier in the process, thereby hardening the paste. That resulted an exceptionally strong, hard-wearing material. The research team showed that a tube measuring just 3 mm across can withstand a tensile load of up to 10 kg and a compressive load of as much as 80 kg with no damage to its structural integrity.

Their discovery has potential uses in soft robotics, where materials that mimic the properties of living tissues are highly sought-after. The ground-breaking process could also be applied to develop biocompatible materials for cartilage prosthetic implants.

References: Hirsch, M., Charlet, A., Amstad, E., 3D Printing of Strong and Tough Double Network Granular Hydrogels. Adv. Funct. Mater. 2020, 2005929.

Provided by EPFL

Potential New Target To Combat Inflammatory Diseases (Medicine)

An international team of researchers have uncovered a drug-like compound that blocks a crucial inflammatory pathway, potentially paving the way for a new treatment for a host of diseases – including COVID-19.

Researchers have uncovered a drug-like compound that could prevent up-regulation of CD14, a key inflammatory protein. ©WEHI

WEHI’s Associate Professor Seth Masters and his research team discovered the compound could prevent up-regulation of CD14, a key inflammatory protein. The discovery was recently published in EBioMedicine.

At a glance

  • Researchers have uncovered a drug-like compound that blocks a key inflammatory pathway, involving the immune cell protein CD14.
  • In the laboratory, the compound reduced CD14 levels, limiting inflammation and preventing it from overwhelming the body.
  • The team hope the compound could lead to the development of new medicines for inflammatory diseases, including COVID-19.

Targeting inflammation

Inflammation is our body’s natural reaction to infection, said Associate Professor Masters. “In the beginning, it helps you fight the infection – but too much inflammation is linked to a range of chronic and acute diseases,” he said.

“In a viral disease such as COVID-19, some patients experience excessive inflammation – called a ‘cytokine storm’ – which can lead to hospitalisation or death. Blocking the CD14 pathway can reduce the severity of many diseases, and potentially save lives.

The team focussed their research on a protein called CD14, that is found on certain inflammatory immune cells called macrophages.

“CD14’s job is to detect infection, helping to drive inflammation to clear a pathogen. But we know that the amount of CD14 increases on macrophages as inflammation progresses, potentially getting out of control, which could lead to worse outcomes for infections or other diseases,” Associate Professor Masters said.

“Our team used CRISPR technology to search for genes that help CD14 levels to rise.

“We found many really interesting genes that were critical – and when we turned these genes off, they could prevent CD14-driven inflammation from overwhelming the body.

“Excitingly, a drug-like inhibitor blocks the protein produced by one of these genes. We found this compound could block the rise in CD14 and consequent inflammation in the laboratory, which is incredibly promising,” Associate Professor Masters said.

Vital first step towards a treatment

Associate Professor Masters said the discovery of a potential anti-inflammatory compound opened the doors for new anti-inflammatory therapies.

“If this compound could be developed into a safe and effective drug, it could potentially assist in the treatment of many inflammatory diseases,

However, once available, the drug would only be beneficial for curbing severe inflammation.

“Inflammation is a critical process for fighting many infectious, so we only need to use an anti-inflammatory drug for the most severe and life-threatening forms of inflammation,” Associate Professor Masters said.

“The next step in this research would be to see if this drug candidate worked against particular diseases in pre-clinical trials. There is great hope this research will one day be translated into an effective treatment for inflammatory illnesses.”

References: Gisela Jiménez-Duran, Rosario, Luque-Martin, Meghana Patel, Emma Koppe, Sharon Bernard, Catriona Sharp et al., “Pharmacological validation of targets regulating CD14 during macrophage differentiation”, VOLUME 61, 103039, NOVEMBER 01, 2020. DOI:

Provided by Walter and Eliza Hall Institute

Bed Dust Microorganisms May Boost Children’s Health (Biology)

In the most extensive study of its kind, researchers from the University of Copenhagen, in collaboration with the Danish Pediatric Asthma Center at Herlev and Gentofte Hospital, have found a link between microorganisms living in the dust of children’s beds and the children’s own bacteria. The correlation suggests that microorganisms may reduce a child’s risk of developing asthma, allergies and autoimmune diseases later on in life.

From previous studies, the researchers also know that pets, older siblings and rural living also contribute to a lowered risk of developing autoimmune diseases. Photo: Gettyimages

Invisible to the human eye, our beds are teeming with microbial life. It is life that, especially during early childhood, can affect how microorganisms in our bodies develop, and thereby how resilient we become to various diseases.

To get a better grasp of this relationship, researchers at the University of Copenhagen’s Department of Biology and the Danish Pediatric Asthma Center analyzed bed dust samples from the beds of 577 infants before comparing them with respiratory samples from 542 children. It is the largest study of its kind, the aim of which was to determine which environmental factors affected the composition of microorganisms in the bed dust and if there was a correlation between bed dust microorganisms and the bacteria in the children’s airways.

