Radically different
Research headed by a team at Stanford Medicine has identified two proteins with opposing functions that are involved in orchestrating the development and maintenance of healthy skin.
The proteins, NEDD8 and SUMO2, are part of a family called ubiquitin-like proteins (UBLs), and the researchers believe that modulating their activity with topical drugs could reduce inflammation, aid wound healing, and slow or halt the growth of skin cancer.
“These two ubiquitin-like protein systems are remarkably dedicated and opposite in their functions,” said Paul Khavari, MD, PhD, chair of dermatology at the Stanford School of Medicine and senior author of the study. “One promotes the stem-cell state while the other drives differentiation. It’s like having two opposing forces that determine a cell’s fate.”
Added clinical instructor of dermatology Mårten Winge, MD, PhD, “What’s really exciting is how specific these effects are. When we manipulate one system or the other, we see very clear and opposite outcomes. This specificity is unusual for ubiquitin-like pathways and makes these systems particularly attractive for therapeutic targeting.”
Khavari, who is the Carl J. Herzog Professor in Dermatology in the School of Medicine, chief of dermatology at Veterans Affairs Palo Alto, and a member of the Stanford Cancer Institute, is senior author, and Winge is co-lead author of the researchers’ published paper in Science, titled “Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation.” The work was carried out in collaboration with researchers at Icahn School of Medicine at Mount Sinai.
Stratified epithelial tissues, such as the skin’s epidermis, differentiate to form protective barriers against environmental attacks, the authors wrote. “This process involves coordinated modulation of thousands of genes and is disrupted in many inflammatory or neoplastic diseases.
Ubiquitination controls the targeted destruction and disposal of unneeded proteins in a cell. “Ubiquitin and related ubiquitin-like proteins (UBLs) comprise a major layer of protein regulation,” the team continued. The study by Khavari and colleagues has now found that in the skin, certain ubiquitin-like proteins switch on or off wide swaths of genes involved in cellular growth and development. In particular, they trigger progenitor, or stem, cells in the lower layer of the skin to either mature and migrate to the skin surface or to self-renew.
The outer layer of your skin can be considered as two distinct compartments. On the lower level, progenitor cells or skin-specific stem cells wait to transform into keratinocytes, a more specialized cell type forming the critical skin barrier that keeps moisture in (and out), excludes infection-causing pathogens, repels DNA-damaging ultraviolet rays, and harbors the nerve endings that allow us to sense our surroundings.
These progenitor cells divide just enough to keep their numbers robust. But when needed—after injury or infection or when skin cells naturally slough off—a subset of progenitor cells differentiate and migrate to the skin’s surface. Disruptions in this delicate balance between stem cell maintenance and their maturation into adult keratinocytes can lead to psoriasis, poor wound healing, and skin cancer.
The researchers were interested in understanding how the differentiation switch is flipped. “We hypothesized that differentiation-dependent proteomic remodeling diverges from RNA-level effects due to posttranslational protein modifications,” they noted. They used a wide swath of experimental approaches to assess dynamic changes in the expression of thousands of genes and proteins at various stages of keratinocyte differentiation. The results found that the maturing cells expressed increasing levels of genes and proteins involved in skin formation and decreasing levels of others associated with stem cell maintenance. Many of the proteins that decreased during differentiation bore small molecular tags that identify locations recognized by other proteins in the ubiquitin pathways—giving a hint that ubiquitination may be involved in the differentiation switch the researchers were seeking.
Disrupting the expression of more than 200 genes in the ubiquitin pathway during keratinocyte maturation highlighted two subpathways essential for proper differentiation: NEDDylation and SUMOylation. Hobbling the NEDDylation pathway supercharged differentiation, while blocking SUMOylation prevented differentiation. Similar results were obtained when the pathways were blocked pharmacologically with existing drugs in both human keratinocytes grown in the laboratory and in human skin organoids—three-dimensional sheets of tissue about the size of a quarter that mimic the multicellular structure of human skin.
Next, the researchers genetically engineered laboratory mice such that the expression of either Nedd8 or Sumo2—two key proteins in the NEDDylation and SUMOylation pathways—could be blocked when a triggering molecule is applied to the animals’ skin. They found that the skin of the mice developed abnormally when either Nedd8 or Sumo2 expression was halted, showing that both proteins are necessary for proper skin development.
