Publisher Health

Worms might not be depressed, per se. But that doesn’t mean they can’t benefit from antidepressants.
In a new study, Northwestern University researchers exposed roundworms (a well-established model organism in biological research) to selective serotonin reuptake inhibitors (SSRIs), a class of drugs used for treating depression and anxiety. Surprisingly, this treatment improved the quality of aging females’ egg cells.
Not only did exposure to SSRIs decrease embryonic death by more than twofold, it also decreased chromosomal abnormalities in surviving offspring by more than twofold. Under the microscope, egg cells also looked younger and healthier, appearing round and plump rather than tiny and misshapen, which is common with aging.
Astounded by the results, the researchers replicated the experiment in fruit flies — another common model organism — and the SSRIs demonstrated the same effect.
Although much more work is needed, the researchers say these findings provide new opportunities to explore pharmacological interventions that might combat infertility issues in humans by improving egg quality and by delaying the onset of reproductive aging.
The study will be published on May 8 in the journal Developmental Biology.
“There is still a great distance between this new finding and the fertility clinic,” said Northwestern’s Ilya Ruvinsky, who led the study. “But the more we study the reproductive system, the better we understand it and the more opportunities we have for developing practical interventions.”

Ruvinsky is an associate research professor at Northwestern’s Weinberg College of Arts and Sciences. Erin Aprison, a research associate in Ruvinsky’s laboratory, is the paper’s first author. Svetlana Dzitoyeva, a postdoctoral researcher in Ruvinsky’s laboratory, co-authored the paper.
Cutting out the middleman
Previously, Ruvinsky’s team discovered that male pheromones slowed the aging of females’ egg cells. Published in the Proceedings of the National Academy of Sciences in May 2022, the previous study exposed female roundworms to male pheromones, which resulted in healthier offspring.
When female roundworms sensed the male pheromones, they shifted their energy and resources away from their overall body health and toward increasing reproductive health. “The pheromone coaxes the female into sending help to her eggs and shortchanging the rest of her body,” Ruvinsky said. “It’s not all or nothing; it’s shifting the balance.”
In the new study, Ruvinsky and his team decided to remove male pheromones from the equation entirely.

“The neurons that signal the body to shift its resources rely on serotonin as the messenger,” he said. “We identified those neurons in previous work and wondered if we could tap directly into that system. Maybe we could stimulate the serotonin system with pharmaceuticals, bypassing the need for male pheromones. Lo and behold, we saw better eggs by every measure.”
Delaying decline
To conduct the study, the team added a low dose of SSRIs to aging roundworms’ food. The researchers primarily explored the effects of fluoxetine (Prozac) but also tested citalopram (Celexa) and zimelidine.
Researchers continuously exposed the aging worms to SSRIs at concentrations comparable to those used to treat anxiety and depression in humans. Although egg quality typically drops precipitously as the worms age, worms treated with fluoxetine managed to stave off the decline.
“When we only delivered a temporary regimen of the drug and then withdrew it, the egg quality stayed high for a while but then quickly decreased,” Ruvinsky said. “We think it’s because they need a continuous signal.”
Ruvinsky and his team also found that, when exposed to fluoxetine, roundworms produced more egg cell precursors. But, in a seemingly counterproductive twist, more of these cells died. However, this, too, is another advantage.
“How do you get the components to make higher-quality eggs? You take components from other eggs,” Ruvinsky explained. “Many eggs die and get sent to the ‘salvage yard.’ You break up the parts and use those for the few eggs that survive.”
Shared signaling
Wondering whether or not the finding was exclusive to worms, Ruvinsky’s team replicated the study in fruit flies. Yet again, exposure to fluoxetine improved the quality of eggs for older female flies.
Although worms, flies and humans might seem very different, they have more in common than most people realize.
“This neuronal system does more or less the same thing in various animals,” Ruvinsky said. “More serotonin in the brain causes animals to focus on food instead of exploring their surroundings. That’s true for mammals, flies and worms. We might not be able to widen the fertility window to 60 years. But even if we could add a year or two to a person’s fertility window, that would make a big difference.”
The study, “Serotonergic signaling plays a deeply conserved role in improving oocyte quality,” was supported by the National Institutes of Health (award number R01GM126125).

A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can’t permeate the blood-brain barrier to reach the aggressive brain tumor.
But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.
The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment.
This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.
Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances.
In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.

