–People who develop multiple sclerosis (MS) as children and grow up in less advantaged neighbourhoods may have a larger volume of inflammation and brain tissue loss on imaging than those who grow up in more advantaged neighbourhoods.
MS rarely develops in children. About 5% of people with MS are diagnosed before age 18.
In addition to neighbourhood location, worse brain imaging outcomes were also seen among people who self-identified as Black or Latino, those from families where the parents had lower education levels, and those who had public health insurance, which is used as a marker of low household income.
“Our findings suggest that social disadvantage in childhood can have lasting effects on MS severity,” said study author Kimberly A. O’Neill, MD, of New York University Grossman School of Medicine. “Childhood is a critical time for exposure to environmental factors associated with increased susceptibility to MS, such as passive smoke, pollution and low sunlight exposure. More studies are needed to understand which and how factors in disadvantaged neighbourhoods increase the risk for MS severity in young people.”
The study involved 138 people with an average age of 20 who were diagnosed with MS before age 18, known as pediatric-onset MS. They had been diagnosed with MS for an average of four years.
All had brain scans to measure areas of brain inflammation and injury due to MS and brain volume loss. Researchers collected information on social factors that may impact a person’s health, including self-reported race and ethnicity, type of health insurance, parents’ education level, and the degree of neighbourhood advantage or disadvantage.
Social factors associated with disadvantage correlated with greater volume of inflammatory lesions in the brain’s white matter and greater black hole volume, which is a sign of irreversible loss of brain tissue. The identified social factors accounted for 26% of the difference in white matter lesion volume and 23% in black hole volume among participants.
Once all factors were taken into account, having public health insurance was the strongest predictor of greater inflammation and tissue loss. People with public health insurance had an average white matter lesion volume larger than people with private insurance. They also had average black hole volumes larger than those with private insurance.
The researchers found that the differences were not explained by how soon a neurologist saw children, how quickly they were started on medication for MS or how compelling their medications were at slowing their disease progress.
“This suggests that access to health care does not explain the more severe disease burden shown in the brain scans of people in disadvantaged groups in our study,” O’Neill said. “While these are associations and not causes, many of these groups have historically been underrepresented in MS research, and our work here is just beginning.”
Wearable electrical nerve stimulation devices can relieve people experiencing the persistent pain and fatigue linked to long COVID, a study co-led by UCLA and Baylor College of Medicine researchers suggests.
Long-COVID, a complex and lingering condition following COVID-19 recovery, affects approximately 1 in 13 adults in the U.S. Symptoms such as widespread pain, fatigue, and muscle weakness often continue to disrupt daily activities, including walking and basic tasks.
The study focused on a wearable Transcutaneous Electrical Nerve Stimulation (TENS) device, which uses low-voltage electrical currents to reduce pain, fatigue, and mobility issues associated with long-COVID.
However, the device could have broader applications.
“While this study focused on managing pain and fatigue caused by long COVID, it may also have potential applications for addressing similar symptoms in individuals with other respiratory diseases, those who have experienced extended ICU stays and developed post-hospitalization weaknesses, and conditions involving chronic fatigue and pain, such as fibromyalgia or chemotherapy-related side effects,” Najafi said. “But further studies are needed to confirm these potential uses.”
In the study, 25 participants with chronic musculoskeletal pain, fatigue, and gait difficulties were assigned either a high-dose (active) TENS device or a low-dose (placebo) device. Both groups used the TENS device for three to five hours daily over four weeks.
Researchers measured participants’ pain levels, fatigue, and walking performance before and after the therapy period. Findings indicated that the high-dose TENS group experienced notable improvements in pain relief (26.1% more relief than placebo) and walking ability (8% during fast walking), suggesting that wearable TENS therapy may help reduce long-COVID’s impact on daily life.
The high-dose TENS group also reported a slightly higher perceived benefit (71.2%) than the low-dose group (61.4%), underscoring the potential of wearable TENS technology to support long-term COVID recovery.
Najafi said one factor in the study’s success was likely the high rate of daily device usage. The wearable nature of the TENS device allowed participants to use it seamlessly throughout the day without disrupting their routines.
“This wearable TENS system offered immediate, on-demand relief from pain and fatigue, making it easy to integrate into daily activities,” Najafi said.
Chronic diseases such as diabetes are on the rise and are costly and challenging to treat. Whitehead Institute Member Richard Young and colleagues have discovered a common denominator driving these diverse diseases, which may prove to be a promising therapeutic target: Proteolethargy, or reduced protein mobility, in the presence of oxidative stress.
