Insights into versatile molecular death switch

The enzyme caspase-8 induces a molecular cell death programme called pyroptosis without involving its enzymatic activity, a new study by Hamid Kashkar published in Nature shows. In order to safeguard healthy and functioning tissues, cells utilize different cell death mechanisms to dispose of unwanted cells (e.g. infected or aged cells). Apoptosis is a ‘cellular suicide programme’ that does not cause tissue injury and is induced by caspase-8. Necroptosis is another mode of regulated cell death which causes cellular damage and is normally engaged when caspase-8 is inhibited. Pyroptosis describes an inflammatory mode of regulated cellular death process, which is normally activated in response to microbial pathogens and is central for mounting anti-microbial immunity. Hamid Kashkar and his team have now shown that caspase-8 not only controls apoptosis and necroptosis but pyroptosis as well. The study ‘Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis’ was published in Nature.

The research team studied the biological roles of caspase-8 in cell cultures and mice. Kashkar’s group showed that the enzymatic activity of caspase-8 is required to inhibit pyroptosis. ‘We found out that the expression of inactive caspase-8 causes embryonic lethality and inflammatory tissue destruction. This could only be restored when necroptosis and pyroptosis were simultaneously blocked,’ Hamid Kashkar explains. The lack of caspase-8 enzymatic activity primarily causes necroptotic cell death. Interestingly, when necroptosis is blocked, the inactive caspase-8 serves as a protein scaffold for the formation of a signalling protein complex called inflammasome, which ultimately induces pyroptosis. ‘Microbial pathogens are heavily reliant on the fate of infected cells and have evolved a number of strategies to inhibit apoptosis and necroptosis,’ Hamid Kashkar adds.

The current study hypothesises that these strategies may have driven the counter-evolution of pyroptosis to secure cellular death as a host defence mechanism. The caspase-8-mediated switch between different modes of cell death adds a critical layer to the plasticity of cell death-induced immunity, which is increasingly involved in aging-associated disorders.

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Materials provided by University of Cologne. Note: Content may be edited for style and length.


Journal Reference:

  1. Melanie Fritsch, Saskia D. Günther, Robin Schwarzer, Marie-Christine Albert, Fabian Schorn, J. Paul Werthenbach, Lars M. Schiffmann, Neil Stair, Hannah Stocks, Jens M. Seeger, Mohamed Lamkanfi, Martin Krönke, Manolis Pasparakis, Hamid Kashkar. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature, 2019; DOI: 10.1038/s41586-019-1770-6

Cite This Page:

University of Cologne. “Insights into versatile molecular death switch.” ScienceDaily. ScienceDaily, 26 November 2019. <www.sciencedaily.com/releases/2019/11/191126121202.htm>.

University of Cologne. (2019, November 26). Insights into versatile molecular death switch. ScienceDaily. Retrieved November 26, 2019 from www.sciencedaily.com/releases/2019/11/191126121202.htm

University of Cologne. “Insights into versatile molecular death switch.” ScienceDaily. www.sciencedaily.com/releases/2019/11/191126121202.htm (accessed November 26, 2019).

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What keeps cells in shape? New research points to 2 types of motion

The health of cells is maintained, in part, by two types of movement of their nucleoli, a team of scientists has found. This dual motion within surrounding fluid, it reports, adds to our understanding of what contributes to healthy cellular function and points to how its disruption could affect human health.

“Nucleolar malfunction can lead to disease, including cancer,” explains Alexandra Zidovska, an assistant professor in New York University’s Department of Physics and the senior author of the study, which appears in the journal eLife. “Thus, understanding the processes responsible for the maintenance of nucleolar shape and motion might help in the creation of new diagnostics and therapies for certain human afflictions.”

Recent discoveries have shown that some cellular compartments don’t have membranes, which were previously seen as necessary to hold a cell together. Researchers have since sought to understand the forces that maintain the integrity of these building blocks of life absent these membranes.

What has been observed is the nature of this behavior. Specifically, these compartments act as liquid droplets made of a material that does not mix with the fluid around them — similar to oil and water. This process, known as liquid-liquid phase separation, has now been established as one of the key cellular organizing principles.

In their study, the researchers focused on the best known example of such cellular liquid droplet: the nucleolus, which resides inside the cell nucleus and is vital to cell’s protein synthesis.

“While the liquid-like nature of the nucleolus has been studied before, its relationship with the surrounding liquid is not known,” explains Zidovska, who co-authored the study with Christina Caragine, an NYU doctoral student, and Shannon Haley, an undergraduate in NYU’s College of Arts and Science at the time of the work and now a doctoral student at the University of California at Berkeley. “This relationship is particularly intriguing considering the surrounding liquid — the nucleoplasm — contains the entire human genome.”

Yet, unclear is how the two fluids interact with each other.

