Why Is It So Hard To Withdraw From Some Antidepressants? (Psychiatry)

Researchers at the University of Illinois Chicago are a step closer to discovering why it is so difficult for people to withdraw from some antidepressant medications.  

The paper “Antidepressants produce persistent Gαs associated signaling changes in lipid rafts following drug withdrawal,” published in the journal Molecular Pharmacology, addresses the molecular and cellular mechanisms that cause antidepressant withdrawal syndrome. 

The study’s authors, Mark Rasenick, distinguished professor of physiology and biophysics and psychiatry at UIC and research career scientist at the Jesse Brown VA Medical Center, and Nicholas Senese, a postdoctoral fellow at UIC, explained that current antidepressants can take approximately two months to take effect in patients who then continue taking these drugs for years. Weaning patients from these drugs can result in unpleasant symptoms that can range from flu-like feelings and persistent pain or itch to Parkinson’s-like conditions that can last for weeks.

One in six Americans have, or will, suffer from depression; for veterans, the estimated rate is twice that. 

Previous research has demonstrated that antidepressant drugs collect gradually in cholesterol-rich membrane structures called lipid rafts. When a neurotransmitter (such as serotonin, which is involved with mood) binds to a receptor on the outside of a cell, a protein in the lipid raft –— called Gs alpha –— conveys the signal into the cell’s interior where it can elicit a variety of actions. One of those actions is the production of an intracellular signaling molecule called cyclic AMP. In the brains of people with depression, cyclic AMP is low; but with effective antidepressant treatment, cyclic AMP is returned to normal. 

For their new study, Rasenick and Senese looked at the activity of Gs alpha molecules by using fluorescent light to determine how they moved in and out of the lipid rafts. They found that while withdrawal of some antidepressant drugs balances Gs alpha action in and out of the lipid rafts, other drugs suppress the return of Gs alpha to rafts. This suppression, the researchers believe, is what causes persistent and undesired effects of some antidepressants.  

Lipid rafts appear to be relevant for both the delayed therapeutic effects of antidepressants as well as the difficulty in weaning off from these drugs. It takes a long time for these drugs to sort into rafts and a long time for the drugs to exit –— some more than others. Curiously, rapid-acting antidepressants like ketamine have similar effects on Gs alpha and lipid rafts, but without the delay, Rasenick said.  

“This validates the notion that intracellular molecules that result from an active Gs alpha protein are a very good biomarker for the functioning of antidepressants,” Rasenick said. “We think we have achieved some clarity on this issue and we’d like to move forward toward using technology to create a personalized treatment for depression.” 

Rasenick explained that by looking at how an individual patient’s cells metabolize Gs alpha proteins, they can better predict what antidepressant medication could work for them. This can be accomplished in days and not weeks and months of trial and error to find the right medication. A company using this UIC-developed technology, Pax Neuroscience, has been formed to develop the technology for the market.  

Additionally, the cellular fluorescent indicators allow testing at a cellular level to develop new antidepressant medications. 

This study was funded by the Veterans Administration (VA Merit BX001149) and the National Institutes of Health (T32 MH067631 and R01 AT009169).

Featured image: Mark Rasenick, distinguished professor of physiology and psychiatry at the University of Illinois Chicago. © UIC

Provided by UIC

How Metals Work Together To Weaken Hardy Nitrogen-nitrogen Bonds? (Chemistry)

Study yields clues into how nitrogenase, an enzyme critical for life, converts nitrogen into ammonia.

Nitrogen, an element that is essential for all living cells, makes up about 78 percent of Earth’s atmosphere. However, most organisms cannot make use of this nitrogen until it is converted into ammonia. Until humans invented industrial processes for ammonia synthesis, almost all ammonia on the planet was generated by microbes using nitrogenases, the only enzymes that can break the nitrogen-nitrogen bond found in gaseous dinitrogen, or N2.

These enzymes contain clusters of metal and sulfur atoms that help perform this critical reaction, but the mechanism of how they do so is not well-understood. For the first time, MIT chemists have now determined the structure of a complex that forms when N2 binds to these clusters, and they discovered that the clusters are able to weaken the nitrogen-nitrogen bond to a surprising extent.

“This study enables us to gain insights into the mechanism that allows you to activate this really inert molecule, which has a very strong bond that is difficult to break,” says Daniel Suess, the Class of ’48 Career Development Assistant Professor of Chemistry at MIT and the senior author of the study.