Jennifer Cook-Chrysos/Whitehead Institute
Chronic diseases, such as type 2 diabetes and inflammatory disorders like rheumatoid arthritis, significantly impact humanity. They are among the leading causes of disease burden and deaths worldwide, posing both physical and economic challenges. Furthermore, the number of individuals affected by these diseases is rising.
Treating chronic diseases has proven challenging because they do not have a single, straightforward cause, such as a specific gene mutation that a treatment could target. However, research conducted by Richard Young, a member of the Whitehead Institute, and his colleagues, published in the journal Cell on November 27, reveals that many chronic diseases may share a common factor driving their dysfunction: reduced protein mobility. This means that approximately half of the proteins active in cells tend to slow down their movement when the cells are in a chronic disease state, which diminishes the proteins’ functions. The researchers’ findings suggest that protein mobility could be a crucial factor in the decreased cellular function observed in chronic diseases, making it a promising target for therapy.
In this paper, Young and his colleagues, including postdoc Alessandra Dall’Agnese, graduate students Shannon Moreno and Ming Zheng, and research scientist Tong Ihn Lee, describe their discovery of a shared mobility defect they call proteolethargy. They explain the underlying causes of this defect, how it leads to cell dysfunction, and propose a new therapeutic hypothesis for treating chronic diseases.
“I’m excited about the potential impact of this research on patients,” says Dall’Agnese. “I hope this leads to the development of a new class of drugs that can restore protein mobility, which could help individuals with various diseases that share this common mechanism.”
According to Lee, this project involved biologists, physicists, chemists, computer scientists, and physician-scientists. “Bringing together this diverse expertise is a strength of the Young lab. By examining the problem from various perspectives, we gained valuable insights into how this mechanism might function and its potential to reshape our understanding of the pathology of chronic diseases.”
Commuter delays cause work stoppages in the cell
How do proteins moving slowly through a cell lead to significant cellular dysfunction? Dall’Agnese explains that every cell functions like a tiny city, with proteins acting as the workers who keep everything running smoothly. Proteins must travel through dense traffic within the cell, moving from where they are produced to where they are needed. The quicker their commute, the more efficient their work becomes. Now, imagine a city that starts experiencing traffic jams on all its roads. Stores may not open on time, groceries could get stuck in transit, and meetings might be postponed. Essentially, all operations within the city slow down.
The slowdown of cellular operations in cells with reduced protein mobility follows a similar pattern. Normally, most proteins move rapidly throughout the cell, colliding with other molecules until they find the one they need to interact with or affect. When a protein moves more slowly, it encounters fewer other molecules, making it less likely to perform its function effectively. Young and colleagues discovered that these slowdowns in protein movement result in measurable decreases in the proteins’ functional output. When numerous proteins are unable to complete their tasks on time, cells begin to face various issues, which are commonly observed in chronic diseases.
Discovering the protein mobility problem
Young and his colleagues first suspected that cells affected by chronic diseases might have issues with protein mobility after observing changes in the behaviour of the insulin receptor. The insulin receptor is a signalling protein that reacts to insulin’s presence, prompting cells to absorb sugar from the bloodstream. In individuals with diabetes, cells become less responsive to insulin, a condition known as insulin resistance, which leads to elevated blood sugar levels. In research published in Nature Communications in 2022, Young and his colleagues reported that the mobility of insulin receptors could be significant in the context of diabetes.
Knowing that many cellular functions are altered in diabetes, the researchers considered the possibility that altered protein mobility might somehow affect many proteins in cells. To test this hypothesis, they studied proteins involved in a broad range of cellular functions, including MED1, a protein involved in gene expression; HP1α, a protein involved in gene silencing; FIB1, a protein involved in the production of ribosomes; and SRSF2, a protein involved in splicing of messenger RNA. They used single-molecule tracking and other methods to measure how each of those proteins moves in healthy cells and in cells in disease states. All but one of the proteins showed reduced mobility (about 20-35%) in the disease cells.
“I’m excited that we were able to transfer physics-based insight and methodology, which are commonly used to understand the single-molecule processes like gene transcription in normal cells, to a disease context and show that they can be used to uncover unexpected mechanisms of disease,” Zheng says. “This work shows how the random walk of proteins in cells is linked to disease pathology.”
