Tag Archives: #stress

Novel Research Identifies Gene Targets of Stress Hormones in the Brain (Neuroscience)

Chronic stress is a well-known cause for mental health disorders. New research has moved a step forward in understanding how glucocorticoid hormones (‘stress hormones’) act upon the brain and what their function is. The findings could lead to more effective strategies in the prevention and treatment of mental health disorders.

The study, led by academics at the University of Bristol and published today [6 August] in Nature Communicationshas discovered a link between corticosteroid receptors – the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) – and ciliary and neuroplasticity genes in the hippocampus, a region of the brain involved in stress coping and learning and memory.

The aim of the research was to find out what genes MR and GR interact with across the entire hippocampus genome during normal circadian variation and after exposure to acute stress. The research team also wanted to discover whether any interaction would result in changes in the expression and functional properties of these genes.

The study combined advanced next-generation sequencing, bioinformatics and pathway analysis technologies to enable a greater understanding into glucocorticoid hormone action, via MRs and GRs, on gene activity in the hippocampus.

The researchers found a previously unknown link between the MR and cilia function. Cilia are small hair-like structures that protrude from cell bodies. Effective cilia function is vitally important for brain development and ongoing brain plasticity, but how their structure and function is regulated in neurons is largely unknown.

The discovery of the novel role of MR in cilia structure and function in relation to neuronal development has increased knowledge of the role of these cell structures in the brain and could help resolve cilia-related (developmental) disorders in the future.

The team also found that MR and GR interact with many genes which are involved in neuroplasticity processes, such as neuron-to-neuron communication and learning and memory processes.  Some of these genes, however, have been linked to the development of mental health disorders like major depression, anxiety, PTSD as well as schizophrenia spectrum disorders. Consequently, glucocorticoid hormone dysfunction, as observed in chronic stress, could have a harmful effect on mental health through their action on these vulnerability genes, providing a potential new mechanism to explain the long-known involvement of glucocorticoids in the aetiology of mental health disorders.

Although further research on the role glucocorticoid hormones play in the regulation of these genes is needed, the findings fill the gap between the long-known involvement of glucocorticoids in mental health disorders and the existence of vulnerability genes.  

Hans Reul, Professor of Neuroscience in Bristol Medical School: Translational Health Sciences (THS), said: “This research is a substantial step forward in our efforts to understand how these powerful glucocorticoid hormones act upon the brain and what their function is.

“We hope that our findings will trigger new targeted research into the role these hormones play in the aetiology of severe mental disorders like depression, anxiety and PTSD.”

Next steps for the research include studying how glucocorticoid hormone action via MR and GR on the hippocampus genome changes under chronic stress conditions and, thanks to a new BBSRC grant, glucocorticoid action via MR and GR upon the female brain genome.  Very little is known about this research area in females as most studies on stress and glucocorticoid hormones have been conducted in males.

The study, supported by the BBSRC and a Wellcome Trust Neural Dynamics PhD studentship, was carried out by the Neuro-Epigenetics Research Group led by Professor Hans Reul and Dr Karen Mifsud, in collaboration with Bristol’s Stem Cell Biology Group – Dr Oscar Cordero Llana and Ms Andriana Gialeli – and sequencing specialists and bioinformaticians at the University of Oxford. 

Featured image: A magnified image of developing young human neurons. The mineralocorticoid receptor, coloured red, was found in the cell nucleus of these neurons. Credit: University of Bristol


Paper

Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors‘ by Karen R. Mifsud, Johannes M. H. M et al. in Nature Communications [open access]


Provided by University of Bristol

New Microchip Sensor Measures Stress Hormones from Drop of Blood (Medicine)

A Rutgers-led team of researchers has developed a microchip that can measure stress hormones in real time from a drop of blood.

The study appears in the journal Science Advances.

Cortisol and other stress hormones regulate many aspects of our physical and mental health, including sleep quality. High levels of cortisol can result in poor sleep, which increases stress that can contribute to panic attacks, heart attacks and other ailments.

Currently, measuring cortisol takes costly and cumbersome laboratory setups, so the Rutgers-led team looked for a way to monitor its natural fluctuations in daily life and provide patients with feedback that allows them to receive the right treatment at the right time.