Alex McSkimming, a former MIT postdoc who is now an assistant professor at Tulane University, is the lead author of the paper, which appears today in Nature Chemistry.

Nitrogen fixation

Nitrogen is a critical component of proteins, DNA, and other biological molecules. To extract nitrogen from the atmosphere, early microbes evolved nitrogenases, which convert nitrogen gas to ammonia (NH3) through a process called nitrogen fixation. Cells can then use this ammonia to build more complex nitrogen-containing compounds.

“The ability to access fixed nitrogen on large scales has been instrumental in enabling the proliferation of life,” Suess says. “Dinitrogen has a really strong bond and is really unreactive, so chemists basically consider it an inert molecule. It’s a puzzle that life had to figure out: how to convert this inert molecule into useful chemical species.”

All nitrogenases contain a cluster of iron and sulfur atoms, and some of them also include molybdenum. Dinitrogen is believed to bind to these clusters to initiate the conversion to ammonia. However, the nature of this interaction is unclear, and until now, scientists had not been able to characterize N2 binding to an iron-sulfur cluster.

To shed light on how nitrogenases bind N2, chemists have designed simpler versions of iron-sulfur clusters that they can use to model the naturally occurring clusters. The most active nitrogenase uses an iron-sulfur cluster with seven iron atoms, nine sulfur atoms, a molybdenum atom, and a carbon atom. For this study, the MIT team created one that has three iron atoms, four sulfur atoms, a molybdenum atom, and no carbon.

One challenge in trying to mimic the natural binding of dinitrogen to the iron-sulfur cluster is that when the clusters are in a solution, they can react with themselves instead of binding substrates such as dinitrogen. To overcome that, Suess and his students created a protective environment around the cluster by attaching chemical groups called ligands.

The researchers attached one ligand to each of the metal atoms except for one iron atom, which is where N2 binds to the cluster. These ligands prevent unwanted reactions and allow dinitrogen to enter the cluster and bind to one of the iron atoms. Once this binding occurred, the researchers were able to determine the structure of the complex using X-ray crystallography and other techniques.

They also found that the triple bond between the two nitrogen atoms of Nis weakened to a surprising extent. This weakening occurs when the iron atoms transfer much of their electron density to the nitrogen-nitrogen bond, which makes the bond much less stable.

Cluster cooperation

Another surprising finding was that all of the metal atoms in the cluster contribute to this electron transfer, not only the iron atom to which the dinitrogen is bound.

“That suggests that these clusters can electronically cooperate to activate this inert bond,” Suess says. “The nitrogen-nitrogen bond can be weakened by iron atoms that wouldn’t otherwise weaken it. Because they’re in a cluster, they can do it cooperatively.”

The findings represent “a significant milestone in iron-sulfur cluster chemistry,” says Theodore Betley, chair of the Department of Chemistry and Chemical Biology at Harvard University, who was not involved in the study.

“Although the nitrogenase enzymes known to fix atmospheric nitrogen are composed of fused iron-sulfur clusters, synthetic chemists have never, until now, been able to demonstrate dinitrogen uptake using synthetic analogues,” Betley says. “This work is a major advance for the iron-sulfur cluster community and bioinorganic chemists at large. More than anything, this advance has shown that iron-sulfur clusters have a rich reaction chemistry yet to be discovered.”

The researchers’ findings also confirmed that simpler versions of the iron-sulfur cluster, such as those they created for this study, can effectively weaken the nitrogen-nitrogen bond. The earliest microbes to develop the ability to fix nitrogen may have evolved similar types of simple clusters, Suess says.

Suess and his students are now working on ways to study how the more complex, naturally occurring versions of iron-sulfur clusters interact with dinitrogen.

The research was funded by the MIT Research Support Committee Fund.

Featured image: MIT chemists have determined the structure of the complex that forms when gaseous dinitrogen, or N2, binds to an iron-sulfur cluster, offering clues as to how microbes (in yellow) use nitrogenases to break the nitrogen-nitrogen bond (in pink and green). © Jose-Luis Olivares, MIT

Reference: McSkimming, A., Suess, D.L.M. Dinitrogen binding and activation at a molybdenum–iron–sulfur cluster. Nat. Chem. (2021). https://doi.org/10.1038/s41557-021-00701-6

Provided by MIT

‘Rescue Mutations’ that Suppress Harmful DNA Changes Could Shed Light On Origins of Genetic Disorders (Biology)

The biological phenomenon may play an important role in genetic diseases such as cancer or rare developmental disorders, and explain why certain patients suffer from more severe disease than others

New insights into the ability of DNA to overcome harmful genetic changes have been discovered by scientists at the Wellcome Sanger Institute, the University of Lausanne and their collaborators. The team found that 26 per cent of harmful mutations were suppressed by naturally occurring variants in at least one wild yeast strain. In each instance examined in detail, a single ‘rescue mutation’ was responsible for cancelling out another mutation that would have threatened the organism’s survival.

