Yet scientists understand little about how this essential protein does its crucial work at the molecular level. “People have been studying this protein for decades without a clear consensus on what it is doing, where it binds to the genome, and what its functions are,” says Rockefeller’s Shixin Liu. Now, a new study from Liu’s laboratory sheds light on how the protein, MeCP2, interacts with DNA and chromatin.

The findings, published in Nature Structural & Molecular Biology, provide insight into this master regulator, and could open up new avenues for Rett syndrome therapies.

A single-molecule approach

MeCP2 is a baffling protein. While it has been implicated in the regulation of thousands of genes and is thought to be central to neurodevelopment, its impacts on the genome are tricky to pin down. Insufficient amounts of wildtype MeCP2 causes Rett syndrome, but too much of the protein causes a similarly debilitating neurological disorder known as MeCP2 duplication syndrome.

Liu and colleagues leveraged the lab’s area of expertise — single-molecule observation and manipulation — to better understand how MeCP2 interacts with DNA. The team tethered a single piece of DNA between micron-sized plastic beads, each held by a laser, and then incubated the DNA with fluorescently labeled MeCP2 proteins. This setup allowed them to closely monitor the mysterious protein’s dynamic behavior.

MeCP2 is generally thought to exclusively perform its functions on DNA that is modified with methylated cytosines, but lacked a satisfactory explanation for such specificity, since the protein readily binds both methylated and unmethylated DNA. The team found that MeCP2 dynamically moves on DNA, but in a much slower manner in regards to the methylated form compared to the unmethylated one. They further showed that these different dynamics allow MeCP2 to recruit another regulatory protein more efficiently to methylated DNA sites, which may help direct MeCP2’s gene regulatory functions towards specific locations within the genome. “We found that MeCP2 slides along unmethylated DNA faster, and this difference in motion may explain how the protein differentiates between the two,” says Gabriella Chua, a graduate fellow in Liu’s lab and first author on the paper.

“That’s something we could only have discovered using a single-molecule technique.”

Liu and Chua also found that the protein shows a very strong preference for binding to nucleosomes, protein spools that are wound with our genetic material, over bare DNA. This interaction stabilizes nucleosomes in a way that may suppress gene transcription — hinting at how MeCP2 itself regulates gene expression.

New thinking about nucleosomes

The observation that a master regulator of gene expression most often interacts with this tightly wound form of DNA helps bolster a growing notion that nucleosomes are far more than inert “storage spools” of DNA, and that scientists need to begin thinking of MeCP2’s function more in the context of nucleosomes.

“Our data is one of the most definitive examples of this phenomenon to date,” Liu says. “It’s clear that MeCP2 prefers binding to nucleosomes.” In this way, MeCP2 functions as a chromatin-binding protein, contrasting the conventional view that sees it chiefly as a methyl-DNA-binding protein. In this study, the team has also narrowed in on the part of the protein that is responsible for its nucleosome-binding activity.

“Bare DNA is in the minority — nucleosomes are pervasive in our genomes,” Chua says. “Several recent studies have demonstrated that nucleosomes are not merely passive barriers to transcription, but active hotspots for gene regulation.” A particularly striking example of such nucleosome functionality is how MeCP2 interacts with it.

In future work, the team plans to expand beyond the present in vitro study to examine MeCP2 in vivo, where interactions between the protein and the nucleosome are expected to be more complex. They also intend to use the techniques described in this paper to better study the many MeCP2 mutations that cause diseases such as Rett syndrome. The hope is that a more complete understanding of the protein central to this devastating disease may one day lead to therapies. “There’s no cure for Rett, but the community of researchers studying it are determined and energized. Many found our data intriguing when we shared it with them,” Chua says. “Our findings highlight how basic research can help the clinical community better understand a disease.”

Films are an interesting phenomenon for psychologists. “Films are so fascinating because they not only depict every human emotion, but they also evoke them. Negative emotions, such as anger or fear, play a central role in many films,” says Esther Zwiky, a psychologist at MLU. Up until recently, relatively little was known about the connection between film preferences and the processing of negative emotions in the brain.

The researchers investigated this interplay in detail by analysing data from 257 people. As part of a larger study, the respondents also provided information about their film preferences. In addition, the participants’ brain activity was analysed using functional magnetic resonance imaging (fMRI). Subjects were shown fearful or angry faces and geometric shapes while lying in an MRI machine. “With this established test, we can measure how the brain processes emotional stimuli,” explains Zwiky.