“Generation of conditional knockout mice established essential roles for NEDD8 in progenitor maintenance, skin regeneration, and inflammation, whereas SUMO2 was required for differentiation,” they commented. Mice unable to make Nedd8 had an overgrowth of keratinocytes on their skin’s surface (similar to psoriasis), and animals lacking Sumo2 showed impaired differentiation and a loss of the distinct layers that make up healthy skin.
In addition to changes in the skin cells, the loss of Nedd8 and Sumo2 led to striking changes in the amounts and kinds of immune cells populating the skin. Nedd8 loss resulted in an increase in the numbers of immune cells called neutrophils in the skin and caused inflammation, while Sumo2 loss caused an increase in the numbers of another immune cell called a T cell. “In skin, NEDD8 maintained the undifferentiated epidermal state, enabled wound healing, and restrained neutrophilic inflammation,” they said. “SUMO2 promoted proper epidermal differentiation and suppressed T lymphocyte infiltration.”
Khavari commented: “We’re not just changing individual cells—we’re changing the whole tissue microenvironment. Manipulating these pathways could have therapeutic applications for wounds, inflammation, skin aging, and even cancer.”
Further experiments showed that the effect of Nedd8 on cell differentiation is due to its association with an RNA-binding protein called HNRNPU. “NEDD8 loss modulated the RNA binding and stabilizing functions of HNRNPU,” the team explained. In the absence of Nedd8, HNRNPU latches onto and stabilizes sets of RNA messages encoding genes for proteins essential for the differentiation of progenitor cells into keratinocytes, but when Nedd8 attaches to HNRNPU, the protein instead binds to and stabilizes RNA messages encoding proteins necessary for progenitor cell maintenance.
“Thus, NEDD8 and SUMO2 play opposite roles in epithelial homeostasis, regeneration, and inflammation, demonstrating multiple ways ubiquitin-like networks govern tissue homeostasis,” the team reported in their paper. “The researchers are now exploring whether topical drug treatments targeting the NEDDylation or SUMOylation pathways could tilt the balance of keratinocyte differentiation to progenitor cell maintenance and to treat a variety of skin diseases and disorders.
“The beauty of understanding these fundamental switches is that we can apply them to multiple disease states,” said co-lead author Leandra Jackrazi, an MD/PhD student. “Whether it’s promoting wound healing, reducing inflammation, or controlling cancer growth, having the ability to toggle between stemlike and differentiated states opens many doors.”
The post Two Proteins with Opposing Functions Found to Support Healthy Skin Maintenance appeared first on GEN – Genetic Engineering and Biotechnology News.
Nature Medicine, Published online: 29 June 2026; doi:10.1038/s41591-026-04516-1
We developed a tool, Talos, for automated reanalysis of genomic data from patients with a rare disease and show that frequent reanalysis can be delivered at scale and low cost. Talos is open source, thereby enabling broad adoption by the clinical and research communities.
Methylphenidate is a stimulant medication used to treat symptoms of ADHD. It helps the brain regulate attention, focus, and impulsive behaviors.
It’s one of the two stimulants widely used in ADHD medications. Methylphenidate is the active ingredient in Ritalin and Concerta, among others. The other commonly used stimulant, amphetamine, is the active ingredient in Adderall and Vyvanse, among others. Both stimulants work by increasing levels of dopamine and norepinephrine, chemicals in the brain that control attention, focus, and impulsivity. If a child doesn’t do well on the first stimulant medication they try, they may respond better to a different formulation of that type or the other type of stimulant.
Methylphenidate is somewhat less powerful than amphetamine and tends to have milder side effects.
If your child is under 12 and has just been diagnosed with ADHD, a doctor is likely to prescribe a methylphenidate medication first, to see how well the medication reduces their ADHD symptoms, and whether the side effects are problematic.
Methylphenidate is also many doctors’ first choice for younger children because it has been used to treat ADHD much longer than amphetamine. Ritalin (methylphenidate-based) was FDA approved in 1955, while Adderall (amphetamine-based) wasn’t approved until 1996. In countries outside the United States, amphetamine-based ADHD medications are less widely approved than those based on methylphenidate.