The study, published today (27 May 2021) in Molecular Systems Biology, provides important information about how DNA variants can suppress undesirable genetic changes. If confirmed in humans, this biological phenomenon could have an important role in genetic diseases such as cancer or rare developmental disorders, and explain why certain patients suffer from more severe disease than others.

Mutations are changes to the letters of DNA that form the genetic code of multi-cellular organisms. They can be a result of errors when DNA replicates during cell division, or the influence of environmental exposures such as ultraviolet light. While most mutations will have no significant effect on how the cell functions, some can be harmful and lead to genetic diseases such as cancer. Other mutations can be beneficial and contribute to genetic diversity in a species through the natural process of evolution1.

With six billion letters of DNA in the human genome, the implications of natural genetic variation are vast. As a result, the precise effect of mutations on the function of genes and cells is not fully understood. Mutations that are harmful in one individual may have no negative effect on another. In some cases, this is because the healthy or resilient individuals carry additional mutations, called suppressors, which counteract harmful DNA changes.

In this study, researchers at the University of Toronto screened 1,106 temperature-sensitive alleles2 from 580 essential genes3 in 10 wild yeast strains to see if natural genetic variation would allow the yeast to grow when exposed to an unfavourably high temperature.

They found that 26 per cent of the 580 essential genes could be circumvented by natural variants in at least one wild yeast strain. Yeast colonies that continued to grow were then sequenced at the Wellcome Sanger Institute, in order to search for specific mutations that could be suppressing the temperature-sensitive allele.

“The proportion of harmful mutations in essential genes that could be supressed was unexpected, and because we only sampled a small fraction of wild yeast strains the percentage of mutations that can be suppressed by natural variants is likely to be much higher. The frequency of suppression suggests it could make an important contribution in other contexts as well – including, potentially, for human disease.”

Professor Jolanda van Leeuwen,a senior author of the paper from the University of Lausanne

Researchers at the University of Lausanne examined 10 instances of suppression in detail to better understand the suppression effect and how it protected cells. To their surprise, in each case a single mutation was responsible for suppressing the temperature-sensitive allele and enabling cells to live and reproduce.

“In biology, explanations tend to be complex, so it’s unusual to find a single ‘smoking gun’. We might have expected a number of genes to combine to overcome a serious genetic defect like the temperature-sensitive allele, so for this to be the result of a single mutation is very surprising.”

Dr Leopold Parts,a senior author of the paper from the Wellcome Sanger Institute

Work is already underway at the Sanger Institute to conduct a similar study in human cells to see how relevant these findings are to the human genome, using commercially available human cell lines from healthy donors. If the same biological phenomenon is at play, it could provide valuable information about how genetic diseases arise and whether ‘rescue mutations’ might one day help clinicians to treat these diseases.

More information

1 For an overview of genetic mutations, see yourgenome.org

2 An allele is a variant form of the same gene. The combination of alleles influences an individual’s physical traits, such as eye colour. For more information, see yourgenome.org

3 Essential genes are those that are absolutely required for the cell to live and reproduce.


Leopold Parts, Amandine Batté and Maykel Lopes et al. (2021). Natural variants suppress mutations in hundreds of essential genes. Molecular Systems Biology. DOI: https://doi.org/10.15252/msb.202010138


This work was supported by Wellcome, the Swiss National Science Foundation and the Foundation for Medical Research.

Featured image credit: Jolanda van Leeuwen

Provided by Wellcome Sanger Institute

Study Finds Infected Ants Live Much Longer (Biology)

Life expectancy of tapeworm-infected worker ants is significantly higher than that of their uninfected nest-mates and resembles that of ant queens

Ant workers that are infected with a tapeworm live much longer than their uninfected nest-mates. Parasitic infections are usually harmful to their hosts, but there are some exceptions. According to the results of a multi-year scientific study, ants of the species Temnothorax nylanderi show exceptionally high survival rates when infected with a tapeworm. “The lifespan of the infected ants is significantly prolonged. According to our observations, such workers have a survival rate similar to that of queens,” said Professor Susanne Foitzik of Johannes Gutenberg University Mainz (JGU), leader of the study. Queens of this species can live for up to 20 years, while female workers rarely reach the age of two. Among possible explanations for this extended lifespan are the change in the physiology of infected ants caused by the parasites and the fact that infected workers are better supplied with food.