“This is potentially a huge advance for glioblastoma patients,” said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.
Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.
The paper will be published May 2 in The Lancet Oncology.
The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain.
In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.

Blood-brain barrier recloses after an hour
The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.
“There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” Sonabend said.
Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.
In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.
Clinical trial for patients with recurrent glioblastoma
The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial — in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique — is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.
In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.
Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy.
“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said.
Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, K. A. Schmidt, D.Y. Zhang, C. Gomez, J.F. Bebawy, B.P. Liu, I.B. Helenowski, R.V. Lukas, K. Dixit, P. Kumthekar, V. A. Arrieta. Lesniak, H. Zhang and R. Stupp.
This work is funded by the grants 1R01CA245969-01A1 and P50CA221747 from the National Cancer Institute of the National Institutes of Health and SPORE support from the Moceri Family Foundation and the Panattoni family.

Most chromosomes have been around for millions of years. Now, researchers from the Stowers Institute for Medical Research have revealed the dynamics of a new, very young chromosome in fruit flies that is similar to chromosomes that arise in humans and is associated with treatment-resistant cancer and infertility. The findings may one day lead to developing more targeted therapies for treating these conditions.
A new study published in Current Biology on May 4, 2023, reveals how this small chromosome that arose less than 20 years ago has persisted in a single, lab-reared strain of the fruit fly, Drosophila melanogaster, and is correlated with supernumerary (extra) chromosomes in humans.
“I feel kind of like an astronomer who’s watching the birth of a star,” said Stowers Investigator Scott Hawley, Ph.D. “We are getting to watch the birth of a chromosome and are starting to understand both its capabilities and limitations.”
Previous research from the Hawley Lab had first identified these small, extra chromosomes, but little was known about their form, function, or dynamics during cell division. Former Hawley Lab Postdoctoral Researcher Stacey Hanlon, Ph.D., realized that this discovery could be an ideal system to investigate how new chromosomes arise, which may lead to more effective cancer treatments and methods to overcome infertility.
Supernumerary chromosomes in humans are found in cancer cells and frequently interfere with drugs designed to target tumors, making these types of cancers, like osteosarcoma, difficult to treat. In addition, the presence of supernumerary chromosomes in men can disrupt normal chromosome segregation during sperm production, which can cause infertility.
“Being able to understand how supernumerary chromosomes arise and what their structures are can potentially illuminate their vulnerabilities,” said Hawley. “This may enable the development of potential therapeutic targets.”
Called B chromosomes — as opposed to the standard “A” set of essential chromosomes — these genetic elements naturally appeared in a single laboratory stock of fruit flies in Hawley’s lab. Now, the researchers are witnessing chromosome birth and evolution in less than two decades.

How does something like this new chromosome apparently arise from nothing? More important, as these newly born B chromosomes do not possess any known essential genes for fruit fly function, how do they persist in a genome? In short, by cheating.
“I like to call these B chromosomes genetic renegades,” said Hanlon. “They do not follow the rules.”
Hanlon discovered that the fruit fly B chromosomes are maintained by a mechanism called “meiotic drive” that enables the them to rebel against the usual rules of inheritance. The B chromosomes drive their way into the next generation during the formation of the egg to ensure their own persistence in more than half of the next generation.
“Their genetic background — meaning the unique features in the B chromosome flies’ genetic make-up — supports their preferential transmission to the next generation,” said Hanlon. “That buys these guys evolutionary time to become a new chromosome, whether that’s picking up an essential gene or acquiring something that enables them to better cheat.”
Importantly, meiotic drive is a powerful force that can shape how genomes evolve. These findings originating in the Hawley Lab and actively investigated by Hanlon, now in her own lab at the University of Connecticut, can be used to understand the mechanisms behind what keeps meiosis fair and ensures that cheaters, like the B chromosomes, do not prosper. Additionally, Hanlon is examining how specific mutations can lead to chromosome breakage and new chromosome formation, revealing the mechanism of how supernumeraries arise and become requisite components of a genome.
“We’re always looking for Achilles heels to get rid of these kinds of things,” said Hawley of problematic supernumeraries in humans. “If we can identify what encouraged their formation, we may be able to identify individuals more likely to form them and take better measures to look for and deal with them.”
This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (award K99/R00HD099276) of the National Institutes of Health (NIH) and by institutional support from the Stowers Institute for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Neuropathic pain — abnormal hypersensitivity to stimuli — is associated with impaired quality of life and is often poorly managed. Estimates suggest that 3 percent to 17 percent of adults suffer from neuropathic pain, including a quarter of people with diabetes and a third of people with HIV.
In a paper published in the journal Neuron, researchers report that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord both initiates and maintains neuropathic pain. Moreover, they show that targeting spinal Tiam1 with anti-sense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity.
“Thus, our study has uncovered a pathophysiological mechanism that initiates, transitions and sustains neuropathic pain, and we have identified a promising therapeutic target for treating neuropathic pain with long-lasting consequences,” said Lingyong Li, Ph.D., an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively.”
Li and Kimberley Tolias, Ph.D., a professor at Baylor College of Medicine in Houston, Texas, were co-leaders of the research.
It was known that one feature of neuropathic pain is maladaptive changes in neurons of the spinal dorsal horn — increases in the size and density of dendritic spines, the primary postsynaptic sites of excitatory synapses. However, the mechanisms driving this synaptic plasticity were unclear. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons. The spinal dorsal horn is one of the three gray columns of the spinal cord.
In related work, Li and Tolias last year found that chronic pain in a mouse model leads to an activated Tiam1 in anterior cingulate cortex pyramidal neurons of the brain, resulting in an increased number of spines on the neural dendrites. 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 chronic pain-related depression in the mouse model.