To better understand this dynamic, the scientists examined the motion and fusion of human nucleoli in live human cells, while monitoring their shape, size, and smoothness of their surface. The method for studying the fusion of the nucleolar droplets was created by the team in 2018 and reported in the journal Physical Review Letters.

Their latest study showed two types of nucleolar pair movements or “dances”: an unexpected correlated motion prior to their fusion and separate independent motion. Moreover, they found that the smoothness of the nucleolar interface is susceptible to both changes in gene expression and the packing state of the genome, which surrounds the nucleoli.

“Nucleolus, the biggest droplet found inside the cell nucleus, serves a very important role in human aging, stress response, and general protein synthesis while existing in this special state,” observes Zidovska. “Because nucleoli are surrounded by fluid that contains our genome, their movement stirs genes around them. Consequently, because the genome in the surrounding fluid and nucleoli exist in a sensitive balance, a change in one can influence the other. Disrupting this state can potentially lead to disease.”

This research was supported by grants from the National Institutes of Health (R00-GM104152) and the National Science Foundation (CAREER PHY-1554880, CMMI-1762506).

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Materials provided by New York University. Note: Content may be edited for style and length.

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‘Hundreds more cases’ in Shropshire maternity scandal

Over 200 new families have contacted an inquiry into mother and baby deaths at an NHS hospital trust.

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Health24.com | SA’s first children’s book on ADHD is ‘impressing teens and adults alike’

One in 20 children in South Africa suffers from Attention Deficit Hyperactivity Disorder (ADHD), along with an estimated one million adults. Launched this month, All Of These Things Are Important To Me is the country’s first fictional book about ADHD, and aims to create awareness for early detection and intervention. 

The book explores the adventurous life of Zee in a short and colourful narrative in English, Afrikaans, Xhosa, Zulu and Sesotho, and through its captivating storytelling explains how a child with ADHD perceives and lives in the world.

The second part of the book offers a simple but accurate explanation of ADHD: what it is, how it is diagnosed and how it is managed. It offers valuable advice for parents, educators and healthcare professionals in understanding and managing ADHD.

Professor Renata Schoeman, a psychiatrist in private practice and associate professor in leadership at Stellenbosch Business School, and Health24’s resident expert, provided the academic input for the book as a resource for parents to answer their children’s – and their own – questions about ADHD.

She also, with in depth conversations with Refiloe Moahloli (children’s author) and David Griessel (illustrator) ensured that they really were able to capture the minds and experiences of a child with ADHD through their creative contributions.

Schoeman chatted to us about the process of the book, from start to completion:

This is your debut novel. How does it feel?

It is a debut novel, but I can’t claim that it’s my novel – nor that it is a novel! The idea behind the book, and the academic input is mine, while the protagonist, Zee, that we based the story on was inspired by patients that I’ve met through the years in my practice, so it’s really a tribute to all these children and all the children out there that still need help and that we haven’t yet reached. Also, without the creative input from Refiloe and David, the book would have remained a dream!

Have you always thought about producing a book on ADHD?

I suppose, as an academic, you write a lot, and there’s always this idea of getting information out there for everyone that’s easily “readable”. So the idea of a book was always there, and sometimes you don’t always plan – sometimes it just happens serendipitously. 

About 18 months ago, I realised, it was time. And I realised it wasn’t something I had the creative talent to do on my own. I was looking for someone who has the ability to write in rhyme because children with ADHD often do not like reading, and I approached Refiloe directly.

She has a lot of energy and passion, and I liked her other books and her writing style, and so we met and discussed the project. We had a lot of conversations in terms of telling a story about what the children struggle with, and also educating her on ADHD.

So Refiloe put the storyline into that lovely rhyme that she wrote in English, and she translated it into isiXhosa. I had been following David Griesel’s work for a while and just loved what he created, and realised his sketches would work well for the book. (It also happens that we were both born and bred in Boemfontein!).

I wrote the academic content at the end of the book, because I think it’s so important that people obtain accurate information. There’s such a lot of misinformation out there about ADHD on the internet.

And people often want a resource where they can get all the crucial information together, such as what ADHD is, why people get it, how it’s diagnosed, and all the misconceptions about medication and treatment. 

How long did it take for the book to be produced?

The entire process – from planning to production and publishing – took around 18 months, because we also had to secure funding before we could really buckle down.

The book contains three colours: yellow, grey and white. Is there any particular reason for this selection?

We talked about the use of colours upfront, and factored in three things. We wanted it either greyscale with yellow because of its association with The Goldilocks and Bear Foundation’s logo and brand. Yellow is also such an optimistic, happy colour, and it’s gender neutral. The third factor we considered was printing costs – it would’ve cost more had it been in full colour. 

Children with ADHD are very visual. One of the first children who had the book in her hands said: “Yipee, now I can colour in!” It is therefore also an opportunity for the kids to personalise it for themselves.