Social care in the nest linked to longer life

In the case of ants, there is a stark divergence in lifespan between female castes. Many ant queens can survive for several decades. They spend almost all their lives safely in the nest where they are cared for by the workers, their daughters. In contrast, ant workers live for only a few weeks or months or, in rare cases, a few years. The infertile workers carry out all tasks in the nest, starting in brood care and progressing to riskier activities outside the colony as they grow older, such as foraging for food. The high life expectancy of queens is due to their low mortality rate, which is attributable to the high levels of social care they receive, their safe environment, and the activation of physiological repair mechanisms.

These factors may also contribute to the extremely high survival rates of Temnothorax-nylanderi workers infected with a tapeworm. This species of ant is common in Central Europe and forms small colonies on the forest floor, inside acorns or wooden branches. The insects are relatively small, with a body length of just two to three millimeters. They serve as an intermediate host for the tapeworm Anomotaenia brevis, whereby a single ant can be infected by up to 70 parasitic larvae. The parasites survive in the hemolymph, the body fluid of insects. Their complex life cycle is completed once they have been ingested by a woodpecker that feeds on the ants.

The research team led by Professor Susanne Foitzik looked at the long-term consequences of the parasitic infection by collecting ant colonies from forests around Mainz and observing them in the laboratory. “We tracked the survival rate of the workers and queens in both infected and uninfected ant colonies over three years, until more than 95 percent of the uninfected workers had died,” explained Foitzik. At that point, over half of the infected workers were still alive – exhibiting a survival rate practically identical to that of the long-lived queens. “It is quite extraordinary that a parasite can trigger such a positive change in its host. This lifespan extension is very unusual,” emphasized the JGU-based evolutionary biologist.

Infected workers differ in appearance, behavior, and physiology

The infected ants are easily distinguished from their brown nest-mates due to their lighter, yellow color, an effect that results from their cuticle being less pigmented. They are also less active and receive enhanced care from other workers in the nest. “The infected insects get more attention and are fed, cleaned, and looked after better. They even benefit from slightly more care than the nest’s queen,” explained Professor Susanne Foitzik. The tests also revealed that infected ants have metabolic rates and lipid levels similar to those of younger ants. It would seem that these ants remain in a permanent juvenile stage as a result of the infection. This is likely down to both the tapeworm larvae altering the expression of ant genes that affect aging and to the parasites’ release of proteins containing antioxidants into the ants’ hemolymph.

Even though the mystery of their long life has not yet been fully resolved, the behavior of the infected ants themselves does not seem to be the decisive factor. The research team, which included scientists from the Max Planck Institute for Biology of Ageing and Tel Aviv University, found no evidence that the insects actively beg for better care. However, chemical signals on the cuticle of infected ants were found to elicit more attention of their nest-mates. “The infected insects live a life of luxury, but the fact that they receive more social care cannot alone account for their prolonged lifespan,” concluded Foitzik. The scientists will undertake further research in order to identify the factors, particularly on the molecular and epigenetic level, behind the infected workers death-defying attributes.

Featured image: Two ants of the species Temnothorax nylanderi: The lighter colored ant is infected with larvae of the tapeworm Anomotaenia brevis (bottom right) and thus has a different cuticle color as well as, more importantly, a considerably longer lifespan. © photo: Susanne Foitzik

S. Beros et al., Extreme lifespan extension in tapeworm-infected ant workers, Royal Society Open Science, 19 May 2021,
DOI: 10.1098/rsos.202118

Provided by JGU

When Cancer Cells “Put All Their Eggs in One Basket” (Biology)

The Takeaway

Normal cells usually have multiple solutions for fixing problems that may arise. But cancer cells may “put all their eggs in one basket,” getting rid of all backup plans and depending on just one solution. CSHL Professor Christopher Vakoc’s lab discovered that a particular type of blood cancer, acute myeloid leukemia, came to depend on a single DNA repair method, whereas normal cells use at least two pathways for repair. They developed a drug that shut down the remaining pathway in lab-grown cells, killing the cancer cells and leaving normal cells unharmed.