The researchers used the same technologies used to fabricate computer chips to build sensors thinner than a human hair that can detect biomolecules at low levels. They validated the miniaturized device’s performance on 65 blood samples from patients with rheumatoid arthritis.

“The use of nanosensors allowed us to detect cortisol molecules directly without the need for any other molecules or particles to act as labels,” said lead author Reza Mahmoodi, a postdoctoral scholar in the Department of Electrical and Computer Engineering at Rutgers University-New Brunswick.

With technologies like the team’s new microchip, patients can monitor their hormone levels and better manage chronic inflammation, stress and other conditions at a lower cost, said senior author Mehdi Javanmard, an associate professor in Rutgers’ Department of Electrical and Computer Engineering.

“Our new sensor produces an accurate and reliable response that allows a continuous readout of cortisol levels for real-time analysis,” he added. “It has great potential to be adapted to non-invasive cortisol measurement in other fluids such as saliva and urine. The fact that molecular labels are not required eliminates the need for large bulky instruments like optical microscopes and plate readers, making the readout instrumentation something you can measure ultimately in a small pocket-sized box or even fit onto a wristband one day.”

The study included Rutgers co-author Pengfei Xie, a Ph.D. student, and researchers from the University of Minnesota and University of Pennsylvania. The research was funded by the DARPA ElectRX program.


Reference: S. Reza Mahmoodi, Pengfei Xie, Daniel P. Zachs, Erik J. Peterson, Rachel S. Graham, Claire R. W. Kaiser, Hubert H. Lim, Mark G. Allen, Mehdi Javanmard, “Single-step label-free nanowell immunoassay accurately quantifies serum stress hormones within minutes”, Science Advances  30 Jun 2021: Vol. 7, no. 27, eabf4401 DOI: https://doi.org/10.1126/sciadv.abf4401


Provided by Rutgers University

New Study Uncovers Details Behind the Body’s Response to Stress (Medicine)

Findings could lead to new treatments for post-traumatic stress disorder and other conditions

The biological mechanisms behind stress-related psychiatric conditions, including major depressive disorder and post-traumatic stress disorder (PTSD), are poorly understood.

New research now details the interplay between proteins involved in controlling the body’s stress response and points to potential therapeutic targets when this response goes awry. The study, which was conducted by an international team led by investigators at McLean Hospital, appears in the journal Cell Reports.

Study Highlights

  • New research reveals how key proteins interact to regulate the body’s response to stress
  • Targeting these proteins may help treat or prevent stress-related psychiatric disorders

“A dysregulated stress response of the body can be damaging for the brain and promote susceptibility to mood and anxiety disorders,” said lead author Jakob Hartmann, PhD. Hartmann is an assistant neuroscientist in the Neurobiology of Fear Laboratory at McLean and an instructor in psychiatry at Harvard Medical School.

“A key brain region involved in the regulation of the stress response is the hippocampus,” said Hartmann. “The idea for this study occurred to us when we noticed interesting distinctions in hippocampal localization of three important stress-regulating proteins.”

The researchers’ experiments in non-human tissue and postmortem brain tissue revealed how these proteins—the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the FK506-binding protein 51 (FKBP5)—interact with each other.

Specifically, MRs, rather than GRs, control the production of FKBP5 under normal conditions. FKBP5 decreases GRs’ sensitivity to binding stress hormones during stressful situations. FKBP5 appears to fine-tune the stress response by acting as a mediator of the MR:GR balance in the hippocampus.

“Our findings suggest that therapeutic targeting of GR, MR, and FKBP5 may be complementary in manipulating central and peripheral regulation of stress,” said senior author Kerry J. Ressler, MD, PhD. Ressler is the chief scientific officer at McLean Hospital, chief of McLean’s Division of Depression and Anxiety Disorders, and a professor in psychiatry at Harvard Medical School.

“Moreover, our data further underline the important but largely unappreciated role of MR signaling in stress-related psychiatric disorders,” added Ressler. “The findings of this study will open new directions for future research.”

This study was supported by:

  • NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (awarded to Hartmann, grant no. 24774)
  • National Institutes of Health (R01MH108665, P50MH115874)
  • Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01ES100221, awarded to Serena M. Dudek, PhD)
  • Research grants Q10 from NICHD (R21HD088931, R21HD097524), NIMH (R21MH117609), and ERA-Net Neuron (01EW2003), awarded to Torsten Klengel, MD, PhD

Provided by McLean Hospital

New AI Tool Calculates Materials’ Stress and Strain Based on Photos (Material Science)

The advance could accelerate engineers’ design process by eliminating the need to solve complex equations.