The current neuropathic pain study by Li and Tolias used mouse models of neuropathic pain caused by nerve injury, chemotherapy or diabetes. The researchers showed that Tiam1 is activated in the spinal dorsal horn of mice subjected to neuropathic pain and that global knockout of Tiam1 in mice prevented the development of neuropathic pain. Global knockout causes no other apparent abnormalities in the mice.
The UAB and Baylor researchers found that Tiam1 expression in the spinal dorsal horn neurons — but not in the dorsal root ganglion neurons or excitatory forebrain neurons — was essential for the development of neuropathic pain. Furthermore, they found that neuropathic pain development depended on Tiam1 expression in excitatory neurons — not in inhibitory neurons.
After showing where Tiam1 acts in neuropathic pain, Li, Tolias and colleagues showed what Tiam1 does. Tiam1 is known to modulate the activity of other proteins that help build or unbuild the cytoskeletons of cells, and the building of cytoskeleton actin filaments is part of dendritic spine creation. The researchers found that Tiam1 is necessary during the development of neuropathic pain to increase the density of dendritic spines on wide dynamic range neurons from the spinal dorsal horn and to increase synaptic NMDA receptor activity of spinal dorsal horn neurons.
Tiam1 functions to activate the small GTPase Rac1 enzyme that promotes actin polymerization. The researchers showed that the development of Tiam1-mediated neuropathic pain was dependent on Tiam1-Rac1 signaling. They then used a small molecule inhibitor to block Rac1 activation at three different time points — right after peripheral nerve injury, four days after nerve injury when neuropathic pain hypersensitivity gradually develops, or three weeks after nerve injury when chronic neuropathic pain is fully established. They found that neuropathic pain was prevented or reversed at each time point. Thus, Tiam1-Rac1 signaling is essential for the initiation, transition and maintenance of neuropathic pain.
Since Tiam1 appeared to be a promising therapeutic target for treating neuropathic pain, Li and Tolias also tested whether they could reduce neuropathic pain by injecting antisense oligonucleotides, or ASOs — short, synthetic, single-stranded oligodeoxynucleotides designed to alter Tiam1 expression by modulating its mRNA processing or degradation — into the cerebrospinal fluid of the spine.

In a rat model, they found that injecting an ASO against Tiam1 decreased Tiam1 protein levels in the spinal dorsal horn by 50 percent and significantly reduced neuropathic pain hypersensitivity one week after injection, a reduction that lasted another two weeks.
Therefore, Tiam1 is an essential player in the pathogenesis of neuropathic pain that coordinates actin cytoskeletal dynamics, dendritic spine morphogenesis and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage, Li and Tolias say.
The two researchers are corresponding authors of the study, “Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain.”
Co-authors are Qin Ru, Yungang Lu, Xing Fang and Ali Bin Saifullah, Baylor College of Medicine; Guanxing Chen, University of Texas MD Anderson Cancer Center, Houston, Texas; and Changqun Yao, UAB Department of Anesthesiology and Perioperative Medicine.
Support came from the United States Department of Defense grant W81XWH-20-10790, the Mission Connect/TIRR Foundation, and National Institutes of Health grants NS062829 and NS124141.
At UAB, Anesthesiology and Perioperative Medicine is a department in the Marnix E. Heersink School of Medicine.