Normal cells usually have multiple solutions for fixing problems. For example, when DNA becomes damaged, healthy white blood cells can use several different strategies to make repairs. But cancer cells may “put all their eggs in one basket,” getting rid of all backup plans and depending on just one pathway to mend their DNA. Cold Spring Harbor Laboratory (CSHL) Professor Christopher Vakoc focuses on probing cancers to figure out if they have any unique dependencies. His lab was surprised to discover that a single DNA repair method remained in acute myeloid leukemia (AML), an aggressive cancer that originates in bone marrow. They discovered that if they shut down that pathway in cells grown in the laboratory, they could kill the cancer cells while leaving normal cells unharmed.

Cancer cells may unintentionally remove multiple methods for fixing problems as they change their DNA to grow and spread quickly. But developing a dependency on just one repair pathway means that they have no backup plans if it fails. Vakoc explains:

“Sometimes cancer cells, to become “super cells,” they had to get rid of stuff that they thought they didn’t need. You get rid of what you don’t need, you kind of spring clean maybe a little too much, then you realize: ‘Shoot!’ You threw away something you actually do need.”

In normal cells, a particular type of DNA damage can be solved with two different methods: the ALDH2 gene and the Fanconi anemia (FA) pathway. AML cells have inactivated ALDH2 and are dependent on the FA proteins to perform this DNA repair. The researchers showed that if they shut down the FA pathway, it resulted in cancer cell death.

The team hopes their findings will lead to clinical treatments that eliminate cancer cells without harming other cells in the body. Vakoc says:

“The reality is, there aren’t that many differences between cancer cells and normal cells with regard to dependencies. So this is one of the most striking things we’ve found, which is the kind of win-win for us, to discover a dependency that can be modified with a drug is, we think, the way to make new cancer medicines that are safer and more effective.”


National Cancer Institute, Pershing Square Sohn Cancer Research Alliance, National Institutes of Health, Leukemia & Lymphoma Society


Yang, Z., et al., “Transcriptional silencing of ALDH2 confers a dependency on Fanconi anemia proteins in acute myeloid leukemia”, Cancer Discovery, April 23, 2021. DOI: 10.1158/2159-8290.CD-20-1542

Featured image: Normal cells try to minimize risk, relying on multiple solutions for fixing potentially fatal problems. However, cancer cells may “put all their eggs in one basket,” getting rid of backup plans and depending on just one solution. This leaves them vulnerable; if the cell’s remaining pathway fails, it will die. Image: © uckyo

Provided by Cold Spring Harbor Laboratory

U of G Discovery May Point to Parkinson’s Disease Therapies (Neuroscience)

A new discovery by University of Guelph researchers may ultimately help in devising new therapies and improving quality of life for people with Parkinson’s disease.

By showing how entangled proteins in brain cells enable the neurodegenerative disease to spread, the researchers hope their findings will lead to drugs that halt its progression, said PhD candidate Morgan Stykel, first author of a paper published this month in Cell Reports.

Parkinson’s disease is the world’s fastest-growing neurodegenerative disease and Canada has some of the world’s highest rates, according to Parkinson Canada. Its exact cause is unknown.

Current therapies only treat symptoms rather than halting the disease, said Dr. Scott Ryan, a professor in the Department of Molecular and Cellular Biology who led the study.

Parkinson’s disease can be triggered by the misfolding of a protein called alpha-synuclein that accumulates in a part of the brain called the substantia nigra. The disease causes loss of nerve cells in the brain that produce dopamine, a chemical messenger that helps control motor function.

Dr. Scott Ryan © University of Guelph

Misfolded alpha-synuclein aggregates and eventually spreads to other parts of the brain, impairing areas responsible for other functions such as mood and cognition.

The U of G team used stem cells to model neurons with and without Parkinson’s disease and look at the effects of synuclein mutations.

They discovered that in Parkinson’s neurons, misfolded synuclein binds to another protein called LC3B. Normally, LC3B targets misfolded proteins to be degraded. In Parkinson’s disease, the study showed, LC3B gets trapped in the protein aggregates and is inactivated.

Without degradation, the cells eject the aggregates, which then spread to nearby neurons, propagating the disease throughout the brain.

“Normally misfolded proteins are degraded. We found a pathway by which synuclein is being secreted and released from neurons instead of being degraded,” said Ryan. “We hope to turn the degradation pathway back on and stop the spread of disease.”