“We see a correlation between the bacteria we find in bed dust and those we find in the children. While they are not the same bacteria, it is an interesting discovery that suggests that these bacteria affect each other. It may prove to have an impact on reducing asthma and allergy risks in later years,” explains Professor Søren J. Sørensen of UCPH’s Department of Biology.

Constant sheet changing may not be necessary

The science was already clear — a high diversity of microorganisms in the home contributes to the development of a child’s resistance to a host of diseases and allergies. Beds can be a central collector of bacteria, microscopic fungi and other microorganisms.

“We are well aware that microorganisms living within us are important for our health, with regards to asthma and allergies for example, but also for human diseases such as diabetes II and obesity. But to get better at treating these diseases, we need to understand the processes by which microorganisms emerge during our earliest stages of life. And, it seems that the bed plays a role,” says Søren J. Sørensen, adding:

“Microorganisms in a bed are affected by a dwelling’s surroundings, where high bacterial diversity is beneficial. The simple message is that constantly changing bedsheets may not be necessary, but we need to investigate this a bit more closely before being able to say so for sure.”

The benefits of rural life, pets and older siblings

A total of 930 different types of bacteria and fungi were found in the dust collected from the beds of the roughly six-month old children. The richness of bacteria depended largely upon the type of dwelling from which the sample was taken from.

Researchers studied both rural and urban dwellings. Rural homes had significantly higher levels of bacteria compared to urban apartments.

“Previous studies inform us that city-dwellers have less diverse gut flora than people who live in more rural settings. This is typically attributed to their spending greater amounts of time outdoors and having more contact with nature. Our studies demonstrate that changes in bacterial flora in bed dust can be an important reason for this difference as well,” says Søren J. Sørensen

From previous studies, the researchers also know that pets, older siblings and rural living also contribute to a lowered risk of developing autoimmune diseases.

The researchers’ next step is to investigate whether the differences in bacterial flora in bed dust can be correlated directly to the development of diseases such as allergies and asthma.

The research is published in the scientific journal Microbiome Journal 7 August 2020:

Facts: * A total of 930 different types of bacteria were found in beds.
* Dust from the beds of 577 infants was examined along with respiratory samples from 542 children.
* The children were roughly six months old.

Provided by Faculty of Science- University of Copenhagen

Incretin Hormone Levels Linked to Arteriosclerosis (Medicine)

Diabetes is currently treated using incretin hormones to reduce the risk of cardiovascular disease and other medical issues that the illness can trigger. Now researchers from Lund University in Sweden have noted new links between these hormones and arteriosclerosis, and believe their discovery could be significant for treatment of diabetes in the future. The study is published in Diabetes Care.

Martin Magnusson and Amra Jujic (Photo: Tove Gilvad)

When we eat, the incretin hormones GIP and GLP-1 are secreted by the intestine. These stimulate insulin secretion in the pancreas and contribute to the reduction in blood sugar to normal levels following a meal – known as the incretin effect.

This incretin effect is inhibited in those with type-2 diabetes, leading to hampered insulin production. This is why these hormones are currently therapeutic targets for treating insulin levels in diabetes patients.

In the current study, the researchers measured hormone levels in the blood.

“We saw that high levels of GIP were linked to a significantly higher risk of early signs of arteriosclerosis, while high levels of GLP-1 were instead linked to a lower risk. This link maintained statistical significance even after it was corrected for known risk factors”, says Martin Magnusson, adjunct professor at Lund University and senior consultant in cardiology at Skåne University Hospital, as well as Clinical Fellow in diabetes at the Wallenberg Centre for Molecular Medicine at Lund University.

Researchers used data from the major Malmö Diet Cancer population study involving 3 342 participants, 59 percent of whom were women and whose average age was 72. Ten percent of the participants had diabetes.

Martin Magnusson’s research team are also behind a study published in Diabetologia in January 2020 that showed that high levels of GIP are linked to a greater risk of cardiovascular mortality and total mortality.

The current study is the first in which researchers take measurements from people – and across a large population – to investigate the link between the levels of GIP and GLP-1 in the blood and measurements of early arteriosclerosis.

“The findings in this new study indicate that there may be a link between raised GIP levels in the blood and a risk of arteriosclerosis. As we did not have many diabetic participants in the study, we do not yet know how GIP levels affect the arteriosclerosis process in a purely diabetic population and should therefore treat the results as a basis for generating hypotheses”, says Amra Jujic, postdoc at Lund University and the first author of the study.

Martin Magnusson considers the results to be in line with what earlier randomized clinical pharmaceutical studies have also shown. In treatments using GLP-1 agonists, the risk of cardiovascular morbidity fell while studies that indirectly raise GIP and GLP-1 through medicinal treatment using DPP4 inhibitors were not able to demonstrate such positive effects.

The researchers’ hypothesis is that the positive effects of GLP-1 are counteracted by the potentially negative effects of GIP, and that this can explain the lack of cardiovascular-shielding effects in DPP4 inhibitors. Magnusson emphasizes that randomizing clinical studies of DPP4 inhibitors have shown that this medication is not linked to any negative cardiovascular effects and is therefore entirely safe for patients with diabetes to take.