A deep slumber might help buffer against memory loss for older adults facing a heightened burden of Alzheimer’s disease, new research from the University of California, Berkeley, suggests.
Deep sleep, also known as non-REM slow-wave sleep, can act as a “cognitive reserve factor” that may increase resilience against a protein in the brain called beta-amyloid that is linked to memory loss caused by dementia. Disrupted sleep has previously been associated with faster accumulation of beta-amyloid protein in the brain. However, the new research from a team at UC Berkeley reveals that superior amounts of deep, slow-wave sleep can act as a protective factor against memory decline in those with existing high amounts of Alzheimer’s disease pathology — a potentially significant advance that experts say could help alleviate some of dementia’s most devastating outcomes.
“With a certain level of brain pathology, you’re not destined for cognitive symptoms or memory issues,” said Zsófia Zavecz, a postdoctoral researcher at UC Berkeley’s Center for Human Sleep Science. “People should be aware that, despite having a certain level of pathology, there are certain lifestyle factors that will help moderate and decrease the effects.
“One of those factors is sleep and, specifically, deep sleep.”
The research, published Wednesday in the journal BMC Medicine, is the latest in a large body of work aimed at finding a cure for Alzheimer’s disease and preventing it altogether.
As the most prevalent form of dementia, Alzheimer’s disease destroys memory pathways and, in advanced forms, interferes with a person’s ability to perform basic daily tasks. Roughly one in nine people over age 65 have the progressive disease — a proportion that is expected to grow rapidly as the baby boomer generation ages.

In recent years, scientists have probed the ways that deposits of beta-amyloid associate with Alzheimer’s disease and how such deposits also affect memory more generally. In addition to sleep being a foundational part of memory retention, the team at UC Berkeley previously discovered that the declining amount of a person’s deep sleep could act as a “crystal ball” to forecast a faster rate of future beta-amyloid buildup in the brain, after which dementia is more likely set in.
Years of education, physical activity and social engagement are widely believed to shore up a person’s resilience to severe brain pathology — essentially keeping the mind sharp, despite the decreased brain health. These are called cognitive reserve factors. However, most of them, such as past years of education or the size of one’s social network, cannot be easily changed or modified retroactively.
That idea of cognitive reserve became a compelling target for sleep researchers, said Matthew Walker, a UC Berkeley professor of neuroscience and psychology and senior author of the study.
“If we believe that sleep is so critical for memory,” Walker said, “could sleep be one of those missing pieces in the explanatory puzzle that would tell us exactly why two people with the same amounts of vicious, severe amyloid pathology have very different memory?”
“If the findings supported the hypothesis, it would be thrilling, because sleep is something we can change,” he added. “It is a modifiable factor.”
To test that question, the researchers recruited 62 older adults from the Berkeley Aging Cohort Study. Participants, who were healthy adults and not diagnosed with dementia, slept in a lab while researchers monitored their sleep waves with an electroencephalography (EEG) machine. Researchers also used a positron emission tomography (PET) scan to measure the amount of beta-amyloid deposits in the participants’ brains. Half of the participants had high amounts of amyloid deposits; the other half did not.