The team showed that activating LC3B restores degradation, enabling cells to clear the misfolded proteins and prevent disease spread.

portrait of woman in lab smiling at camera
Dr. Morgan Stykel © University of Guelph

“Regular protein turnover is part of a healthy cell,” said Stykel. “With Parkinson’s disease, that system is not working properly.”

Ryan said their finding could help in devising therapies.

“We may not be able to do anything about brain regions that are already diseased, but maybe we can stop it from progressing. We might be able to turn the degradation pathway back on and stop the spread of the disease.”

He cautioned that other biochemical pathways are also likely involved in the spread of the disease through the brain. Still, the finding provides a target for potential drug development.

“Most current therapies centre around increasing the release of dopamine, but that works for a brief period and has a lot of side effects,” said Ryan.

This research may help improve quality of life for Parkinson’s patients. Many patients are diagnosed in their 40s or 50s, meaning that they live with the progressive disease for decades.

“Reduced quality of life can be a huge burden on patients, their families and the health-care system,” he said.

Featured image credit: Sabinevanerp/ Pixabay

Reference: Morgan G. Stykel, Kayla M. Humphries et al., “α-Synuclein mutation impairs processing of endomembrane compartments and promotes exocytosis and seeding of α-synuclein pathology”, Cell Reports, 35(6), 2021. DOI: https://doi.org/10.1016/j.celrep.2021.109099

Provided by University of Guelph

It Takes Some Heat To Form Ice! (Chemistry)

Researchers from TU Graz in Austria and the Universities of Cambridge and Surrey succeeded to track down the first step in ice formation at a surface, revealing that additional energy is needed for water before ice can start to form.

Water freezes and turns to ice when brought in contact with a cold surface – a well-known fact. However, the exact process and its microscopic details remained elusive up to know. Anton Tamtögl from the Institute of Experimental Physics at TU Graz explains: “The first step in ice formation is called ‘nucleation’ and happens in an incredibly short length of time, a fraction of a billionth of a second, when highly mobile individual water molecules ‘find each other’ and coalesce.” Conventional microscopes are far too slow to follow the motion of water molecules and so it is impossible to use them to ‘watch’ how molecules combine on top of solid surfaces.

Findings turn previous understanding of ice formation upside down

With the help of a new experimental technique and computational simulations, Tamtögl and a group of researchers from the Universities of Cambridge and Surrey were able to track down the first step in ice formation on a graphene surface. In a paper published in Nature Communications, they made the remarkable observation that the water molecules repel each other and need to gain sufficient energy to overcome that repulsion before ice can start to form: It has to become hot, so to speak, before ice forms.Talking in the general sense, the lead author Anton Tamtögl says “repulsion between water molecules has simply not been considered during ice nucleation – this work will change all that”.

Following the ‘dance’ of water molecules

The effect was discovered with a method called Helium Spin-Echo (HeSE) – a technique developed at the Cavendish Laboratory in Cambridge and specially designed to follow the motion of atoms and molecules. The machine scatters helium from moving molecules on a surface, similar to the way radio waves scatter from vehicles in a radar speed-trap. By registering the number of scattered helium and their energy / velocity after scattering, it allows to follow the movement of atoms and molecules.

The HeSE experiments show that water molecules on a graphene surface, i.e. a single atomic layer of carbon, repel each other. The repulsion arises due to the same alignment of the molecules, perpendicular to the surface. The scenario is analogous to bringing two magnets with like-poles together: They will push themselves apart. In order for the nucleation of ice to begin, one of the two molecules must reorient itself, only then can they approach each other. Such a reorientation requires additional energy and thus represents a barrier that must be overcome for the growth of ice crystals.

Computational simulations in which the precise energy of water molecules in different configurations was mapped and the interactions between molecules near to each other were calculated, confirm the experimental findings. Moreover, simulations allow to ‘switch’ the repulsion on and off, providing thus further proof of the effect. The combination of experimental and theoretical methods allowed the international scientific team to unravel the behaviour of the water molecules. It captures for the first time, exactly how the first step of ice formation at a surface evolves and allowed them to propose a previously unknown physical mechanism.

Relevance for other fields and applications

The group further suggests the newly observed effect may occur more widely, on other surfaces. “Our findings pave the way for new strategies to control ice formation or prevent icing,” says Tamtögl, thinking, for example, of surface treatments specifically for wind power, aviation or telecommunications.