Isaac Newton may have met his match.

For centuries, engineers have relied on physical laws — developed by Newton and others — to understand the stresses and strains on the materials they work with. But solving those equations can be a computational slog, especially for complex materials.

MIT researchers have developed a technique to quickly determine certain properties of a material, like stress and strain, based on an image of the material showing its internal structure. The approach could one day eliminate the need for arduous physics-based calculations, instead relying on computer vision and machine learning to generate estimates in real time.

The researchers say the advance could enable faster design prototyping and material inspections. “It’s a brand new approach,” says Zhenze Yang, adding that the algorithm “completes the whole process without any domain knowledge of physics.”

The research appears today in the journal Science Advances. Yang is the paper’s lead author and a PhD student in the Department of Materials Science and Engineering. Co-authors include former MIT postdoc Chi-Hua Yu and Markus Buehler, the McAfee Professor of Engineering and the director of the Laboratory for Atomistic and Molecular Mechanics.

Engineers spend lots of time solving equations. They help reveal a material’s internal forces, like stress and strain, which can cause that material to deform or break. Such calculations might suggest how a proposed bridge would hold up amid heavy traffic loads or high winds. Unlike Sir Isaac, engineers today don’t need pen and paper for the task. “Many generations of mathematicians and engineers have written down these equations and then figured out how to solve them on computers,” says Buehler. “But it’s still a tough problem. It’s very expensive — it can take days, weeks, or even months to run some simulations. So, we thought: Let’s teach an AI to do this problem for you.”

The researchers turned to a machine learning technique called a Generative Adversarial Neural Network. They trained the network with thousands of paired images — one depicting a material’s internal microstructure subject to mechanical forces,  and the other depicting that same material’s color-coded stress and strain values. With these examples, the network uses principles of game theory to iteratively figure out the relationships between the geometry of a material and its resulting stresses.

“So, from a picture, the computer is able to predict all those forces: the deformations, the stresses, and so forth,” Buehler says. “That’s really the breakthrough — in the conventional way, you would need to code the equations and ask the computer to solve partial differential equations. We just go picture to picture.”

This visualization shows the deep-learning approach in predicting physical fields given different input geometries. The left figure shows a varying geometry of the composite in which the soft material is elongating, and the right figure shows the predicted mechanical field corresponding to the geometry in the left figure. © MIT

That image-based approach is especially advantageous for complex, composite materials. Forces on a material may operate differently at the atomic scale than at the macroscopic scale. “If you look at an airplane, you might have glue, a metal, and a polymer in between. So, you have all these different faces and different scales that determine the solution,” say Buehler. “If you go the hard way — the Newton way — you have to walk a huge detour to get to the answer.”

But the researcher’s network is adept at dealing with multiple scales. It processes information through a series of “convolutions,” which analyze the images at progressively larger scales. “That’s why these neural networks are a great fit for describing material properties,” says Buehler.

The fully trained network performed well in tests, successfully rendering stress and strain values given a series of close-up images of the microstructure of various soft composite materials. The network was even able to capture “singularities,” like cracks developing in a material. In these instances, forces and fields change rapidly across tiny distances. “As a material scientist, you would want to know if the model can recreate those singularities,” says Buehler. “And the answer is yes.”

This visualization shows the simulated failure in a complicated material by a machine-learning-based approach without solving governing equations of mechanics. The red represents a soft material, white represents a brittle material, and green represents a crack. © MIT

The advance could “significantly reduce the iterations needed to design products,” according to Suvranu De, a mechanical engineer at Rensselaer Polytechnic Institute who was not involved in the research. “The end-to-end approach proposed in this paper will have a significant impact on a variety of engineering applications — from composites used in the automotive and aircraft industries to natural and engineered biomaterials. It will also have significant applications in the realm of pure scientific inquiry, as force plays a critical role in a surprisingly wide range of applications from micro/nanoelectronics to the migration and differentiation of cells.”

In addition to saving engineers time and money, the new technique could give nonexperts access to state-of-the-art materials calculations. Architects or product designers, for example, could test the viability of their ideas before passing the project along to an engineering team. “They can just draw their proposal and find out,” says Buehler. “That’s a big deal.”