After they slept, the participants completed a memory task involving matching names to faces.
Those with high amounts of beta-amyloid deposits in their brain who also experienced higher levels of deep sleep performed better on the memory test than those with the same amount of deposits but who slept worse. This compensatory boost was limited to the group with amyloid deposits. In the group without pathology, deep sleep had no additional supportive effect on memory, which was understandable as there was no demand for resilience factors in otherwise intact cognitive function.
In other words, deep sleep bent the arrow of cognition upward, blunting the otherwise detrimental effects of beta-amyloid pathology on memory.
In their analysis, the researchers went on to control for other cognitive reserve factors, including education and physical activity, and still sleep demonstrated a marked benefit. This suggests that sleep, independent of these other factors, contributes to salvaging memory function in the face of brain pathology. These new discoveries, they said, indicate the importance of non-REM slow-wave sleep in counteracting some of the memory-impairing effects of beta-amyloid deposits.
Walker likened deep sleep to a rescue effort.
“Think of deep sleep almost like a life raft that keeps memory afloat, rather than memory getting dragged down by the weight of Alzheimer’s disease pathology,” Walker said. “It now seems that deep NREM sleep may be a new, missing piece in the explanatory puzzle of cognitive reserve. This is especially exciting because we can do something about it. There are ways we can improve sleep, even in older adults.”
Chief among those areas for improvement? Stick to a regular sleep schedule, stay mentally and physically active during the day, create a cool and dark sleep environment and minimize things like coffee late in the day and screen time before bed. A warm shower before turning in for the night has also been shown to increase the quality of deep, slow-wave sleep, Zavecz said.
With a small sample size of healthy participants, the study is simply an early step in understanding the precise ways sleep may forestall memory loss and the advance of Alzheimer’s, Zavecz said.
Still, it opens the door for potential longer-term experiments examining sleep-enhancement treatments that could have far-reaching implications.
“One of the advantages of this result is the application to a huge population right above the age of 65,” Zavecz said. “By sleeping better and doing your best to practice good sleep hygiene, which is easy to research online, you can gain the benefit of this compensatory function against this type of Alzheimer’s pathology.”

Goldenhar syndrome is a rare congenital disease, affecting early foetal development. This syndrome includes malformations of varying severity, affecting different parts of the face. Its causes and modes of transmission are still poorly understood. An international collaboration led by the University of Geneva (UNIGE) and Beihang University, in China, has discovered that pathogenic variants of the FOXI3 gene — responsible for the development of the ear — cause one form of this developmental disorder. The scientists were also able to identify the modes of transmission of the disease when this particular gene is involved. These results can be found in Nature Communications.
First described in 1952 at the University of Geneva (UNIGE) by the ophthalmologist Maurice Goldenhar (1924-2001), Goldenhar syndrome or oculo-auriculo-vertebral dysplasia is a rare congenital disorder with facial asymmetry, malformations of the auditory and ocular systems, and spinal column anomalies, sometimes associated with mental retardation. It varies greatly in expression and severity depending on the individual and is thought to affect approximately one in 3,500 to 5,600 births.
This syndrome is caused by mutations that appear during foetal development. Do these mutations occur spontaneously or is there an inherited form of the disease? The mode of transmission and the molecular mechanisms involved are still poorly understood. A recent international research effort, led by a joint team from the UNIGE and Beihang University, in China, is providing new elements for understanding the disease. The scientists have identified a gene — FOXI3 — whose pathogenic variants are involved in one form of the disease.
A gene that builds the ear
”FOXI3 is critically involved in the development of the ear. It is an architect gene: it produces a protein that acts as a transcription factor. In other words, it controls the expression of other genes to start the construction of the ear,” explains Stylianos Antonarakis, Emeritus Professor at the UNIGE Faculty of Medicine and co-last author of the study, which was funded by the ChildCare Foundation in Geneva.
To determine the role of FOXI3, the scientists used the genetic profiles of a highly consanguineous Pakistani family involved in a larger research project on rare diseases. In this family, two brothers have the syndrome but not their parents, nor the other four siblings. Both patients have pathogenic mutations in both copies of the FOXI3 gene, while several other members of this family, who do not have Goldenhar syndrome, have a mutation in only one copy of the gene.
”This first analysis allowed us to confirm that pathogenic mutations in both copies of the FOXI3 gene, each inherited from a parent, are necessary for a form of the disease to develop,” explains Stylianos Antonarakis. This is called autosomal recessive inheritance.
Responsible for one form of the disease
To find out whether pathogenic variants in FOXI3 and their autosomal recessive inheritance are systematically involved, the researchers also analysed the genetic profiles of 670 unrelated patients in Europe and China. ”Eighteen pathogenic variants in the FOXI3 gene were identified in twenty-one patients. FOXI3 is therefore only one of the genes that can cause the disease, precisely the specific form observed in our Pakistani patients,” explains Ke Mao, researcher at Beihang University and co-first author of the study with Christelle Borel, senior research associate in the Department of Genetic Medicine and Development at the UNIGE Faculty of Medicine, and Muhammad Ansar, senior research and teaching assistant in the same department and head of the ”Eye Genetics” research group at the Jules-Gonin eye hospital.
Another finding that baffled the researchers was that the mode of inheritance, in many other cases, is seemingly autosomal dominant. In this case, only one of the two copies of the gene needs to carry the mutation for the disease to occur. By carefully studying the genome around the FOXI3 gene, scientists have solved this mystery. There is a functional and frequent, but specific, variant of one copy of the FOXI3 gene that, in combination with a severe mutation in the other copy of the FOXI3 gene, also causes the disorder.
”We also created mouse models with mutations in the FOXI3 gene to validate the results obtained in human families. These mice showed facial deformities equivalent to human characteristics,” adds Professor Yong-Biao Zhang of Beihang University, the study’s co-lead author. These results provide crucial elements for understanding this syndrome and would explain in part the extensive heterogeneity of the disease. They also pave the way for the study of other genes that may be involved in the disease, but also in the healthy development of certain parts of the face, the mechanisms of which are still poorly understood.