“Our findings should absolutely not be used as an argument for diabetes patients to alter their current treatment. However, as many diabetes patients may likely be treated using a new group of medications in the future that directly stimulate both GLP-1 and the GIP receptor, there is major clinical interest in gaining clarity on what lies behind our epidemiological findings”, explains Magnusson.

“The next stage will involve further investigation of the long-term cardiovascular effects of GIP and GLP-1 infusion and whether blocking the GIP receptor could represent an alternative treatment in animal studies. We also want to continue studying the links between GIP levels and cardiovascular risk in purely diabetic human populations in Andis, a project in which all new diabetes patients in Skåne are registered”, concludes Jujic.

References: Amra Jujić, Peter M. Nilsson, Naeimeh Atabaki-Pasdar, Anna Dieden, Tiinamaija Tuomi, Paul W. Franks, Jens Juul Holst, Signe Sørensen Torekov, Susana Ravassa, Javier Díez, Margaretha Persson, Emma Ahlqvist, Olle Melander, Maria F. Gomez, Leif Groop, Martin Magnusson, “Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness”, Diabetes Care 2020 Nov; dc201318.

Provided by LUND University

Mystery Solved: A ‘New Kind of Electrons’ (Physics)

Why do certain materials emit electrons with a very specific energy? This has been a mystery for decades – scientists at TU Wien have found an answer.

It is something quite common in physics: electrons leave a certain material, they fly away and then they are measured. Some materials emit electrons, when they are irradiated with light. These electrons are then called “photoelectrons”. In materials research, so-called “Auger electrons” also play an important role – they can be emitted by atoms if an electron is first removed from one of the inner electron shells. But now scientists at TU Wien (Vienna) have succeeded in explaining a completely different type of electron emission, which can occur in carbon materials such as graphite. This electron emission had been known for about 50 years, but its cause was still unclear.

Florian Libisch, Philipp Ziegler, Wolfgang Werner und Alessandra Bellissimo (left to right). ©TU Wien

Strange electrons without explanation

“Many researchers have already wondered about this,” says Prof. Wolfgang Werner from the Institute of Applied Physics. “There are materials that consist of atomic layers that are held together only by weak Van der Waals forces, for example graphite. And it was discovered that this type of graphite emits very specific electrons, which all have exactly the same energy, namely 3.7 electron volts.”

No known physical mechanism could explain this electron emission. But at least the measured energy gave an indication of where to look: “If these atomically thin layers lie on top of each other, a certain electron state can form in between,” says Wolfgang Werner. “You can imagine it as an electron that is continuously reflected back and forth between the two layers until at some point it penetrates the layer and escapes to the outside.”

The energy of these states actually fits well with the observed data – so people assumed that there is some connection, but that alone was no explanation. “The electrons in these states should not actually reach the detector,” says Dr. Alessandra Bellissimo, one of the authors of the current publication. “In the language of quantum physics one would say: The transition probability is just too low.”

Skipping cords and symmetry

To change this, the internal symmetry of the electron states must be broken. “You can imagine this like rope skipping,” says Wolfgang Werner. “Two children hold a long rope and move the end points. Actually, both create a wave that would normally propagate from one side of the rope to the other. But if the system is symmetrical and both children behave the same way, then the rope just moves up and down. The wave maximum always remains at the same place. We don’t see any wave movement to the left or right, this is called a standing wave”. But if the symmetry is broken because, for example, one of the children moves backwards, the situation is different – then the dynamics of the rope changes and the maximum position of the oscillation moves.

Such symmetry breaks can also occur in the material. Electrons leave their place and start moving, leaving a “hole” behind. Such electron-hole pairs disturb the symmetry of the material, and thus it can happen that the electrons suddenly have the properties of two different states simultaneously. In this way, two advantages can be combined: On the one hand, there is a large number of such electrons, and on the other hand, their probability of reaching the detector is sufficiently high. In a perfectly symmetrical system, only one or the other would be possible. According to quantum mechanics, they can do both at the same time, because the symmetry refraction causes the two states to “merge” (hybridize).

“In a sense, it is teamwork between the electrons reflected back and forth between two layers of the material and the symmetry-breaking electrons,” says Prof. Florian Libisch from the Institute of Theoretical Physics. “Only when you look at them together can you explain that the material emits electrons of exactly this energy of 3.7 electron volts.”

Carbon materials such as the type of graphite analyzed in this research work play a major role today – for example, the 2D material graphene, but also carbon nanotubes of tiny diameter, which also have remarkable properties. “The effect should occur in very different materials – wherever thin layers are held together by weak Van der Waals forces,” says Wolfgang Werner. “In all these materials, this very special type of electron emission, which we can now explain for the first time, should play an important role”.

References: W. Werner et al., Secondary Electron Emission by Plasmon-Induced Symmetry Breaking in Highly Oriented Pyrolytic Graphite, Phys. Rev. Lett. 125, 196603 (2020).

Provided by Vienna University of Technology