The researchers focused on two areas of the brain. First, the amygdala, which is responsible for processing vital emotions. “The amygdala can trigger a fight-or-flight reaction in response to threats,” says Zwiky. The team also investigated the neuronal activity of the nucleus accumbens, known as the reward centre in the brain.

The results were surprising: “We found that fans of action films showed the strongest reactions in both areas. We hadn’t expected this, as action films typically provide many stimuli. Thus, it would have made more sense if action fans had been less easy to stimulate,” Zwiky continues. However, the results suggest that action film aficionados are particularly susceptible to emotional stimuli and find this stimulation appealing. The team found similar brain activity in the brains of people who preferred comedies. A different picture emerged, however, for fans of crime films or thrillers and documentaries. Here, both areas of the brain reacted significantly less to the emotional stimuli than in the other groups of participants. “It appears that people choose the film genres that most optimally stimulate their brains,” concludes Zwiky.

“Only about 65% of women over age 40 are screened for breast cancer, and only about half of those women are getting annual screening — in part because of conflicting guidelines about recommended screening intervals,” said lead author Margarita Zuley, M.D., professor and chief of the Division of Breast Imaging in the Department of Radiology at Pitt and UPMC. “Our study shows that there is a significant benefit for annual screening over biennial screening, including in premenopausal women.”

While many clinical trials have demonstrated the benefits of mammography screening for breast cancer, guidelines differ on how often women should be screened. The American College of Radiology and several other organizations advise annual screening after age 40, whereas the U.S. Preventive Services Task Force recommends biennial screening from age 40.

Because the U.S. does not have a national breast cancer registry, Zuley and her team recently developed a large institutional database to better understand real-world outcomes for breast cancer patients.

To gain more evidence on optimal mammography screening intervals, the researchers used this database to compare 8,145 breast cancer patients who had at least one mammogram on record prior to diagnosis. The screening interval was considered annual if the time between mammograms was less than 15 months, biennial if between 15 and 27 months, and intermittent if greater than 27 months.

The percentage of late-stage cancers — TNM stage IIB or worse — was 9%, 14% and 19% for annual, biennial and intermittent screening groups, respectively. Biennial and intermittent groups had substantially worse overall survival than the annual group.

“The percentage of late-stage cancers increased significantly with increased screening intervals,” said Zuley. “Annual mammograms are crucial for early detection of breast cancer, which increases the likelihood of survival, decreases harms to patients because treatment may not need to be as intense, makes recovery easier and can lower the cost of care.”

One concern with more frequent mammograms is the increased risk of false positives, leading to unnecessary biopsies and anxiety.

“We recognize that there are potential harms associated with calling women back for additional screening, but I don’t think that these harms outweigh the risk of missing cancers and women dying as a result,” said Zuley. “We’re also working on testing screening tools that have lower false positives than mammography and pushing on every front to identify the most cost-effective and accurate way of taking care of our patients.”

Other authors on the study were Andriy Bandos, Ph.D., Durwin Logue, Rohit Bhargava, M.D., Priscilla McAuliffe, M.D., Ph.D., Adam Brufsky, M.D., Ph.D., and Robert M. Nishikawa, Ph.D., all of Pitt and UPMC; and Stephen Duffy, Ph.D., of Queen Mary University of London.

This research was supported in part by the National Cancer Institute (P30CA047904).

The authors found that 3 to 5% of women in the United States who had their tubes tied later reported an unplanned pregnancy. This failure rate led the authors to suggest that patients who really want to avoid future pregnancy should instead use a contraceptive arm implant or intrauterine device (IUD).

The paper appears August 27 in NEJM Evidence.

Interest in permanent contraception has risen since the 2022 U.S. Supreme Court Dobbs decision removed federal protections for abortion services and limited access to abortion services in many states. As a result, the researchers say that information about contraceptive effectiveness is especially important.

“Since the Dobbs decision, many more people are worried about how pregnancy may impact their health and family life,” said first author Eleanor Bimla Schwarz, MD, chief of the UCSF Division of General Internal Medicine at Zuckerberg San Francisco General. “This is especially true for patients with medical conditions like diabetes and high blood pressure that can complicate pregnancy.

“This study shows that tubal surgery cannot be considered the best way to prevent pregnancy,” Schwarz said. “People using a contraceptive arm implant or an IUD are less likely to become pregnant than those who have their tubes tied.”

Many U.S. women get tubal surgeries

About 65 percent of women 15 to 49 in the U.S. use birth control, according to national statistics, and tubal sterilization — an abdominal surgery in which the fallopian tubes are clamped or cut and removed — is used by more than 21% of women ages 30 to 39, and 39% of women older than 40. These surgeries are especially common among low-income people and those with chronic medical conditions.