Once trained, the network runs almost instantaneously on consumer-grade computer processors. That could enable mechanics and inspectors to diagnose potential problems with machinery simply by taking a picture.

In the new paper, the researchers worked primarily with composite materials that included both soft and brittle components in a variety of random geometrical arrangements. In future work, the team plans to use a wider range of material types. “I really think this method is going to have a huge impact,” says Buehler. “Empowering engineers with AI is really what we’re trying to do here.”

Funding for this research was provided, in part, by the Army Research Office and the Office of Naval Research.

Featured image: MIT researchers have developed a machine-learning technique that uses an image of the material’s internal structure to estimate the stresses and strains acting on the material.


Paper: “Deep Learning Model to Predict Complex Stress and Strain Fields in Hierarchical Composites”


Provided by MIT

Can Drinking Cocoa Protect Your Heart When You’re Stressed? (Food)

Increased consumption of flavanols – a group of molecules occurring naturally in fruit and vegetables – could protect people from mental stress-induced cardiovascular events such as stroke, heart disease and thrombosis, according to new research.

Researchers have discovered that blood vessels were able to function better during mental stress when people were given a cocoa drink containing high levels of flavanols than when drinking a non-flavanol enriched drink.

A thin membrane of cells lining the heart and blood vessels, when functioning efficiently the endothelium helps to reduce the risk of peripheral vascular disease, stroke, heart disease, diabetes, kidney failure, tumour growth, thrombosis, and severe viral infectious diseases. We know that mental stress can have a negative effect on blood vessel function.

A UK research team from the University of Birmingham examined the effects of cocoa flavanols on stress-induced changes on vascular function – publishing their findings in Nutrients.

Lead author, Dr. Catarina Rendeiro, of the University of Birmingham’s School of Sport, Exercise and Rehabilitation Sciences, explains: “We found that drinking flavanol-rich cocoa can be an effective dietary strategy to reduce temporary impairments in endothelial function following mental stress and also improve blood flow during stressful episodes”.

“Flavanols are extremely common in a wide range of fruit and vegetables. By utilizing the known cardiovascular benefits of these compounds during periods of acute vascular vulnerability (such as stress) we can offer improved guidance to people about how to make the most of their dietary choices during stressful periods.”

In a randomized study, conducted by postgraduate student Rosalind Baynham, a group of healthy men drank a high-flavanol cocoa beverage 90 minutes before completing an eight-minute mental stress task.

The researchers measured forearm blood flow and cardiovascular activity at rest and during stress and assessed functioning of the blood vessels up to 90 min post stress – discovering that blood vessel function was less impaired when the participants drank high-flavanol cocoa. The researchers also discovered that flavanols improve blood flow during stress.

Stress is highly prevalent in today’s society and has been linked with both psychological and physical health. Mental stress induces immediate increases in heart rate and blood pressure (BP) in healthy adults and also results in temporary impairments in the function of arteries even after the episode of stress has ceased.

Single episodes of stress have been shown to increase the risk of acute cardiovascular events and the impact of stress on the blood vessels has been suggested to contribute to these stress-induced cardiovascular events. Indeed, previous research by Dr Jet Veldhuijzen van Zanten, co-investigator on this study, has shown that people at risk for cardiovascular disease show poorer vascular responses to acute stress.

“Our findings are significant for everyday diet, given that the daily dosage administered could be achieved by consuming a variety of foods rich in flavanols – particularly apples, black grapes, blackberries, cherries, raspberries, pears, pulses, green tea and unprocessed cocoa. This has important implications for measures to protect the blood vessels of those individuals who are more vulnerable to the effects of mental stress,” commented Dr. Rendeiro.

Featured image: Can drinking cocoa protect your heart? © University of Birmingham


Notes to editors:

  • For more information, interviews, please contact Tony Moran, International Communications Manager, University of Birmingham on +44 (0)782 783 2312. For out-of-hours enquiries, please call +44 (0) 7789 921 165.
  • The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 6,500 international students from over 150 countries.
  • ‘Cocoa Flavanols Improve Vascular Responses to Acute Mental Stress in Young Healthy Adults’ – Rosalind Baynham, Jet J.C.S. Veldhuijzen van Zanten, Paul W. Johns, Quang S. Pham and Catarina Rendeiro is published in Nutrients. https://www.mdpi.com/2072-6643/13/4/1103/pdf

Provided by University of Birmingham

Study Could Explain Tuberculosis Bacteria Paradox (Medicine)

TB-causing bacteria remember prior stress, react quickly to new stress

Tuberculosis bacteria have evolved to remember stressful encounters and react quickly to future stress, according to a study by computational bioengineers at Rice University and infectious disease experts at Rutgers New Jersey Medical School (NJMS).