The two stimulants target the same brain chemicals but work slightly differently, says Paul Mitrani, MD, PhD, a child and adolescent psychiatrist at the Child Mind Institute. Methylphenidate increases the levels of dopamine and norepinephrine by blocking what’s called reuptake — the process by which nerve cells reabsorb these chemicals after they’ve been released. As Dr. Mitrani describes it, methylphenidate “enhances” the norepinephrine and dopamine the brain naturally releases by making the chemicals stay around longer. It boosts the stimulation the brain is already getting from whatever activity the child is engaged in.
Amphetamine, on the other hand, not only blocks reuptake but stimulates the release of more dopamine and norepinephrine, which is why it’s considered stronger. “Adding stimulation with amphetamine sometimes helps,” he notes. “But sometimes that added stimulation is too much, and it increases side effects the child experiences.”
There is individual variation in how children respond to the two stimulants. So if methylphenidate doesn’t give the desired symptom relief or produces problematic side effects, it’s recommended practice to try amphetamine, or vice versa. Research shows that 70 percent of children with ADHD respond to a trial of methylphenidate. More than 90 percent will have a beneficial response to one of the stimulants if both methylphenidate and amphetamine are tried. Studies also show that approximately 41 percent respond equally well to both types of stimulant.
Children can also vary in their response to different formulations of the same stimulant, which affect the rate at which the medication goes into the bloodstream. For instance, a short-acting form of Ritalin will kick in quickly and last for 3-4 hours, while Concerta, a delayed-release formula, lasts as long as 10-12 hours. It’s very common for kids to try several before finding the best fit.
Methylphenidate and amphetamine have the same side effects, though they may be less intense with the former.
The most common side effect of stimulants is appetite suppression. It can be especially concerning with long-acting forms of the medication, which are often preferred to get better coverage through the school day. Kids who take a long-acting stimulant in the morning tend to lose their appetite for lunch and may not be interested in eating until after dinnertime.
When this is a problem, Dr. Mitrani notes that taking a shorter-acting form of the medication can help. “For instance, Concerta is a methylphenidate medication that lasts for a long time and can suppress appetite for 10–12 hours.” An alternative might be a medication that lasts for 6–8 hours, such as Metadate CD or Ritalin LA. Some children with more pronounced problems with appetite will do better on a short-acting dose in the morning and then another after lunch, he adds, since it gives them a break during the day where they can eat better.
Kids who take stimulant medication can have trouble falling asleep. This can happen when a long-acting medication or an afternoon dose of a short-acting medication wears off and they get restless or hyperactive around bedtime. Difficulty falling asleep can get better after a few weeks, but if it doesn’t, it may be helpful to change either the timing or the type of the medication that is given. It’s also important to explore whether there are other contributors to sleep challenges, such as worry, screen time too close to bedtime, or lack of a consistent evening routine that helps kids calm down.
Stimulant medications can generate agitation and irritability, which can be especially problematic in kids who are already anxious. For children with anxiety, this can be another reason to start treatment with methylphenidate, because amphetamines can feel more activating.
But Dr. Mitrani notes that treating ADHD can also reduce anxiety: “Some kids are so stressed about school — because they can’t pay attention or arealways getting in trouble — that when you treat the ADHD, they are better able to manage the demands of school and become less anxious.”
That reduction in school anxiety can also affect what happens when they get home from school. “When there is anxiety, it’s like kids are holding it together at school, and then they come home after a stressful day and just let it out,” he says. “So if the school day is less stressful, you may also see that come down at the end of the day.”
Some children report that stimulant medications seem to dull their personality. Dr. Mitrani suggests that this may be connected to the medication stimulating the prefrontal cortex, the part of the brain that not only manages attention and focus, but also helps regulate emotions and impulse control in other brain areas. “Enhanced control of the emotional part of the brain can cause this feeling of dullness,” he notes. “Some people will even say they feel depressed, that they’re just not like themselves because they don’t have the same energy or personality.”
If this happens to a child on methylphenidate, Dr. Mitrani will recommend trying an amphetamine or a non-stimulant medication.
Some families report that their child is irritable or emotional after school or at the end of the day, when the stimulant medication is wearing off. Dr. Mitrani notes that this can coincide with the child being hungry after missing lunch. It can also be connected to the medication level dropping too quickly, and strategies that create a more gradual decrease may help take it away. For example, he might suggest adding a small dose of short-acting form of the stimulant a half hour before the morning medication wears off.