Tubal sterilization aims to permanently end fertility, but as previously reported, women can nonetheless get pregnant. Based on older studies, the American College of Obstetricians and Gynecologists has advised that fewer than 1% of patients become pregnant after tubal sterilization.

In the new study, the authors examined four independent rounds of the National Survey of Family Growth from 2002 to 2015. Data were collected from more than 31,000 women, including 4,184 who reported having undergone tubal sterilization and were the focus of the study.

Within the first year after tubal surgery, the researchers estimated that 2.9% of those who reported having been sterilized in 2013 to 2015 became pregnant. The chance of pregnancy was highest among those who were younger at the time of their tubal surgery.

Patients who had Medicaid-funded procedures were not more likely than those with private insurance to become pregnant. In recent years, the proportion of respondents who reported a tubal sterilization funded by Medicaid has increased from 18% in 2002 to about 36% from 2013 to 2015.

“When choosing what birth control will work best for them, people consider many different things including safety, convenience and how fast they can start to use the method,” Schwarz said. “For people who have chosen a ‘permanent’ method, learning they got pregnant can be very distressing. It turns out this is unfortunately a fairly common experience.”

Led by Ludwig Lausanne’s Ping-Chih Ho and Alessio Bevilacqua and published in the current issue of Science Immunology, the study identifies PPARβ/δ, a master regulator of gene expression, as that essential molecular switch. Ho, Bevilacqua and their colleagues also show that the switch’s dysfunction compromises T cell “memory” of previously encountered viruses as well as the induction of anticancer immune responses in mice.

“Our findings suggest that we might be able to engage this switch pharmacologically to improve the efficacy of cancer immunotherapies,” said Ho.

When killer (or CD8+) T cells, which kill sick and cancerous cells, are activated by their target antigen, they switch on metabolic pathways that most other healthy cells only use when starved of oxygen. This type of metabolism — involving a metabolic process known as aerobic glycolysis — supports multiple processes essential to the killer T cell’s ability to proliferate and destroy its target cells.

Most killer T cells die off after they’ve cleared an infection. A few, however, transform into central memory CD8+ T cells (Tcms) that linger in the circulation to establish what we call immunity: the ability to mount a swift and lethal response to the same pathogen if it is ever encountered again. To achieve this transformation, T cells switch off aerobic glycolysis and otherwise adapt their metabolism to persist over the long term in tissues or in the circulation. How precisely they do this was until now unknown.

Aware that PPARβ/δ activates many of the metabolic processes characteristic of Tcms, Ho, Bevilacqua and their colleagues hypothesized it might play a key role in Tcm formation. They examined immunologic gene expression data collected from yellow fever vaccine recipients long after vaccination and, as expected, saw that the PPARβ/δ was produced abundantly in their Tcms.

Their studies in mice revealed that PPARβ/δ is activated in T cells not in the peak phase of the immune response to viral infection but as that response winds down. Further, CD8+ T cells were unable to make the metabolic switch required to become circulating Tcms if they failed to express PPARβ/δ. Disrupting its expression impaired survival of such Tcms and resident memory T cells in the intestines following infection.

The researchers show that T cell exposure to interleukin-15 — an immune factor important for Tcm formation — and their expression of a protein named TCF1 engages the PPARβ/δ pathway. TCF1 is already known to be critical to the rapid expansion of Tcms when they encounter their target pathogen. The researchers show in this study that it is also important to the maintenance of TCMs.

As it happens, TCF1 expression is a hallmark of a subset of CD8+ T cells — progenitor-exhausted T cells — that are found in tumors. These progenitor-exhausted T cells follow one of two paths: they either become completely lethargic, “terminally exhausted” T cells; or, given the appropriate stimulus, proliferate to produce “effector” CD8+ T cells that kill cancer cells. Checkpoint blockade immunotherapies, like anti-PD-1 antibodies, can provide such stimulus.

The observation that TCF1 modulates the PPARβ/δ pathway in T cells raised the possibility that it might also be essential to the formation and maintenance of progenitor-exhausted T cells. The researchers showed that this is indeed the case. Deleting the PPARβ/δ gene from T cells led to the loss of progenitor-exhausted T cells in a mouse model of melanoma. They also demonstrate that the PPARβ/δ pathway curtails the tendency of progenitor-exhausted T cells to stagger toward terminal exhaustion.

To assess the therapeutic potential of their findings, Ho, Bevilacqua and their colleagues exposed T cells to a molecule that stimulates PPARβ/δ activity and used the treated cells against a mouse model of melanoma. These cells delayed the growth of melanoma tumors in mice more efficiently than their untreated counterparts and bore biochemical hallmarks of progenitor exhausted T cells primed to generate cancer-killing descendants.