What age group is the book particularly suited to?

Our aim was primary school kids, but we soon realised that the reach of the book is much bigger and is actually for anyone who wants to facilitate the conversation around ADHD, whether it’s with other adults, or teachers, parents, occupational therapists, psychologists, psychiatrists, paediatricians – really just anyone who works with children with ADHD.

We even had a young adult who was very excited about the book, and said he could finally explain what he’d been experiencing to his parents and friends. 

Were there any challenges you faced along the way?

Securing funding is not always easy, but the only thing that was particularly challenging was the translation of the story into five languages, and getting it right while maintaining the rhyming flow and making sure it’s correct. 

We also had this brilliant editor-publishing guru (and angel), Wilsa Metz from Metz Press, who was really crucial in assisting us with the book. Without her expertise, the book would have taken much longer to produce – and the process would have been so much more stressful!

Do you have any tips to offer for kids with ADHD who aren’t interested in reading or listening to stories?

I think, because this book is visually appealing, you could even just page through the pictures at first. And when their eyes start to drift to the left and they see the short text, it might intrigue them into thinking, “What’s this over here? I want to understand it.”

So just introducing the visual concept will get their attention, and they will pretty quickly realise that it’s not a typical book. But bear in mind they shouldn’t be forced. They might want you to only read one or two pages, or would just want to look at the butterflies.

For a younger child, perhaps try to initially use it to play a game of “Spot the butterflies [or teddy bears]”, because those are some of the themes found throughout the book.

Do you expect to produce any other books on ADHD in the future?

I would love to! I already got requests to write for teenagers and adults, but it will not happen within the next six months. And obviously we will have a completely different approach. I don’t want to give my ideas away right now, but watch this space…

What advice do you have for parents and teachers supporting children with ADHD?

We included a lot of tips for parents and teachers in the book, so I don’t want to repeat them, but the most important thing to realise – and it’s valid for every child and every adult, regardless of whether they have ADHD or not – is that everyone has strengths. Find that strength that helps you to connect with another human being, and focus on that. We all have seeds of potential, but often no one nourishes those seeds, so my advice is to focus on that strength and not on what frustrates you.

*All proceeds from the book goes to the Goldilocks and the Bear Foundation, founded by Prof Schoeman and athlete Nic de Beer in 2017. The Foundation aims to remove mental health barriers (such as ADHD, anxiety, depression and learning difficulties) through early detection and intervention.

Images: Supplied/Jigsaw Public Relations

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Ketamine may reduce heavy drinkers’ craving

It may help to change habits and memories linked to alcohol, researchers believe.

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Health24.com | Why maintaining muscle in middle age might help men’s hearts later

Middle-aged men who maintain their muscle mass may lower their risk of heart disease as they get older, a new study suggests.

Beginning in the mid-30s, muscle begins to decline by about 3% each decade. Previous studies found that muscle mass is associated with heart attack/stroke risk, but those studies focused on people with heart disease.

Gender disparity

In this new study, the researchers wanted to examine if muscle mass in middle age might be associated with long-term heart health in people without heart disease.

The study included more than 1 000 men and women, aged 45 and older, who were followed for 10 years. During that time, 272 participants developed heart disease, including stroke and minor stroke.

People with the most muscle were 81% less likely to develop heart disease than the least muscular. Those with the most muscle had the lowest rates of risk factors such as high blood pressure, diabetes and obesity, the investigators found.

Further analysis showed that muscle mass was significantly linked to lower heart disease risk among men, but not women.

Preserving lean muscle mass

Possible reasons for this gender disparity include age-related hormonal differences and the fact that the men had more muscle to start with, according to the study authors. Their findings were published online in the Journal of Epidemiology & Community Health.

Because this was an observational study, it can’t establish cause and effect. Even so, the findings “point to the importance of [skeletal muscle mass] preservation in relation to [cardiovascular disease] risk,” the authors wrote in the report.

Regular physical activity, including resistance training, and a diet rich in protein may help preserve lean muscle mass as people get older, the researchers suggested.

Demosthenes Panagiotakos, a professor in the School of Health Science and Education at Harokopio University in Athens, Greece, led the study.

Image credit: iStock

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Milly Main: Hospital infection spiked at time of child’s death

Health Protection Scotland analysed rates of some infections among cancer patients at Glasgow’s children’s hospital.

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Health24.com | How a short period of inactivity can damage your health

26 November 2019

How a short period of inactivity can damage your health

Research shows that we’re not getting enough physical activity, and if we are getting some exercise in and stopping for even a couple weeks, it could be more harmful than what we realise.

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We are often caught up in the hustle and bustle of life that we don’t make time to exercise or engage in physical activity.

For the few who are able to get some exercise in, taking a couple weeks off from their routine could be more harmful.

Image credit: iStock

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