Moreno concurs: “In school, we’re taught to consider changes in protein structure or DNA sequences when looking for causes of disease, but we’ve demonstrated that those are not the only contributing factors. If you only consider a static picture of a protein or a cell, you miss out on discovering these changes that only appear when molecules are in motion.”
Can’t commute across the cell, I’m all tied up right now
Next, the researchers needed to determine what was causing the proteins to slow down. They suspected that the defect had to do with an increase in cells of the level of reactive oxygen species (ROS), molecules that are highly prone to interfering with other molecules and their chemical reactions. Many types of chronic-disease-associated triggers, such as higher sugar or fat levels, certain toxins, and inflammatory signals, lead to an increase in ROS, also known as an increase in oxidative stress. The researchers measured the mobility of the proteins again in cells that had high levels of ROS and were not otherwise in a disease state and saw comparable mobility defects, suggesting that oxidative stress was to blame for the protein mobility defect.
The final part of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only one of the proteins that was unaffected in the experiments, and it had one clear difference from the others: its surface did not contain any cysteines, an amino acid building block of many proteins. Cysteines are especially susceptible to interference from ROS because it will cause them to bond with other cysteines. When this bonding occurs between two protein molecules, it slows them down because the two proteins cannot move through the cell as quickly as either protein alone.
About half of the proteins in our cells contain surface cysteines, so this single protein mobility defect can impact many different cellular pathways. This makes sense when one considers the diversity of dysfunctions that appear in the cells of people with chronic diseases: dysfunctions in cell signalling, metabolic processes, gene expression and gene silencing, and more. All of these processes rely on the efficient functioning of proteins—including the diverse proteins studied by the researchers. Young and colleagues performed several experiments to confirm that decreased protein mobility does, in fact, decrease a protein’s function. For example, they found that when an insulin receptor experiences decreased mobility, it acts less efficiently on IRS1, a molecule to which it usually adds a phosphate group.
From understanding a mechanism to treating a disease
Discovering that decreased protein mobility in the presence of oxidative stress could be driving many of the symptoms of chronic disease provides opportunities to develop therapies to rescue protein mobility. In the course of their experiments, the researchers treated cells with an antioxidant drug called N—acetyl cysteine—something that reduces ROS—and saw that this partially restored protein mobility.
The researchers are pursuing a variety of follow-ups to this work, including the search for drugs that safely and efficiently reduce ROS and restore protein mobility. They developed an assay that can be used to screen drugs to see if they restore protein mobility by comparing each drug’s effect on a simple biomarker with surface cysteines to one without. They are also looking into other diseases that may involve protein mobility, and are exploring the role of reduced protein mobility in aging.
“The complex biology of chronic diseases has made it challenging to come up with effective therapeutic hypotheses,” says Young, who is also a professor of biology at the Massachusetts Institute of Technology. “The discovery that diverse disease-associated stimuli all induce a common feature, proteolethargy, and that this feature could contribute to much of the dysregulation that we see in chronic disease, is something that I hope will be a real game changer for developing drugs that work across the spectrum of chronic diseases.”
A new study has identified distinct neural and behavioural characteristics in autism that a simple computational principle can explain. This research focuses on the “dynamic range” of neurons, which indicates how gradually or sharply they respond to stimuli. The findings suggest that individuals with autism spectrum disorder exhibit an increased dynamic range in their neuronal responses. As a result, they tend to have more detailed responses that are slower to adapt to changes. This study challenges previous views of autism as merely a “broken cog in the machine” and offers a more nuanced understanding of the computational foundations of autism.
Researchers Dr Yuval Hart and Oded Wertheimer from the Psychology Department and the Edmond and Lily Safra Center for Brain Science (ELSC) at the Hebrew University of Jerusalem have developed a new computational model to explain the neural and behavioural differences associated with autism. This model provides new insights into information processing in the brains of individuals with autism, paving the way for future research and deeper understanding.
Autism is known to present unique neural and behavioural characteristics compared to neurotypical individuals, but the underlying computational mechanisms remain complex and multifaceted. The model proposed by Dr Hart and Wertheimer centres around the concept of “dynamic range” within neuronal populations. Dynamic range refers to signals for which neurons elicit discernible responses. In simpler terms, it reflects how gradually or sharply neurons respond to stimuli – a more gradual response entails an increased dynamic range.
“Our model suggests that autism spectrum disorder is not a `broken cog in the machine`, but rather a spectrum of points on the computational tradeoff line between accurate inference and fast adaptation,” said Dr. Yuval Hart. “This computational trade-off proved to be a fruitful framework for explaining many of the neural and behavioural characteristics seen in autism.”
