Shown above are the representative tracks of H3K27ac ChIP-seq at NFATc1, PRDM1, and MYC loci under the indicated conditions. CREDIT UNIST
A research team led by Professor Sung Ho Park in the Department of Biological Sciences at UNIST announced the results of a study on osteoblasts that damage joint bones in patients with rheumatoid arthritis.
In this study, the research team studied the possibility of a treatment method targeting mechanisms related to the differentiation process of osteoblasts that melt bones through enzyme reactions. First, it was confirmed that a super-enhancer is formed near the NFATC1 gene, which is known to be an essential factor in the formation of osteoblasts, and it is formed only in osteoblasts.
In addition, it was confirmed that an enhancer RNA, a type of non-encrypted RNA, is formed in the NFATC1 superinhand during osteoblastic cell formation.
Non-encrypted RNA does not encode proteins, but plays an important role in regulating gene expression. In particular, due to the specificity of the molecular sequence, it can be easily targeted for treatment. In fact, we observed that interfering with NFATC1 superinhancer RNA inhibits the formation of osteoblasts together.
Through this study, it has been confirmed that NFATC1 super-in-hander RNA, which is formed during osteoblast differentiation, can be used as a treatment target.
“[O]ur study is the first to identify SEs and SE-eRNAs in human osteoclasts and provides a better understanding of human osteoclast biology, thereby opening new therapeutic avenues for human pathological bone destruction,” noted the research team.
The findings of this research were made available in December 2022, ahead of its publication in the journal, Cellular and Molecular Immunology. This study has been supported by the National Research Foundation of Korea (NRF) grants, funded by the Ministry of Science and ICT (MSIT).
Chronic pain often leads to depression, which increases suffering and is clinically challenging to treat. Now, for the first time, researchers have uncovered the underlying mechanism that drives those depressive systems, according to a study published in The Journal of Clinical Investigation.
The mechanism acts to cause hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for the treatment of chronic pain-induced depression, say Lingyong Li, Ph.D., and Kimberley Tolias, Ph.D., co-leaders of the research.
The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild the cytoskeletons of cells. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons.
This higher spine density increased the number of connections and the strength of those connections between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model by using an antagonist of Tiam1, relieved the mice of depression and diminished hypersensitivity of the neurons.
The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 in the ACC was activated in two mouse models of chronic pain with depressive or anxiety-like behaviours compared to controls.
To show that Tiam1 in the ACC modulates chronic pain-induced depressive-like behaviors, the researchers used molecular scissors to delete Tiam1 from the forebrain excitatory neurons of the mice. These mice were viable and fertile and displayed no gross alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive- or anxiety-like behaviors in five tests that gauge depression or anxiety.
When researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons specifically mediates chronic pain-induced depressive-like behaviors.
Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is alterations in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus and the amygdala. Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior — they saw a significant increase in dendritic spine density and signs of increased cytoskeleton building. This was accompanied by increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.
These maladaptive changes were not seen in the Tiam1-knockout mice.
Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated the chronic pain-induced depressive-like behaviors, without reducing the chronic pain hypersensitivity itself. The inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitudes.
Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without decreasing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent, maladaptive synaptic plasticity in the mouse ACC neurons.
“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said.
Sandra Purdy, lives with ankylosing spondylitis, a type of arthritis in which the spine and other body areas become inflamed. CREDIT Sandra Purdy
The typical person living with arthritis in the UK is 20% less likely to be in work than their equivalent without the condition, new research shows.
And the most striking finding was that non-university-educated women aged 60-plus are at least 37% less likely to be in work if they have arthritis compared to matched individuals without the condition.
The study, published today by the University of Leeds, matched a group of 18,000 people with arthritis to another group of 18,000 who were the most similar to the first group regarding various characteristics but had not been diagnosed with arthritis. These characteristics included age, gender, level of education, ethnicity and where they lived.
The research shows significant differences in how arthritis affects people’s working lives, depending on their age, level of education and gender.
The team is now suggesting that workplaces provide more support for people living with the condition, so they can keep working as long as they wish.
Principal Investigator Dr Adam Martin, Associate Professor in Health Economics at the University of Leeds’ School of Medicine, said:
“We already know that arthritis is more common amongst women and people from lower socio-economic backgrounds. Our new findings show that substantial inequalities also exist in terms of how the work outcomes of these groups are affected by arthritis.