Triple-negative breast cancer (TNBC) is the most aggressive and deadly form of breast cancer with limited treatment options and a high probability of recurrence. Tumor growth and relapse of TNBC are driven by breast cancer stem cells, and improved therapies that can eliminate those hardy cells are urgently needed. Researchers from the University of Frieburg discovered that coordinated differentiation and changes in the metabolism of breast cancer stem cells make them invisible for the immune system. Counteracting the metabolic change with the drug zolendronate could make immunotherapy using gamma delta T cells more efficient against TNBC. The research team was led by Prof. Dr. Susana Minguet from the Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies at the University of Freiburg, in collaboration with Dr. Jochen Maurer from the University Hospital RWTH Aachen, Dr. Mahima Swamy from the Universtiy of Dundee/Scotland and collaborators from the University Hospital Freiburg. The study was published in the Journal Cancer Immunology Research, a journal of the American Association for Cancer Research.
TNBC cells hide from gamma delta T cells
Gamma delta T cells recognize and kill cells that produce stress-induced molecules and phosphoantigens, a common characteristic of cancer cells. Because gamma delta T cells work differently to other types of T cells, they are being investigated as an alternative to existing immunotherapies. In the current study, the researchers tested the effect of gamma delta T cells on TNBC using isolated cancer cells and a recently developed mouse model that closely replicates the tumor properties found in human patients.
While the gamma delta T cells worked well against isolated breast cancer stem cells from patients, they had a much weaker effect in the mouse model. This was due to adaptations of the cancer cells that let them stay unnoticed by the immune system, the researchers found. These adaptations included the downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens — one of the classes of molecules that gamma T cells recognize. This escape mechanism likely also happens in patients with TNBC: analysis of public patient databases showed that reduced expression of key molecules of the mevalonate pathway correlate with a worse prognosis.
The immune evasion of TNBC cells is reversible
This newly discovered escape mechanism can be counteracted by the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastasis. When the researchers treated the escapist cells with zolendronate, the gamma T cells became a lot more efficient in clearing the cancer. “Our findings explain why current clinical trials using gamma delta T cells are not resulting in the expected success,” Minguet summarizes. “We found a possible pharmacological-based approach to revert immune escape, which paves the way for novel combinatorial immunotherapies for triple negative breast cancer.”

This was observed in a study conducted at the Gerontology Research Center at the Faculty of Sport and Health Sciences, University of Jyväskylä (Finland). The study examined differences in depressive symptoms and life satisfaction between current 75- and 80-year-olds and the same-aged people who lived in the 1990s.
The results showed that 75- and 80-year-old men and women today experience fewer depressive symptoms than those who were 75 and 80 years old in the 1990s. The differences were partly explained by the better perceived health and higher education of those born later.
“In our previous comparisons, we found that older people today have significantly better physical and cognitive functioning at the same age compared to those born earlier,” says Professor Taina Rantanen from the Faculty of Sport and Health Sciences. “These new results complement these positive findings in terms of mental well-being.”
Today, 75- and 80-year-olds are more satisfied with their lives to date. However, there was no similar difference in satisfaction with their current lives. In fact, 80-year-old men who lived in the 1990s were even more satisfied with their current lives than 80-year-old are men today.
“These men born in 1910 had lived through difficult times, which may explain their satisfaction with their current lives in the 1990s when many things were better than before,” says postdoctoral researcher Tiia Kekäläinen.
“Individuals adapt to their situation and living conditions. Both in the 1990s and today, the majority of older adults reported being satisfied with their current lives.”
The study was conducted at the Faculty of Sport and Health Sciences and Gerontology Research Center at University of Jyväskylä, Finland. The first cohort consisted of 617 individuals born in 1910 and 1914 who participated in the Evergreen study in 1989-1990. The second cohort consisted of 794 individuals born in 1938-1939 and 1942-1943 who participated in the AGNES study in 2017-2018. In both cohorts, the participants were assessed at the age of 75 or 80 years. The study was funded by the Academy of Finland and the European Research Council.