“Based on these findings,” said Bevilacqua, “we suggest that targeting PPARβ/δ signaling may be a promising approach to improve T cell-mediated anti-tumor immunity.

How exactly this might be achieved in people is a subject for further study that will doubtless be pursued by the Ho laboratory.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the European Research Council, the Swiss Cancer Foundation, the Cancer Research Institute, Helmut Horten Stiftung, the Melanoma Research Alliance, the Taiwan Ministry of Science and Technology, the NYU Abu Dhabi Research Institute Award and Academia Sinica.

Ping-Chih Ho is a member of the Lausanne Branch of the Ludwig Institute for Cancer Research and a full professor at the University of Lausanne.

“As pharmacies close, more and more Americans are left without easy access to medications, with disproportionate consequences on certain communities. We found that patients in counties with higher social vulnerabilities and fewer primary care providers were up to 40% more likely to reside in a region with a pharmacy desert,” said Timothy Pawlik, MD, senior author of the study and holder of the Urban Meyer III and Shelley Meyer Chair for Cancer Research at the OSUCCC — James. Pawlik also serves as surgeon-in-chief at The Ohio State University Wexner Medical Center and as chair of the Department of Surgery in the Ohio State College of Medicine.

The U.S. Centers for Disease Control (CDC) defines social vulnerability as “potential negative effects on communities caused by external stresses on human health.”

“These findings highlight how disparities compound the lack of access to basic health care and how it can lead to many people not taking their prescribed medications and having worse health outcomes, especially for chronic conditions like diabetes and hypertension,” Pawlik added.

Study results were published today in JAMA Network Open.

Methods and Results

Researchers reviewed data on communities located less than 10 miles from the nearest retail pharmacy from the publicly available TelePharm Map. Counties were noted as having a high pharmacy desert density if the number of pharmacy deserts per 1,000 residents was in the 75th percentile. Social vulnerability index (SVI) and healthcare provider data were obtained from the CDC’s Agency for Toxic Substances and Disease Registry and the Area Health Resource File databases, respectively. The researchers used statistical methods to analyze the relationships between these factors.

The study found almost 46% of the 3,143 counties had at least one pharmacy desert. Counties with a high density of pharmacy deserts had higher social vulnerability and fewer primary care providers. People in these high-density pharmacy desert areas were more likely to face difficulties accessing medications and healthcare services.

Collaborators in this study include Giovanni Catalano, MD, Muhammad Muntazir Mehdi Khan, MBBS, and Odysseas P. Chatzipanagiotou, MD.

Researchers recruited participants experiencing prolonged stress from the COVID-19 pandemic for a two-week randomized controlled trial. Half of the participants were randomly assigned to a nondeceptive placebo group and the other half to the control group that took no pills. The participants interacted with a researcher online through four virtual sessions on Zoom. Those in the nondeceptive placebo group received information on the placebo effect and were sent placebo pills in the mail along with and instructions on taking the pills.

The study, published in Applied Psychology: Health and Well-Being, found that the nondeceptive group showed a significant decrease in stress, anxiety and depression in just two weeks compared to the no-treatment control group. Participants also reported that the nondeceptive placebos were easy to use, not burdensome and appropriate for the situation.

“Exposure to long-term stress can impair a person’s ability to manage emotions and cause significant mental health problems long-term, so we’re excited to see that an intervention that takes minimal effort can still lead to significant benefits,” said Jason Moser, co-author of the study and professor in MSU’s Department of Psychology. “This minimal burden makes nondeceptive placebos an attractive intervention for those with significant stress, anxiety and depression.”

The researchers are particularly hopeful in the ability to remotely administer the nondeceptive placebos by health care providers.

“This ability to administer nondeceptive placebos remotely increases scalability potential dramatically,” said Darwin Guevarra, co-author of the study and postdoctoral scholar at the University of California, San Francisco, “Remotely administered nondeceptive placebos have the potential to help individuals struggling with mental health concerns who otherwise would not have access to traditional mental health services.”

The study, published in BMC Biology, is the first to successfully edit genomes in Nile grass rats. As diurnal rodents, Nile grass rats have similar sleep/awake patterns to humans which could be advantageous in preclinical or translational research.

Currently, preclinical research relies heavily on laboratory mice, which are nocturnal rodents who are active at night and sleep during the day. With these different sleep patterns, diurnal and nocturnal mammals have evolved differently, including having a distinct wiring of neural circuits and gene-regulatory networks.