Published online in the open-access journal mSystems, the research identifies a genetic mechanism that allows the TB-causing bacterium, Mycobacterium tuberculosis, to respond to stress rapidly and in manner that is “history-dependent,” said corresponding author Oleg Igoshin, a professor of bioengineering at Rice.

Researchers have long suspected that the ability of TB bacteria to remain dormant, sometimes for decades, stems from their ability to behave based upon past experience.

Oleg Igoshin (Photo by Jeff Fitlow/Rice University)

Latent TB is an enormous global problem. While TB kills about 1.5 million people each year, the World Health Organization estimates that 2-3 billion people are infected with a dormant form of the TB bacterium.

“There’s some sort of peace treaty between the immune system and bacteria,” Igoshin said. “The bacteria don’t grow, and the immune system doesn’t kill them. But if people get immunocompromised due to malnutrition or AIDS, the bacteria can be reactivated.”

One of the most likely candidates for a genetic switch that can toggle TB bacteria into a dormant state is a regulatory network that is activated by the stress caused by immune cell attacks. The network responds by activating several dozen genes the bacteria use to survive the stress. Based on a Rice computational model, Igoshin and his longtime Rutgers NJMS collaborator Maria Laura Gennaro and colleagues predicted just such a switch in 2010. According to the theory, the switch contained an ultrasensitive control mechanism that worked in combination with multiple feedback loops to allow hysteresis, or history-dependent behavior.

“The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don’t have that much of a response,” Igoshin explained. “But if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back.”

Maria Laura Gennaro (Photo courtesy of Rutgers NJMS)

In later experiments, Gennaro’s team found no evidence of the predicted control mechanism in Mycobacterium smegmatis, a close relative of the TB bacterium. Since both organisms use the same regulatory network, it looked like the prediction was wrong. Finding out why took years of follow-up studies. Gennaro and Igoshin’s teams found that the TB bacterium, unlike their noninfectious cousins, had the hysteresis control mechanism, but it didn’t behave as expected.

“Hysteretic switches are known to be very slow, and this wasn’t,” Igoshin said. “There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results. “

Igoshin and study co-author Satyajit Rao, a Rice doctoral student who graduated last year, revisited the 2010 model and considered how it might be modified to explain the paradox. Studies within the past decade had found a protein called DnaK played a role in activating the stress-response network. Based on what was known about DnaK, Igoshin and Rao added it to their model of the dormant-active switch.

Satyajit Rao (Photo courtesy S. Rao)

“We didn’t discover it, but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we’d observed,” Igoshin said. “What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK.”

DnaK was known to play the role of chaperone in helping rid cells of unfolded proteins, but it plays an additional role in the stress-response network by keeping its sensor protein in an inactive state.

“When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network,” Igoshin said. “So once there are enough unfolded proteins to ‘distract’ DnaK, the organism responds to the stress.”

Gennaro and co-author Pratik Datta conducted experiments at NJMS to confirm DnaK behaved as predicted. But Igoshin said it is not clear how the findings might impact TB treatment or control strategies. For example, the switch responds to short-term biochemical changes inside the cell, and it’s unclear what connection, if any, it may have with long-term behaviors like TB latency, he said.

“The immediate first step is to really try and see whether this hysteresis is important during the infection,” Igoshin said. “Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host.”

Featured image: 3D illustration of the bacterial pathogen Mycobacterium tuberculosis. (Image courtesy of 123rf)


Reference: Satyajit D. Rao, Pratik Datta, Maria Laura Gennaro, Oleg A. Igoshin, “Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response”, American Society for Biology (MSystems), 2021. https://msystems.asm.org/content/6/1/e00979-20


Provided by Rice University

Study Reveals How a Longevity Gene Protects Brain Stem Cells From Stress (Neuroscience)

A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by Weill Cornell Medicine investigators.

Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3). That discovery led Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.

