Posted on Pain Management

Scientists reveal mechanism for colon pain and inflammation

PAR2 in normal and inflamed tissue


In normal tissue, PAR2—seen here in fluorescent green—is found on the surface of cells, but in inflamed tissue, it moves from the surface of cells to compartments within cells called endosomes. CREDIT Bunnett Lab, NYU Dentistry

Researchers at the NYU Pain Research Center have identified a mechanism that underlies inflammation and pain in the colon, and demonstrated that blocking a key receptor from entering colon cells can inhibit inflammation and pain, uncovering a potential target for treating pain in inflammatory bowel disease. 

Their study, published in the Proceedings of the National Academy of Sciences (PNAS), was conducted in mice with colitis, an inflammatory disease marked by chronic and sometimes painful inflammation of the large intestine.

The digestive tract is home to a large number of proteases, or enzymes that break down proteins. These proteases come from a variety of sources, including the microbiota, inflammatory cells, or digestive enzymes in the intestine.

While proteases are important for digestion and help to degrade proteins in the gut, many also signal cells by activating specific G protein-coupled receptors (GCPRs). GCPRs are a large family of receptors that regulate many processes in the body and are the target of one third of clinically used drugs. When proteases activate one such GCPR—protease-activated receptor-2, or PAR2—on nerve cells, it causes the release of mediators that produce pain.

Studies show that protease activation of PAR2 is involved in gastrointestinal diseases that can be associated with pain, including inflammatory bowel disease, irritable bowel syndrome, and cancer. But until now, scientists have not fully understood the receptor’s signaling mechanism and how it induces pain.

To pinpoint PAR2’s location in the gut, the researchers created a mouse model in which the gene for PAR2 is fused to a green fluorescent protein. When a cell expresses PAR2, it lights up green, allowing the researchers to precisely see where the receptor is positioned. They found that PAR2 was very highly expressed on the surface or membrane of the epithelial cells that line the small and large intestines, and to a lesser extent in nerve fibers in these areas.

The researchers then discovered a key difference in the location and behavior of PAR2 in healthy mice versus mice with colitis. In healthy mice, PAR2 was found on the membrane of colonic epithelial cells, but in mice with colitis, it shifted from the surface of cells to compartments within cells called endosomes. When the receptor moved into endosomes, it generated signals that cause inflammation and pain by disrupting the normal protective function of cells lining the colon. 

“We identified not only where this receptor is in the digestive tract, but also how it signals inflammation and pain in the colon,” said Nigel Bunnett, PhD, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and the study’s senior author. “This more complete understanding of PAR2 and its signaling mechanism could ultimately help us to better treat inflammatory and painful diseases of the colon.”

Additional studies using human colon tissue confirmed that activating PAR2 induces inflammation in the colon.

If PAR2 moving from the surface of cells into endosomes leads to inflammation and pain, could blocking the receptor from entering cells limit inflammation and pain? To test this idea, the researchers prevented the movement of PAR2 into cells by knocking down the expression of a protein called dynamin-2. Keeping the receptor out of cells did, in fact, inhibit signaling and significantly reduced pain and inflammation.

The findings suggest that PAR2—and specifically, PAR2 in endosomes—may be a useful target in treating pain in inflammatory bowel disease.

“This could be achieved through blocking PAR2 from entering cells, as we did in this study by inhibiting dynamin-2,” said Bunnett. “It could also mean getting drugs that activate PAR2 not just to the surface of cells, but into the interior of cells using nanoparticles to reach the receptorin endosomes.”

Posted on Autism, Patient Talk

Gene-environment interactions that drives autism

Medium Spiny Neuron located in the nucleus accumbens, one of the neural networks of the reward system.


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.

Posted on autoimmune conditions

The protein that stands between us and autoimmunity

Tet-Mediated B Cell Tolerance


Tet2/3-deficient B cells are activated by self-antigen and express exaggerated amount of CD86. Then those B cells stimulate autoreactive CD4<sup>+</sup> T cells, resulting in autoimmune response. CREDIT Osaka University

 Our immune system is supposed to protect us from external microbial invaders, but sometimes it turns its efforts inward, potentially resulting in autoimmune diseases. In a new study, researchers from Osaka University discovered how reversible modifications to our DNA by certain proteins protect us from autoimmune diseases and, conversely, how the absence of these proteins paves the way to autoimmunity.