Dr. Mitrani usually starts a child on a short-acting form of methylphenidate for two reasons: as a quick test to see if the child will experience side effects and to have an opportunity to try it twice in a day, to have more chances to assess for positive changes.
He recommends starting the medication on a weekend or a break from school and giving the child some tasks that are challenging for them because of their ADHD, like reading or something else that requires concentration, such as cleaning their room or doing household chores. “After lunch you want to try it again, to have another time point to check on. Because if you only give one dose of the medication, you don’t know if the child’s behavior was a result of the medication or some other factor. The more data points that we have, or more trials, the more information we get.”
He recommends keeping the child on short-acting doses for at least several days before trying a longer-acting formula.
Practice guidelines for psychiatrists recommend starting children on a low dose to assess any side effects the child might experience and gradually increasing it over 1-2 weeks with careful monitoring of response until you reach the minimum dose that will give the best symptom relief.
There is a great deal of variation in how children respond to these medications, so starting with an “average” effective dose, even adjusted by body weight, would be under-medicating some kids and overmedicating others.
For instance, for a 6- or 7-year-old child, a common starting dose of a short-acting medication might be about 2.5 mg, going up to 5 mg if more is needed for symptom relief and side effects are not an issue, Dr. Mitrani says.
Liquid versions of either stimulant have an advantage when it comes to getting exactly the right dose, he notes: “You can do, 1 milliliter, 1.5, 1.6, depending on the syringe.”
Long-acting formulations that come in capsules can be especially frustrating, he adds — since they come in set doses and can’t be opened and divided effectively, because the beads inside are made to be triggered at different time periods.
Dr. Mitrani stresses that small differences in the formulation of a medication can make a difference in a child’s reaction.
For instance, Focalin (dexmethylphenidate) is a refined form of methylphenidate. Standard methylphenidate medications contain two mirror-image forms, or isomers, but most of the benefit comes from one of them. Focalin contains only this more active isomer. For some children, it works better, causes fewer side effects, or feels smoother.
He also notes that variations in the release patterns among long-acting formulations can affect a child’s experience. “Take Concerta, which has a unique mechanism for the extended release,” he explains. “There are three phases: a really immediate phase, then a regular Ritalin kind of phase and, then a slow extrusion of the remaining methylphenidate throughout the day that helps it last as long as 12 hours.”
By contrast, he describes Ritalin LA, which tends to last for 6-8 hours, as “50-50” — 50 percent of the dose is immediate released and the other half is delayed release. Other formulations are “40-60” or “30-70.” “These subtle differences can result in some kids responding better to one than the other, while other kids can do well on any of them.”
So even within the methylphenidate group, there may be reason to try a child on number of different formulations to get the best fit. And, of course, other reasons for trying different versions are limits on what insurance covers —which can change suddenly — and what’s available because of shortages. “And that can be really frustrating for families,” he says. “What I hear is, ‘My child was on Concerta or on Metadate CD and they made me switch to this one and now my kid’s not doing as well.’ “
When families cannot get a medication that has been working, finding another medication that’s available, that’s effective, and that insurance will approve can be a lot of hoops to jump through, he adds.
The post Treating ADHD With Methylphenidate (Ritalin, Concerta) appeared first on Child Mind Institute.