In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment will support the new cells’ survival.

“Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives,” said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”

Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.

“We learned that the FOXO3 protein is directly modified by oxidative stress,” she said. This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.

The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.

“Without SAM, lamin can’t form this strong barrier and DNA starts leaking out,” she said.

The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.

“This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons,” Dr. Paik explained. “If new cells were made in such stressful conditions they would be killed. It’s better for stem cells to remain dormant and wait until the stress is gone to produce neurons.”

The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives—they may help people keep a good reserve of brain stem cells. It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness. But Dr. Paik cautioned it is too early to know whether this new information could be used to create new therapies for brain diseases.

“It could be a double-edged sword,” Dr. Paik explained. “Over activating FOXO3 could be very harmful. We don’t want to keep this on all the time.”

To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.

Featured image: Antioxidant treatment boosts the birth of new neurons from stem cells by suppressing stress signaling. Image courtesy of the Paik lab.


Reference: Hwang, I., Uchida, H., Dai, Z. et al. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nat Commun 12, 640 (2021). https://www.nature.com/articles/s41467-020-20839-0 https://doi.org/10.1038/s41467-020-20839-0


Provided by Weill Cornell Medicine

Cold Sores: Here’s How Stress, Illness and Even Sunburn Trigger Flareups (Medicine)

Researchers at the School of Medicine have shed light on what causes herpes simplex virus to flare up, explaining how stress, illness and even sunburn can trigger unwanted outbreaks.

The discovery could lead to new ways to prevent cold sores and recurrent herpes-related eye disease from reoccurring, the researchers report.

“Herpes simplex recurrence has long been associated with stress, fever and sunburn,” said researcher Anna R. Cliffe, PhD, of UVA’s Department of Microbiology, Immunology and Cancer Biology. “This study sheds light on how all these triggers can lead to herpes simplex-associated disease.”

ABOUT COLD SORES (HSV)

Once you’re infected with herpes simplex virus (HSV) – and more half of Americans are – the virus never really goes away. Instead, it lurks inside neurons, waiting for the right moment to strike again, a process known as reactivation.

Cold sores, also known as fever blisters, are one of the most common symptoms of HSV reactivation. Recurrent reactivation in the eye leads to herpes keratitis, which, if left untreated, can result in blindness. HSV infection has also been linked to the progression of Alzheimer’s disease.

Recurrences of HSV are typically associated with stress, illness or sunburn, but doctors have been uncertain exactly what causes the virus to reactivate. Cliffe and her collaborators found that when neurons harboring the virus were exposed to stimuli that induce “neuronal hyperexcitation,” the virus senses this particular change and seizes its opportunity to reactivate.

Working in a model developed by the Cliffe lab using mouse neurons infected with HSV, the researchers determined that the virus highjacks an important immune response within the body. In response to prolonged periods of inflammation or stress, the immune system releases a particular cytokine, Interleukin 1 beta. This cytokine is also present in epithelial cells in the skin and eye and is released when these cells are damaged by ultraviolet light.

Interleukin 1 beta then increases the excitability in the affected neurons, setting the stage for HSV to flare up, the UVA researchers discovered.

“It is really remarkable that the virus has hijacked this pathway that is part of our body’s immune response,” Cliffe said. “it highlights how some viruses have evolved to take advantage of what should be part of our infection-fighting machinery.”

The scientists say that more research will need to be done to fully understand the potential factors which play into herpes simplex disease. It may vary depending on the virus strain or the type of neuron infected, even. And it is still unknown if the virus alters how neurons respond to cytokines such as Interleukin 1 beta. But the new insights help doctors better understand what is happening in neurons and the immune system, and that could lead to ways to prevent unwanted outbreaks, the researchers hope.

“A better understanding of what causes HSV to reactivate in response to a stimulus is needed to develop novel therapeutics,” Cliffe said. “Ultimately, what we hope to do is target the latent virus itself and make it unresponsive to stimuli such as Interleukin 1 beta.”

FINDINGS PUBLISHED

The researchers have published their findings in the scientific journal eLife. The research team consisted of Sean R. Cuddy, Austin R. Schinlever, Sara Dochnal, Philip V. Seegren, Jon Suzich, Parijat Kundu, Taylor K. Downs, Mina Farah, Bimal N. Desai, Chris Boutell and Cliffe.