“Government and employers should consider how interventions in workplaces could better support people living with arthritis and improve their health and employment prospects, whilst also potentially tackling inequalities and address the need to support people in their 50s and 60s to stay in work for longer if they want to.
“Given the increasing prevalence of arthritis and the trend towards older retirement ages, this need for better support represents a substantial and growing challenge for society.”
Deborah Alsina MBE, Chief Executive of Versus Arthritis, said: “This is a vital and important study and reinforces what we have heard from people with arthritis about how the condition robs them of their health, independence, and careers.
“We know work matters to people with arthritis, benefitting health and wellbeing as well as their finances, yet this evidence demonstrates how arthritis is truly an unfair and unequal condition.
“We as a country need to tackle these health inequalities. Arthritis should no longer disproportionately and unfairly impact women and those less well served in our society, potentially driving millions into disability and unemployment.”
Patient experience
Sandra Purdy, 61, from Churwell in Leeds, had to retrain due to chronic pain caused by ankylosing spondylitis, a type of arthritis in which the spine and other body areas become inflamed.
She said: “I had problems with pain since my late teens and was misdiagnosed several times.
“When I was younger, I had manual jobs, but the pain meant I often couldn’t work. There’s a stigma in saying you have back pain at work, so I tried to hide it, but it got more difficult as the pain worsened.
“Eventually, I started looking for an office job which I thought would be more manageable. I got a job in a bank but sitting down all day was worse. Due to morning stiffness, I needed to get up at 4.30 am to be ready for 7.30 am. I needed crutches and sticks to walk at the start of the day. I wouldn’t need them by the end of the day, so I’d worry that people thought I was making it up. But during a bad flare-up, the pain would last all day, and I couldn’t move.
“When I was 45, I developed iritis, a painful eye condition which causes swelling and irritation in the iris. I was referred to a rheumatologist and had an MRI scan, and they diagnosed me with ankylosing spondylitis.
“I took part in a trial for a drug called infliximab, which was liquid gold. It changed my life – but at the end of the trial, I had a severe flare-up. Because of this, I was moved onto a drug called adalimumab, which I still take now. However, it lowers my immune system, so I pick up many bugs.
“I found a new job with a more understanding employer, where I could move about during the day. I now have a management role so I’m less customer-facing and can work from home.
“I hear a lot of people at my hospital patient participation group talking about how they have been treated and their employers aren’t great.
“I have always worried about losing my job, especially at first. I left school with no qualifications, so I had to sit exams in English and maths to get work in an office. I’ve had to adapt, but not everyone can do this.
“Patients need better access to diagnostics, and more joined-up thinking between employers and the health service.”
Research findings
The Nuffield Foundation-funded research used two decades of data about people aged 18-80. The team compared 18,000 people with arthritis to 18,000 people without the condition to better understand how it affects people’s lives.
The study showed that as people with arthritis reach middle age, their likelihood of being in work diminishes at a faster rate than those who do not have the condition. Many of these will have taken early retirement. This effect is more pronounced for people without a university-level education, possibly as symptoms may be easier to manage in professional jobs than in manual roles.
And once both men and women reach 60, their chances of being in work when living with arthritis are markedly more reduced compared to people without the condition.
The chart below shows the percentage reduction in the likelihood of being in work for each group compared to their counterparts without arthritis.
Age:
30
40
50
60
Men with a degree
6.3%
2.0%
2.0%
14.1%
Men without a degree
12.6%
5.3%
5.3%
25.0%
Women with a degree
12.8%
5.3%
5.3%
25.4%
Women without a degree
24.3%
14.0%
12.6%
37.2%
People with a history of working in routine (such as lorry drivers or bar staff) and intermediate (such as paramedics or bank staff) occupational groups were also much less likely to work if they had arthritis. However, this was not the case for people in professional work (such as lawyers or architects). For them, arthritis did not seem to affect the likelihood of being in work, although some people with arthritis in this group did work fewer hours and had lower earnings if they had arthritis. This was especially true for working women aged over 40.
Among people living with arthritis, those with a history of working at small private companies were also generally less likely to be in work than people with arthritis who had worked in larger companies or the public sector. The team’s discussions with people living with arthritis indicated that this might be due to smaller firms having fewer resources available or less scope for them to adjust work patterns or take on alternative roles.
Dr Martin said: “In light of this research, people with arthritis told us that potential interventions could involve making appropriate adjustments to the working environment, tackling workplace discrimination and supporting changes in people’s roles.