Understanding the microscopic processes at work during ice formation, is also essential to predicting the formation and melting of ice, from individual crystals to glaciers and ice sheets. The latter is crucial to our ability to quantify environmental transformation in connection with climate change and global warming.

This research area is anchored in the Field of Expertise ‘Advanced Materials Science’, one of five research foci of TU Graz.

Featured image: The study results of Anton Tamtögl et al lead to a completely new understanding of ice formation: Water molecules require additional energy before they freeze into ice. © Lunghammer – TU Graz


Details of the original publication
“Motion of water monomers reveals a kinetic barrier to ice nucleation on graphene”. Anton Tamtögl, Emanuel Bahn, Marco Sacchi, Jianding Zhu, David J. Ward, Andrew P. Jardine, Stephen J. Jenkins, Peter Fouquet, John Ellis & William Allison. Nature Communications, May 2021. DOI: 10.1038/s41467-021-23226-5.

Provided by TuGraz

New Research May Explain Why Some People Derive More Benefits From Exercise than Others (Physiology)

Although everyone can benefit from exercise, the mechanistic links between physical fitness and overall health are not fully understood, nor are the reasons why the same exercise can have different effects in different people. Now a study published in Nature Metabolism led by investigators at Beth Israel Deaconess Medical Center (BIDMC) provides insights related to these unanswered questions. The results could be helpful for determining the specific types of exercise most likely to benefit a particular individual and for identifying new therapeutic targets for diseases related to metabolism.

“While groups as a whole benefit from exercise, the variability in responses between any two individuals undergoing the very same exercise regimen is actually quite striking. For example, some may experience improved endurance while others will see improved blood sugar levels,” said senior corresponding author Robert E. Gerszten, MD, Chief of the Division of Cardiovascular Medicine at BIDMC. “To date, no aspects of an individual’s baseline clinical profile allow us to predict beforehand who is most likely to derive a significant cardiorespiratory fitness benefit from exercise training.”

To uncover the details behind exercise’s effects on the body and how these might differ from one person to the next, the team, including first author Jeremy Robbins, MD, of the Division of Cardiovascular Medicine at BIDMC, measured the blood levels of approximately 5,000 proteins in 650 sedentary adults before and after a 20-week endurance exercise program.

“We were particularly interested at looking at proteins in the blood to study the effects of exercise because there is a growing body of evidence showing that exercise stimulates the secretion of chemicals into circulation that can impart their effects on distant organs,” Robbins said.

A set of 147 proteins in the blood indicated an individual’s cardiorespiratory fitness, or VO2max, at the start of the study. Another set of 102 proteins indicated an individual’s change in VO2max following the completion of the exercise program.

“We identified proteins that emanate from bone, muscle, and blood vessels that are strongly related to cardiorespiratory fitness and had never been previously associated with exercise training responses,” said Gerszten, who is also the Herman Dana Professor of Medicine at Harvard Medical School and a Senior Associate Member of the Broad Institute of MIT and Harvard.

Robbins added, “Even though prior studies have shown that an individual’s baseline fitness level is unrelated to their response to exercise training, it was fascinating to see that there was minimal overlap between the protein profiles of baseline VO2max and its response to the exercise training intervention.”

With this information, the research team developed a protein score that improved their ability to predict an individual’s trainability, or change in VO2max. For example, the score identified individuals who were unable to significantly improve their cardiorespiratory fitness despite participating in the standardized exercise program. “Baseline levels of several proteins predicted who would respond to the exercise training protocol far better than any of our established patient factors,” Gerszten said.

In a separate community-based study, though part of the same paper, the scientists found that some of these proteins were linked to an elevated risk of early death, highlighting the link between cardiorespiratory fitness and long-term health outcomes.

“We now have a detailed list of new blood compounds that further inform our understanding of the biology of fitness and exercise adaptation, and predict individual responses to a given exercise regimen,” said Gerszten, who is also the Director of the Program in Personal Genomics and Cardiometabolic Disease at BIDMC. “While no pill is ever likely to recapitulate the diversity of benefits from exercise, our study has helped create a roadmap to further explore potential interventions and provides an important step in individualizing exercise as a therapy.” He noted that additional research is needed to expand the study’s findings to larger populations and to further refine the precise effects of the different proteins before and after exercise.

