This mini documentary tells the stories of three people who have been impacted by Chronic Fatigue Syndrome – a devastating, energy-sapping disease that affects roughly 836,000-2.5 million people in the U.S. and receives little research funding.
A new and free tool called the wallet card helps people with autism communicate with law enforcement officers.
director of the Institute of Structural Biology at the University Hospital Bonn (UKB), looking at a cryo-electron microscopy carrier. Photo: Johann F. Saba/UKB
Researchers at the Universities of Bonn and Regensburg have elucidated the structure of a central cellular inflammatory switch. Their work shows which site of the giant protein called NLRP3 inhibitors can bind to. This opens the way to develop new pharmaceuticals that could target inflammatory diseases such as gout, type 2 diabetes or even Alzheimer’s disease. The results are published in the journal Nature.
In their study, the researchers investigated a protein molecule with the cryptic abbreviation NLRP3. This is a kind of danger sensor in the cell: It sounds the alarm when the cell is under stress, such as from a bacterial infection or toxins.
NLRP3 then induces the formation of pores within the cellular membrane, which ultimately results in the cell’s death. Before that, however, the sensor molecule stimulates the formation of inflammatory messenger substances that are released through the perforated membrane. These so-called cytokines recruit more immune cells to the site and ensure that cells in the surrounding area commit suicide – thereby preventing a bacterium or virus from further spreading.
“The result is a massive inflammatory response,” explains study leader Prof. Dr. Matthias Geyer from the Institute of Structural Biology at the University of Bonn. “This is certainly very useful for the defense against pathogens. But if this response is overdosed or triggered by even harmless cues, it can lead to chronic inflammatory diseases – such as type II diabetes, gout, Crohn’s disease, or even dementias like Alzheimer’s.”
Targeted containment of inflammation
Researchers around the globe are therefore seeking for ways to target inflammatory processes without disrupting the entire mechanism of the immune response. As early as 20 years ago, the US pharmaceutical company Pfizer published an interesting finding in this regard: Certain active substances prevent the release of cytokines, the most important inflammatory messengers. How these CRIDs (Cytokine Release Inhibitory Drugs) do this, however, was unknown until now.
It has been known for several years that CRIDs somehow prevent cellular danger sensors from sounding the alarm. “We have now discovered the way in which they exert this effect,” explains Geyer’s colleague Inga Hochheiser. This involved isolating large amounts of NLRP3 from cells, purifying it, and adding the inhibitor CRID3. Hochheiser dropped minute portions of this mixture onto a carrier and then froze them rapidly.
This method creates a thin film of ice containing millions of NLRP3 molecules to which CRID3 is bound. These can be observed with an electron microscope. Since the molecules fall differently as they drop, different sides of them can be seen under the microscope. “These views can be combined to create a three-dimensional image,” Hochheiser explains.
The cryo-EM images allow a detailed insight into the structure of the hazard sensor inactivated by CRID3. They reveal that NLRP3 in its inactive form assembles into a mega-molecule. It consists of ten NLRP3 units that together form a kind of cage. “The most exciting result of our work, however, is that we were able to identify the CRID3 molecule docked into its binding site,” Geyer is pleased to report. “That was a tough nut that many groups worldwide have been trying to crack.”
Inhibitor prevents the activation of the giant molecule
The binding sites (structural biologists also speak of “pockets”) are located inside the cage. Each of the ten NLRP3 units has one of these pockets. When occupied by CRID3, the inhibitor blocks a flap mechanism required for NLRP3 activation. Similar to a blooming rose, which can only be visited by a bee in this state, certain parts of the NLRP3 protein reach the surface of the cage when the flap is turned over and thus become accessible.
NLRP3 is a representative of an entire family of similar proteins. Each of them presumably performs its very specific task in different inflammatory processes. “Based on our research, we believe that the pockets of all these NLRPs are different,” Geyer says. “A specific inhibitor can therefore probably be found for each of them.” This gives researchers a whole arsenal of potential new weapons against diverse, inflammatory diseases.
For example, the current work allows a targeted search for more effective alternatives to CRID3 that also have fewer side effects. But that is just the beginning, says Geyer, who is also a member of the ImmunoSensation2 Cluster of Excellence at the University of Bonn. “I am convinced that our study opens up a fruitful new field of research that will keep researchers busy for decades to come.”
Purchases of sugary drinks could be reduced by pictorial health warnings, reports research publishing February 1st in the open access journal PLOS Medicine. A trial in a naturalistic store setting found parents bought fewer sugary drinks when products displayed pictorial warnings about type 2 diabetes or heart damage, as compared with barcode labels. The study suggests that policies requiring pictorial health warnings on sugary drinks could reduce purchases of these products.