The study led by Professor Julie Henry from UQ’s School of Psychology looked at why self-directed ageism is common.
“Older people are regularly exposed to ageism such as negative assumptions about their worth, capacity or level of understanding, as well as jokes about older age,” Professor Henry said.
“At the same time, as we grow older, we rely more strongly on prior knowledge and cues from our environment to guide how we feel, think and behave.
“In a world that devalues ageing, these cognitive changes make it more difficult for older people to challenge internalised ageist beliefs, known as self-directed ageism.”
Self-directed ageism can present as self-doubt — ‘I’m too old to learn this new technology’ or ‘I’m too old to make new friends’ — and negative perceptions of one’s own aging, such as ‘I’m so much worse at this than I used to be’.
Self-directed ageism can also present as concern over being judged according to age-based stereotypes, such as ‘If I forget to do this, they’re going to think it’s because I’m old’.
Professor Henry said when ageism is internalised and becomes self-directed, it has been linked to a shorter lifespan, poorer physical and mental health, slower recovery from disability and cognitive decline.
“It can also be harmful when older adults allow their negative beliefs about ageing to undermine their confidence to take on new or challenging experiences and opportunities,” Professor Henry said.
“Interventions, such as creating more opportunities for positive social interactions between younger and older people, are needed to prevent negative views of ageing from developing in the first place.
“Our research also suggests that older adults will benefit directly from a reduction in cues to ageism in our wider social environment.
“If fewer ageist cues attract older people’s attention, the risk of self-directed ageism should be reduced.”
The paper is published in Trends in Cognitive Sciences.

Published35 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy James GallagherHealth and science correspondentA “very concerning” rise in the number of people catching measles in the UK has been reported by health officials. The virus spreads incredibly easily and a fall in vaccination rates is leaving more children vulnerable to infection.There were 54 cases of measles in the whole of last year. However, there have already been 49 in the first four months of 2023.The UK Health Security Agency (UKHSA) is encouraging parents to ensure their children’s vaccinations are up to date.The main symptoms of measles are a fever and a rash. But it can cause more serious complications including meningitis, and an infection can be fatal. That is why the measles, mumps and rubella (MMR) vaccine is part of routine childhood immunisations. Vaccination rates had been falling in the UK before the Covid pandemic. However, the disruption caused by Covid has dented vaccination programmes around the world, including in the UK, meaning even more children have missed out. The World Health Organization has already warned of a “perfect storm” for measles, because the fewer people who receive protection from vaccines, the easier it is for outbreaks to happen. Measles jumps from person to person so readily that 95% of people need to be immunised to block its spread. However, the UKHSA said only 85% of five-year-olds in England have received the recommended two doses. The increase in UK measles cases is centred on London, but there have been infections elsewhere. Twelve of the cases were caught while abroad, with the rest reflecting spread within the UK.”It is very concerning to see cases starting to pick up this year,” said Dr Vanessa Saliba, from the UKHSA. She added: “We are calling on all parents and guardians to make sure their children are up to date with their two MMR doses. It’s never too late to catch up, and you can get the MMR vaccine for free on the NHS whatever your age.” The UKHSA said it was particularly important to get vaccinated before the summer as measles may be more common in other countries, and festivals are a well-known source of measles outbreaks. Measles vaccinations were introduced in the UK in 1968. Since then, they are estimated to have prevented 20 million measles cases and 4,500 deaths.More on this storyUS sees biggest measles outbreak since 201929 December 2022Child measles warning as MMR jab rate drops1 February 2022