“Existing evidence suggests that providing personalised case management by an occupational health practitioner could help to encourage constructive dialogue between employees, healthcare practitioners and employers.
“Our study indicates that such support could be especially cost-effective if designed for and targeted for the people we identified who are most at risk of poor work outcomes.”
Notes to Editors The 18,000 people aged 18-80 in the data who said they had been diagnosed with arthritis were collected between 2001 and 2019. This group was compared with 18,000 selected people from the same datasets who were similar in terms of age, gender, ethnicity, education level and where they live but who had not been diagnosed with the condition.
Using statistical models, comparisons were made between the two groups based on the likelihood that each individual had a job, what their earnings were and their weekly working hours. The team then looked at differences in age, gender, degree status, occupation (professional, administrative, technical or routine) and employer characteristics (size of the organisation; public or private sector).
The team expected that some people with arthritis might experience poorer work outcomes than those without the condition, such as job loss or slower career progression. Their study set out to determine how significant the differences in work outcomes were and if particular age groups or genders doing specific jobs were especially at risk.
A University of Massachusetts Amherst researcher has been awarded a National Institutes of Health (NIH) grant to study bilingualism in children with autism whose household speaks a language other than English.
“This is a group that often is excluded from existing research or intervention studies,” says Megan Gross, assistant professor of communication disorders in the School of Public Health and Health Sciences. “And I think there’s still a lot of misinformation that can get out there to bilingual families about what language to speak at home with their child.”
The five-year, $755,000 career development grant will enable Gross to be mentored by a multidisciplinary team of experienced researchers from the fields of psychology, communication disorders and public health as she recruits 60 families in western Massachusetts for her sequential mixed-methods project, combining both quantitative and qualitative measures.
“I’ve worked clinically with autistic children, but I have not done research in the area of autism, so I think this career development award will be really beneficial for gaining training in how to conduct research with this population responsibly,” Gross says.
Until relatively recently, bilingual families who have a child with autism were often encouraged by professionals to stick to one language in the home.
“I think they’re still getting advice that if language is hard for their child, two languages will be even harder, so they should just speak English,” Gross says. “And that has a lot of negative potential ramifications for the child’s positive development in terms of identity, their ability to communicate and interact with family members who may not speak English and so on. So, for a condition like autism, where communication is one of the areas that can be a source of challenge, adding to that by creating a language barrier between the child and their family member can be really problematic.”
Recent studies have shown that bilingual exposure is not detrimental to the development of children on the autism spectrum, Gross points out. “We need to move beyond that to understanding how we promote bilingual development in autistic children,” she says.
Gross will examine the type of bilingual environment to which children with autism , ages 4-6, are exposed, as well as the different factors that relate to their ability to speak or understand both Spanish and English. She will also consider the children’s social communication and social-cognitive skills, such as cognitive flexibility, as well as their ability to understand and communicate in two languages.
To make it possible to include children who do not speak, Gross will use innovative eye-tracking technology to analyze their ability to comprehend bilingual spoken language. A camera at the bottom of a laptop computer will track the child’s eye movement as a word or phrase in English and Spanish is played out loud.
“By following their eye movements over time, we can tell whether they’ve understood the word or phrase that they heard because they should look at the corresponding picture,” Gross says. “This is a group I’m especially interested in including in my study. Even if they are not speaking, we need a way to measure what they are understanding when people are speaking to them in Spanish and English. And what skills might they have that they aren’t able to show us through their spoken language?”
Gross will spend the first year of her research in training and preparing materials, and will start recruiting families in 2024. Ultimately, she will interpret the quantitative findings within the context of in-depth qualitative interviews, focusing on family perspectives and challenges. The long-term goal is to collaborate with families and support services to develop community-based programs that promote bilingual children’s linguistic and social-cognitive development across the autism spectrum.
“It’s been a great interest of mine to contribute to the evidence base at the intersection between dual-language learning and autism,” Gross says.
This piece uses both identity-first (autistic person) and person-first language (person with autism) out of respect for differing preferences expressed among autistic adults, family members and community advisory board members for this project.
We use cookies on our website to give you the most relevant experience by remembering your preferences and repeat visits. By clicking “Accept”, you consent to the use of ALL the cookies.
This website uses cookies to improve your experience while you navigate through the website. Out of these, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these cookies. But opting out of some of these cookies may affect your browsing experience.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.