Background: Office work is increasingly carried out outside conventional office settings, particularly during and after the COVID-19 pandemic. This highlights the need to understand the complexity of aspects that may influence health across different office work environments. Objective: This study aimed to (1) identify aspects that office workers perceive as supporting or hindering their health during office work, and (2) formulate novel questions about office work for quantitative studies. Methods: In February 2021, we conducted a digitally distributed photovoice study in Sweden, in which a convenience sample of 17 office workers from 5 companies took photos and provided written comments on what they perceived as supporting or hindering their health in places where they performed office work. For objective 1, we carried out both qualitative formal analysis and analysis without a theoretical frame, as well as quantified the content of the photos and comments. The identified aspects and their interactions were summarized in a visual framework. For objective 2, findings from the photovoice study were used to adapt selected items from the 2019 Swedish Work Environment Survey, capturing office work performed across multiple settings. Results: Of a total of 63 photos, 70% (44/63) were taken at home, 24% (15/63) in an office, and 6% (4/63) outdoors. The comments on photos taken in conventional office settings largely highlighted health-promoting aspects, while the interpretations of home office photos showed greater variability regarding their impact on health. We identified 9 aspects and categorized them into two groups: (1) environmental perspective, including space, ergonomic, technical, and aesthetic-sensuous aspects and (2) behavioral perspective, including flexibility, focus, breaks-recovery, physical activity, and eating habits. Whether the aspects supported or hindered health depended on the environment where office work was performed and the employees’ living conditions. Our visual framework illustrates how these two perspectives interact with each other, bridged by space and flexibility. The study also resulted in a battery of multiple-choice questions about work in offices, at home, in public places, and outdoors that can be used in future research to better capture variation in modern work arrangements. Conclusions: This study extends the notion that office environments play a central role in supporting employee health by suggesting that this also applies to home offices. The results emphasize the need for tailored health-promoting interventions that account for the diverse environments in which office work is performed and for individual needs. The developed visual framework for analyzing health-promoting work environments for office workers and the battery of survey questions can contribute to future research and the advancement of sustainable, health-promoting office environments.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/5ec51afe1b4c20241033ac2a6da36395" />
Helminth parasites of the Schistosoma genus cause roughly 290,000 deaths annually, primarily in tropical and subtropical regions. In addition, an estimated 250 million people are currently chronically infected with Schistosoma parasites—with an additional 800 million people at risk of getting the infection—making schistosomiasis second only to malaria among the world’s deadliest tropical parasitic diseases.
The larvae, which live in fresh water, penetrate the skin and develop into adults. Schistosomiasis can be found in nearly 80 countries and is common in sub-Saharan Africa.
Now, new research shows promise for a vaccine being tested to prevent and treat schistosomiasis. SchistoShield® (Sm-p80 + GLA-SE) is a leading vaccine candidate for schistosomiasis that has successfully completed Phase I (USA) and Phase Ib (Africa) safety and immunogenicity clinical trials. Findings in a new report suggest that the vaccine triggered an adaptive immune effector and memory responses.
This work is published in npj Vaccines in the paper, “Schistosomiasis vaccine SchistoShield® induces functional immune memory responses in U.S. and African populations.”
Afzal Siddiqui, PhD, director of the Center for Tropical Medicine and Infectious Diseases and chair of the Department of Immunology and Molecular Microbiology at the TTUHSC School of Medicine has devoted decades to creating SchistoShield.
In this study, samples taken from people who’ve received trial doses of the vaccine in both the United States and Africa now demonstrate the vaccine’s effectiveness. Using Peripheral Blood Mononuclear Cells (PBMCs) obtained from intercontinental Phase I and Phase Ib trial participants, the team analyzed adaptive immune effector and memory responses to SchistoShield.
“The SchistoShield vaccine,” Siddiqui notes, “induced robust cell-mediated effector and memory responses, hallmarks of a potentially efficacious vaccine against schistosome/helminth parasites.”
More specifically, the paper reports results demonstrating that “the vaccine induced pronounced effector and memory T-cell responses. Upon recall with Sm-p80 antigen, cytokines including IFN-γ, TNF-α, IL-17A, IL-9, and granzyme B were produced, indicating the generation of functionally heterogeneous CD4 T-helper and cytotoxic lymphocyte responses. Consistent with T-helper responses that promote humoral immunity, Sm-p80 antigen-specific antibody-secreting plasmablasts were detected in vaccinated volunteers who were tracked longitudinally.”
“The people we have vaccinated, in both the U.S. and in Africa, have the memory response, both B-cell and T-cell-based,” Siddiqui said. “The vaccine is doing what it is supposed to. But always remember that these trials are very small 50 to 100 people. Now it has to go to thousands of people. So that’s where we are moving into.”
Schistosomiasis is considered a “neglected disease” because it predominantly affects impoverished communities in tropical and subtropical regions. There’s only one drug available to treat people, but it does not prevent re-infection. Through his efforts, and the support of TTUHSC, federal grants and national and international charitable and non-profit groups, Siddiqui has been able to develop SchistoShield as a humanitarian effort, rather than making it for profit.
“Our purpose from the beginning has been to expand access to care,” Lori Rice-Spearman, PhD, president of TTUHSC said. “Dr. Siddiqui’s work reflects that commitment through research that could help address a disease affecting millions of people around the world.”
The post Schistosomiasis Vaccine Shows Strong Immune Memory in Early Clinical Trials appeared first on GEN – Genetic Engineering and Biotechnology News.