Children in the US consume more than the recommended levels of sugary drinks, increasing their risk of a variety of chronic diseases, including type 2 diabetes and heart disease. Research has found that text warnings can reduce sugary drink consumption, but the effects of pictorial warnings remain largely uninvestigated.
Marissa G Hall and colleagues at the University of North Carolina at Chapel Hill randomly assigned 325 parents of children aged 2-12 to an intervention arm or control arm and asked them to choose a drink and a snack for their child plus a household item in a naturalistic store laboratory. The intervention group had pictorial health warnings about type 2 diabetes or heart disease displayed on drinks, while controls had barcode labels.
In the control group 45% of parents bought a sugary drink for their child, compared to 28% in the pictorial warning group. Calories (kcal) from purchased sugary drinks were also reduced, with an average of 82 kcal for controls vs. 52 kcal for the pictorial warnings group. Parents in the intervention arm reported thinking more about their decision and the impacts of sugary drinks as well as lower intentions to serve sugary drinks to their child. Pictorial warnings could be a promising option for reducing purchases of sugary drinks for children, and related health outcomes.
Corresponding author Lindsey Smith Taillie adds, “Kids in the US consume too many sugary drinks, increasing their risk of a variety of health problems, from dental caries to chronic diseases like type 2 diabetes. We know from tobacco control research that warnings that include images are effective for reducing consumption. Our study is one of the first to show that this type of policy works for sugary drinks, too. This data provides evidence to support policies to require strong front-of-package warnings as a strategy to reduce children’s intake of sugary drinks.”
Medium Spiny Neuron located in the nucleus accumbens, one of the neural networks of the reward system.C REDIT Camilla Bellone – UNIGE
The research team led by Camilla Bellone, a professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine and director of the Synapsy National Centre of Competence in Research, had already demonstrated the role of the reward system in the social interaction deficit in autistic mice. Indeed, the motivation that drives individuals to interact with their peers is closely linked to the reward system, through the activation of the neuronal networks that make it up.
But what are the cellular and molecular mechanisms at the origin of the deficits in social interaction? To understand this process and thus decipher how the symptoms appear, the scientists studied so-called heterozygous mice, i.e. mice carrying a deletion of only one of the two copies of the SHANK3 gene, but not showing social behavioural disorders. With 1-2% of all autism cases, this is indeed one of the most common monogenic causes of the disease.
“Humans carry a mutation in only one of the two copies of SHANK3, a gene that is essential for the functioning of synapses and communication between neurons,” points out Camilla Bellone. “In animal models of the disease, however, mutation of a single copy of SHANK3 only slightly affects the behaviour of mice, which explains why the behavioural phenotypes observed are not homogeneous”.
The role of neuronal hyperexcitability
The researchers first inhibited the expression of SHANK3 in the neural networks of the reward system in order to identify the other genes whose expression was modified. Several genes related to the inflammatory system were detected, including one of them, Trpv4, which is also involved in the functioning of communication channels between neurons. “By inducing massive inflammation, we observed an overexpression of Trpv4, which then led to a neuronal hyperexcitability concomitant to the onset of social avoidance behaviours that our mice did not exhibit until now,” stresses Camilla Bellone. Moreover, by inhibiting Trpv4, the scientists were able to restore normal social behaviour.
“This provides evidence that autistic disorders are indeed the result of an interaction between a genetic susceptibility and an external trigger – in this case, massive inflammation. Neuronal hyperexcitability disrupts communication channels, thereby altering the brain circuits governing social behaviour.” This would also explain why the same genetic predisposition can lead, depending on the environmental factors encountered and the type of inflammation they trigger, to a diversity of symptoms of equally variable severity.
Irreversible damage during development?
In this study, the inflammation was induced in adult animals. The resulting deficit in social behaviour was not only reversible, but also disappeared naturally after a few days. “We now need to replicate our research during the critical phases of neurodevelopment — i.e. during gestation and immediately after birth — in order to observe the impact of hyperexcitability on the developing neural networks. This could damage the construction of neural networks beyond repairs,” says Camilla Bellone.
This study constitutes a proof-of-principle of a direct causality between inflammation and the appearance of behavioural symptoms in the presence of genetic vulnerability, and highlights the importance of environmental factors, which have been largely underestimated until now. It also highlights the fact that the understanding of the mechanisms behind autistic disorders still needs to be refined in order to intervene effectively. Indeed, depending on the gene-environment interactions and inflammatory mechanisms specific to each patient, it would be possible to identify a treatment that would correspond exactly to the cellular and molecular modification at stake in the brain circuits.