The researchers found that an increased dynamic range, indicating a gradual response of a neuronal population to changes in input, accounts for neural and behavioural variations in individuals diagnosed with autism across diverse tasks. This gradual response enables more accurate encoding of details but comes with a trade-off: slower adaptation to changes. By contrast, a narrower dynamic range allows for quick, threshold-based reactions, facilitating fast adaptation but potentially at the expense of fine discrimination.
Testing their model across diverse simulations and behavioural tasks, including finger-tapping synchronization, orientation reproduction, and global motion coherence, the researchers demonstrated that increased dynamic range might underlie specific autism r-related behaviours. This variation in response could stem from differences in how individual neurons activate. For instance, increased variability in individual neurons’ half-activation point, where the neuron’s response is half of its maximal value, could lead to a broader dynamic range at the population level, influencing how sensory input is processed and interpreted by the brain.
“We show how heterogeneity in the half-activation points of single neurons can result in a more gradual population response and can thus lead to an increased dynamic range,” explained Oded Wertheimer. “Given the vast literature that maps autism to mutations in genes related to neuronal receptors, the proposed biological mechanism is highly relevant – many sources of heterogeneity in these neuronal features can lead to increased dynamic range. This model provides a new lens for understanding autism spectrum disorder that bridges biological mechanisms at the neuronal level with computational principles.”
Dr. Hart and Wertheimer’s findings also provide insight into why autism spectrum disorder research often yields conflicting results. Differences in the dynamic range within the autism spectrum disorder population may contribute to the variation in findings across studies, highlighting the need for larger participant groups to ensure robust results.
Their model aligns with existing theories that relate autism spectrum disorder to atypical sensory processing, supporting a connection to broader biological and genetic factors. Specific genetic mutations associated with autism spectrum disorder, such as those affecting synaptic regulation, may contribute to this increased dynamic range. These biological factors could lead to a more variable neuronal response, creating the nuanced, analogue-like encoding seen in individuals with autism spectrum disorder individuals.
By exploring this computational trade-off, the study not only introduces a new perspective on autism spectrum disorder but also suggests future directions for study. The researchers propose that examining this dynamic range at different developmental stages or through animal models could further clarify its impact on autism spectrum disorder-related behaviors.
• Americans over the age of 40 could live an extra 5.3 years if all were as active as the top 25% of the population
• For the least active 25% of Americans aged 40+, an extra hour’s walk could add an average of 6.3 hours of additional life expectancy.
According to a new study led by Griffith University researchers, if everyone in the United States population was as active as the top 25 per cent, individuals over 40 could add five years to their lives.
Physical activity has long been recognized as beneficial for health; however, estimates have varied regarding the extent of benefits derived from specific amounts of activity, both for individuals and populations.
This latest study used accelerometry to gain an accurate view of the population’s physical activity levels instead of relying on survey responses, as in other studies. It found that the benefits were around twice as substantial as previous estimates.
It found the most active quarter of people in the community had a 73 per cent lower risk of death than their least active counterparts.
For the least active quartile, a one-hour walk could potentially provide around six additional hours of life.
Lead researcher Professor Lennert Veerman said this least-active cohort had the most significant potential for health gains.
“If you’re already very active or in that top quartile, an extra hour’s walk may not make much difference as you’ve, in a sense, already ‘maxed out’ your benefit,” he said.
“If the least active quartile of the population over age 40 were to increase their activity level to that of the most active quartile, however, they might live, on average, about 11 years longer.
“This is not an unreasonable prospect, as 25 per cent of the population is already doing it.
“It can be any type of exercise but roughly the equivalent of just under three hours of walking per day.”
The research team suggested low levels of physical activity could even rival the adverse effects of smoking, with other research finding each cigarette could take 11 minutes from a smoker’s life.
By extension, a more active lifestyle could also offer protective effects against heart disease, stroke, certain cancers, and other chronic illnesses. The study’s findings highlight a need for national physical activity guidelines to be revisited using these methods.
Dr Veerman said physical activity had been vastly underestimated in its capacity to improve health outcomes, suggesting even modest increases in movement could lead to significant life-extension benefits.
“If there’s something you could do to more than halve your risk of death, physical activity is enormously powerful,” he said.
“If we could increase investment in promoting physical activity and creating living environments that promote it, such as walkable or cyclable neighbourhoods and convenient, affordable public transport systems, we could increase longevity and reduce pressure on our health systems and the environment.”
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