The work was supported by the National Institutes of Health’s National Institute of Neurological Disorder and Stroke, grant R01NS105630; the National Institute of Allergy and Infectious Diseases, grant T32AI007046;the National Eye Institute, grant F30EY030397; the National Institute of General Medical Sciences, grants T32GM008136, T32GM007267, GM108989 and GM007055and Medical Research Council grant MC_UU_12014/5.

Featured image: Researchers Sean R. Cuddy and Anna R. Cliffe of the University of Virginia School of Medicine have shed light on what causes cold sores to flare up. The discovery could lead to new ways to prevent cold sores and recurrent herpes-related eye disease from reoccurring, they say. Courtesy Cliffe lab at UVA


Provided by UVA Health

A Plant’s Nutrient-Sensing Abilities Can Modulate Its Response To Environmental Stress (Botany)

Understanding how plants respond to stressful environmental conditions is crucial to developing effective strategies for protecting important agricultural crops from a changing climate. New research led by Carnegie’s Zhiyong Wang, Shouling, Xu, and Yang Bi reveals an important process by which plants switch between amplified and dampened stress responses. Their work is published by Nature Communications.

To survive in a changing environment, plants must choose between different response strategies, which are based on both external environmental factors and internal nutritional and energy demands. For example, a plant might either delay or accelerate its lifecycle, depending on the availability of the stored sugars that make up its energy supply.  

“We know plants are able to modulate their response to environmental stresses based on whether or not nutrients are available,” Wang explained. “But the molecular mechanisms by which they accomplish this fine tuning are poorly understood.”  

For years, Carnegie plant biologists have been building a treasure trove of research on a system by which plants sense available nutrients. It is a sugar molecule that gets tacked onto proteins and alters their activities. Called O-linked N-Acetylglucosamine, or O-GlcNAc, this sugar tag is associated with changes in gene expression, cellular growth, and cell differentiation in both animals and plants.

The functions of O-GlcNAc are well studied in the context of human diseases, such as obesity, cancer, and neurodegeneration, but are much less understood in plants. In 2017, the Carnegie-led team identified for the first time hundreds of plant proteins modified by O-GlcNAc, providing a framework for fully parsing the nutrient-sensing network it controls.

In this most recent report, researchers from Wang’s lab—lead author Bi, Zhiping Deng, Dasha Savage, Thomas Hartwig, and Sunita Patil—and Xu’s lab—Ruben Shrestha and Su Hyun Hong—revealed that one of the proteins modified by an O-GlcNAc tag provides a cellular physiological link between sugar availability and stress response. It is an evolutionarily conserved protein named Apoptotic Chromatin Condensation Inducer in the Nucleus, or Acinus, which is known in mammals to play numerous roles in the storage and processing of a cell’s genetic material.

Through a comprehensive set of genetic, genomic, and proteomic experiments, the Carnegie team demonstrated that in plants Acinus forms a similar protein complex as its mammalian counterpart and plays a unique role in regulating stress responses and key developmental transitions, such as seed germination and flowering. The work further demonstrates that sugar modification of the Acinus protein allows nutrient availability to modulate a plant’s sensitivity to environmental stresses and to control seed germination and flowering time.

“Our research illustrates how plants use the sugar sensing mechanisms to fine tune stress responses,” Xu explained. “Our findings suggest that plants choose different stress response strategies based on nutrient availability to maximize their survival in different stress conditions.”

Looking forward, the researchers want to study more proteins that are tagged by O-GlcNAc and better understand how this important system could be harnessed to fight hunger.

“Understanding how plants make cellular decisions by integrating environmental and internal information is important for improving plant resilience and productivity in a changing climate,” Wang concluded. “Considering that many parts of the molecular circuit are conserved in plant and human cells, our research findings can lead to improvement of not only agriculture and ecosystems, but also of human health.”        

This work was supported by the U.S. National Institutes of Health and the Carnegie Institution for Science endowment.

Featured image: Photo of flowering Arabidopsis Thaliana © Shutterstock


Reference: Bi, Y., Deng, Z., Ni, W. et al. Arabidopsis ACINUS is O-glycosylated and regulates transcription and alternative splicing of regulators of reproductive transitions. Nat Commun 12, 945 (2021). https://doi.org/10.1038/s41467-021-20929-7


Provided by Carnegie Science