My little boy Finn is four years old and has autism. It is very common for autistic children to be picky eaters, for a variety of different reasons. I go into more detail about the reasoning behind this here: https://www.myfussyeater.com/autism-f… but I thought it might also be helpful for other parents if I showed an average day of eating for Finn.
The long-standing enigma of why so many patients suffering with high blood pressure (known as hypertension) also have diabetes (high blood sugar) has finally been cracked by an international team led by the universities of Bristol, UK, and Auckland, New Zealand.
The important new discovery has shown that a small protein cell glucagon-like peptide-1 (GLP-1) couples the body’s control of blood sugar and blood pressure.
Professor Julian Paton, a senior author, and Director of Manaaki Mãnawa – The Centre for Heart Research at the University of Auckland, said: “We’ve known for a long time that hypertension and diabetes are inextricably linked and have finally discovered the reason, which will now inform new treatment strategies.”
The research, published online ahead of print in Circulation Researchtoday [1 February], involved contributions from collaborating scientists in Brazil, Germany, Lithuania, and Serbia, as well as the UK and New Zealand.
GLP-1 is released from the wall of the gut after eating and acts to stimulate insulin from the pancreas to control blood sugar levels. This was known but what has now been unearthed is that GLP-1 also stimulates a small sensory organ called the carotid body located in the neck.
The University of Bristol group used an unbiased, high-throughput genomics technique called RNA sequencing to read all the messages of the expressed genes in the carotid body in rats with and without high blood pressure. This led to the finding that the receptor that senses GLP-1 is located in the carotid body, but less so in hypertensive rats.
David Murphy, Professor of Experimental Medicine from Bristol Medical School: Translational Health Sciences (THS) and senior author, explained: “Locating the link required genetic profiling and multiple steps of validation. We never expected to see GLP-1 come up on the radar, so this is very exciting and opens many new opportunities.”
Professor Paton added: “The carotid body is the convergent point where GLP-1 acts to control both blood sugar and blood pressure simultaneously; this is coordinated by the nervous system which is instructed by the carotid body.”
People with hypertension and/or diabetes are at high risk of life-threatening cardiovascular disease. Even when receiving medication, a large number of patients will remain at high risk. This is because most medications only treat symptoms and not causes of high blood pressure and high sugar.
Professor Rod Jackson, world-renowned epidemiologist from the University of Auckland, said “We’ve known that blood pressure is notoriously difficult to control in patients with high blood sugar, so these findings are really important because by giving GLP-1 we might be able to reduce both sugar and pressure together, and these two factors are major contributors to cardiovascular risk.”
Mr Audrys Pauža, a British Heart Foundation-funded PhD student in Professor David Murphy’s lab in the Bristol Medical School and lead author on the study, added: “The prevalence of diabetes and hypertension is increasing throughout the world, and there is an urgent need to address this.
“Drugs targeting the GLP-1 receptor are already approved for use in humans and widely used to treat diabetes. Besides helping to lower blood sugar these drugs also reduce blood pressure, however, the mechanism of this effect wasn’t well understood.
“This research revealed that these drugs may actually work on the carotid bodies to enact their anti-hypertensive effect. Leading from this work, we are already planning translational studies in humans to bring this discover into practice so that patients most at risk can receive the best treatment available.”
But GLP-1 is just the start. The research has revealed many novel targets for ongoing functional studies that the team anticipate will lead to future translational projects in human hypertensive and diabetic patients.
Sleep apnea in pregnancy may increase the risk for brain and behavioral changes associated with autism, especially in males, according to a study in rats by Amanda Vanderplow, Michael Cahill, and colleagues at the University of Wisconsin-Madison, and publishing February 3rd in the open-access journal PLOS Biology. The findings support evidence in humans of a link between sleep apnea and neurodevelopmental disorders, and provide a potential mechanism to explain the link.
During episodes of sleep apnea, breathing is partially or completely interrupted, often hundreds of timers per night, causing intermittent hypoxia, or decreased blood oxygenation. The incidence of sleep apnea during pregnancy is on the rise, in line with the obesity epidemic, and occurs in about 15% of uncomplicated pregnancies and more than 60% of high-risk pregnancies by the third trimester. Sleep apnea during pregnancy is known to have detrimental effects on the newborn, but the impacts on neurodevelopment have not been well studied.
To investigate such impacts, the authors subjected pregnant rats to intermittent low oxygen levels during times of rest, during the second half of their gestational period. The treatment induced hypoxia in the mothers, but (as expected) not in the fetuses. Behavioral abnormalities in the offspring were observed beginning shortly after birth, including altered distress vocalization patterns in both males and females. Maternal hypoxia also impaired cognitive and social function in male, but not female, offspring, both of which persisted into adulthood. Effects included reduction in working memory and longer-term memory storage, and reduced interest in socially novel situations.
These behavioral changes were accompanied by significant abnormalities in the density and morphology of dendritic spines, the outgrowths on neurons that receive and integrate signals from other neurons. In adolescents of both sexes, but much more so in males, the density of dendritic spines was elevated compared to age-matched control animals, an increase due mainly to lack of spine “pruning,” or reduction, a process that begins in childhood and is critical for normal brain development. How maternal hypoxia induced these changes in fetuses not themselves experiencing hypoxia remains unclear.
The authors found that affected offspring had excessive activity of a cell signaling pathway known as the mTOR pathway, a feature identified in the cortex of humans with autism, and that treatment with rapamycin, an mTOR inhibitor, partially mitigated the behavioral effects of maternal hypoxia in the offspring.
“To our knowledge, this is the first direct demonstration of the effects of maternal intermittent hypoxia during gestation on the cognitive and behavioral phenotypes of offspring,” Cahill says. “Our data provide clear evidence that maternal sleep apnea may be an important risk factor for the development of neurodevelopmental disorders, particularly in male offspring.”
Cahill adds, “Based on clinical correlations, maternal sleep apnea during pregnancy has been theorized to potentially increase risk for autism diagnosis in her offspring; however, functional studies are lacking. Here we show that sleep apnea during gestation produces neuronal and behavioral phenotypes in rodent offspring that closely resemble autism, and demonstrate the efficacy of a pharmacological approach in fully reversing the observed behavioral impairments.”
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.”