DNA contains all information that cells in our body need to function by providing specific codes to produce specific proteins. Nonetheless, not all parts of DNA are accessible in all cells at all times. The regulated production of proteins ensures that different cells and organs can be developed from the same DNA code. An important regulatory mechanism is the reversible addition (methylation) or removal (demethylation) of chemical bonds, so-called methyl groups, to segments of DNA. This modifies the readout of said DNA segment. Proteins of the ten-eleven translocation (Tet) family are known DNA demethylases that decrease the production of certain proteins in immune cells. How Tet proteins play into the development of autoimmune diseases has remained unknown—until now.

“Epigenetics deals with how reversible changes in DNA affect gene activity and protein expression,” says corresponding author of the study Tomohiro Kurosaki. “Disrupting this machinery can have dramatic effects on cellular function. The goal of our study was to understand how epigenetic control in a specific type of immune cells, called B cells, affects the development of autoimmune diseases.”

To achieve their goal, the researchers developed a novel mouse line in which B cells did not produce the epigenetic regulator proteins Tet2 and Tet3. They found that these mice developed a mild form of systemic lupus erythematosus, an autoimmune disease that can affect the joints, skin, kidneys and other organs, and for which there is currently no curative treatment. Similar to human patients, the mice showed increased serum levels of autoantibodies and damage to their kidneys, lungs and liver.

“These findings suggest that Tet2 and Tet3, as well as proteins whose expression is regulated by Tet2 and Tet3, might play a fundamental role in the development of systemic lupus erythematosus,” says lead author of the study Shinya Tanaka. “We wanted to gain a deeper molecular understanding of the mechanism behind the effects of Tet2 and Tet3 on the immune system.”

The researchers next investigated a different type of immune cell, called T cells, which often interact with B cells, and found that T cells were excessively activated in the Tet2/Tet3 knockout mice. By examining the molecular interaction between B and T cells closer, the researchers found that the protein CD86 was produced at higher levels in B cells of Tet2/Tet3 knockout mice, leading to aberrant T cell activation and autoimmunity.

“These are striking results that show how Tet proteins suppress autoimmune diseases by inactivating B cells and thus ultimately preventing them from attacking our bodies,” says Kurosaki. “Our findings provide new insights into the contribution of epigenetics to the development of autoimmune disease. Regulating Tet proteins and their downstream effectors could be a novel treatment for autoimmune diseases.”

Posted on Autism

10 Things NOT to Say to Someone with Autism

10 Things NOT to Say to Someone with Autism - YouTube




This week’s mental health tips are 10 things NOT to say to someone with Autism. more in-depth mental health information for you
1.YOU can’t be autistic, you seem so normal.
2.Do you take any medications to help that?
3.Autism? Oh, it’s totally from mercury in vaccines. That’s why I’m never vaccinating my children. I wouldn’t want them to end up with autism.
4.I mean, we’re all a little autistic, right?


5.I’m so sorry! It must be awful.
6.Stop using autism as an excuse!
7.Your habits are really annoying. It’s actually embarrassing.
8.You must be amazing at math or music!
9.You’re married?
10.NOTHING

Posted on Autism

Checklist for Asperger’s/Autism in Females | Going Over the Samantha Craft Unofficial Checklist

Asperger's/Autism Checklist | Going Over the Tania Marshall Screener for Aspien Women - YouTube


If you’re wondering about things to look for in females with Asperger’s or Autism, the Samantha Craft checklist is a great list to look over. Being a female on the spectrum, I wanted to sit down and go over the checklist and talk to you guys about the ones that apply to me personally and those that don’t. This might help you or someone you know, too! In this video, I share my thoughts on the itemized list that is commonly explored for people suspecting they may have Asperger’s or autism. While I do go over the list itself, I also insert whether or not I personally relate to the items on the list as well as share some examples of what that has looked like for me.