Co-authors include Bennet Peterson, Daniela Schranner, Usman A. Tahir, Shuliang Deng, Michelle J. Keyes, Daniel H. Katz, Changyu Shen of BIDMC; Theresa Rienmuller and Christian Baumgartner of Graz University of Technology; Pierre M. Jean Beltran and Steven A. Carr of the Broad Institute of MIT and Harvard; Jacob L. Barber and Mark A. Sarzynski of Arnold School of Public Health, University of South Carolina; Sujoy Ghosh of Duke-NUS Graduate Medical School; Lori L. Jennings of Novartis Institutes for Biomedical Research; Robert Ross of Queen’s University; and Claude Bouchard of Pennington Biomedical Research Center.

This work was funded in part by grants from the National Institute of Health (K23 HL150327-01A1, R01 HL132320; HL133870, U24 DK112340, R01 HL45670, HL47317, HL47321, HL47323, HL47327, NR019628 and HL146462); the NIH-funded COBRE Grant (NIH 8 P30GM118430-01); and the National Institute of General Medical Sciences (NIGMS) of the NIH ( grant U54 GM104940). For a complete list of funders, please refer to the study.

Provided by Beth Israel Deaconess Medical Center

Escape from Oblivion: How the Brain Reboots after Deep Anesthesia (Neuroscience)

Innovative experiment demonstrates the resilience of the healthy human brain despite deep general anesthesia.

Millions of surgical procedures performed each year would not be possible without the aid of general anesthesia, the miraculous medical ability to turn off consciousness in a reversible and controllable way.

Researchers are using this powerful tool to better understand how the brain reconstitutes consciousness and cognition after disruptions caused by sleep, medical procedures requiring anesthesia, and neurological dysfunctions such as coma.

In a new study published in the journal eLife, a team led by anesthesiologists George Mashour, M.D., Ph.D. of University of Michigan Medical School, Michigan Medicine, Max Kelz, M.D., Ph.D. of the University of Pennsylvania Medical School, and Michael Avidan, MBBCh of the Washington University School of Medicine used the anesthetics propofol and isoflurane in humans to study the patterns of reemerging consciousness and cognitive function after anesthesia.

In the study, 30 healthy adults were anesthetized for three hours. Their brain activity was measured with EEG and their sleep-wake activity was measured before and after the experiment. Each participant was given cognitive tests—designed to measure reaction speed, memory, and other functions—before receiving anesthesia, right after the return of consciousness, and then every 30 minutes thereafter.

The study team sought to answer several fundamental questions: Just how does the brain wake up after profound unconsciousness—all at once or do some areas and functions come back online first? If so, which?

“How the brain recovers from states of unconsciousness is important clinically but also gives us insight into the neural basis of consciousness itself,” says Mashour.

After the anesthetic was discontinued and participants regained consciousness, cognitive testing began. A second control group of study participants, who did not receive general anesthesia and stayed awake, also completed tests over the same time period.

Analyzing EEG and test performance, the researchers found that recovery of consciousness and cognition is a process that unfolds over time, not all at once. To the investigators’ surprise, one of the brain functions that came online first was abstract problem solving, controlled by the prefrontal cortex, whereas other functions such as reaction time and attention took longer to recover.

“Although initially surprising, it makes sense in evolutionary terms that higher cognition needs to recover early. If, for example, someone was waking up to a threat, structures like the prefrontal cortex would be important for categorizing the situation and generating an action plan,” says Kelz.

The EEG readings revealed that the frontal regions of the brain were especially active around the time of recovery. Importantly, within three hours of being deeply anesthetized for a prolonged period of time, participants were able to recover cognitive function to approximately the same level as the group that stayed awake during that time. Furthermore, their sleep schedule in the days after the experiment did not appear to be affected.

“This suggests that the healthy human brain is resilient, even with a prolonged exposure to deep anesthesia. Clinically, this implies that some of the disorders of cognition that we often see for days or even weeks during recovery from anesthesia and surgery—such as delirium—might be attributable to factors other than lingering effects of anesthetic drugs on the brain,” says Avidan.

This study was funded by a collaborative grant from the James S. McDonnell Foundation, St. Louis, MO; National Institutes of Health (Bethesda, MD, USA) grant T32GM112596; and the anesthesiology departments of the University of Michigan, University of Pennsylvania and Washington University.

Featured image credit: Jacob Dwyer, Michigan Medicine

Paper Cited: “Recovery of consciousness and cognition after general anesthesia in humans,” eLifeDOI: 10.7554/eLife.59525

Provided by University of Michigan