“The differences between diurnal and nocturnal mammals present a significant translational flaw when applying the research findings obtained from mice to humans. Numerous therapeutic agents such as neuroprotectants proven effective in mouse or rat models of cerebral ischemia have failed in human clinical stroke trials, with mounting evidence suggesting the nocturnal and diurnal differences causing such failures,” said Lily Yan, co-author of the study and professor in MSU’s Department of Psychology.

Katrina Linning-Duffy and Jiaming Shi, also co-authors on the research, work in Yan’s Lab.

Because the differences between diurnal and nocturnal animals are complex, the researchers believe a diurnal model is essential to untangle the relationship between genes and behaviors that are relevant to human health and disease.

The method developed includes a superovulation protocol that can yield nearly 30 eggs per female. They also developed protocols for in vitro — outside of the body — embryo culture and manipulation and in vivo — in the living body — gene targeting using GONAD, or Genome editing via Oviductal Nucleic Acids Delivery, methods.

The Nile grass rat colony is a unique resource available at MSU. Thanks to the joint efforts of the departments of Psychology and Integrative Biology and the Transgenic and Genome Editing Facility, a Nile grass rat colony was established on campus in 1993.

Research projects at MSU involving Nile grass rats have been continuously funded for more than 30 years. Animals from the MSU grass rat colony have been shared with over 20 research labs in the U.S., Canada, Belgium, China and Japan that study topics including circadian rhythms and sleep, mood and cognition, immune function, metabolic syndromes and evolutionary biology.

Huirong Xie is the program director of MSU’s Transgenic and Genome Editing Facility.

“We hope that Nile grass rats will eventually become an alternative mammalian model to investigate genes’ roles in any biological processes, particularly in which chronotype (diurnal vs. nocturnal) is a critical biological variable,” Yan said. “This study will be an essential first step towards the far-reaching goal.”

Co-authors on the research are Huirong Xie, program director of MSU Transgenic and Genome Editing Facility; Katrina Linning-Duffy and Jiaming Shi, who work in Yan’s Lab.

Dr. Pumpki Lei Su, an assistant professor of speech, language, and hearing in the School of Behavioral and Brain Sciences, is co-lead author on two recent articles in which researchers examined the sounds babies make. The results suggest that children in their first year are more active than previously thought in their acquisition of speech.

“We observed in these studies that infant vocalizations are not produced randomly; they form a pattern, producing three categories of sounds in clusters,” said Su, who also directs the Language Interaction and Language Acquisition in Children Lab (LILAC Lab) at the Callier Center for Communication Disorders. “The home recordings we analyzed included times when adults were interacting with their child and when children were on their own, showing that children explore their vocal capabilities with or without language input from an adult.”

One study, published May 29 in PLOS ONE, focused on typically developing infants, and the other, published Feb. 25 in the Journal of Autism and Developmental Disorders, focused on infants who later received a confirmed diagnosis of autism. The researchers documented how children “play” vocally, learning what actions produce certain sounds and then repeating that process.

Within the past 40 to 50 years, scientists have realized that vocalizations before a child’s first word are meaningful precursors for speech and can be broken into sequential stages of cooing, vocal play and babbling. Su’s team studied a dataset of all-day home recordings from more than 300 children amassed by the Marcus Autism Center, a subsidiary of Children’s Healthcare of Atlanta, and coded by senior author Dr. D. Kimbrough Oller’s team at The University of Memphis.

“Parents tell us that sometimes a baby will just scream or make low-frequency sounds for a really long period. But it’s never been studied empirically,” Su said. “With access to a huge dataset from hundreds of children during the first 12 months of their lives, we set out to quantitatively document how babies explore and cluster patterns as they practice different sound categories.”

Sound types are characterized by pitch and wave frequency as squeals, growls or vowellike sounds. The PLOS ONE study used more than 15,000 recordings from 130 typically developing children in the dataset. Infants showed significant clustering patterns: 40% of recordings showed significantly more squeals than expected by chance, and 39% showed clustered growls. Clustering was common at every age, with the highest rates occurring after 5 months of age.

“Of the 130 infants, 87% showed at least one age at which their recordings showed significant squeal clustering and at least one age with significant growl clustering,” Su said. “There was not a single infant who, on evaluation of all the available recordings, showed neither significant squeal nor growl clustering.”

Su said the study represents the first large-scale empirical study investigating the nonrandom occurrence of the three main sound types in infancy.

In the Journal of Autism and Developmental Disorders article, Su and her colleagues demonstrated that this exploration behavior also occurs during the first year in children who are later diagnosed with autism spectrum disorder.

“Whether or not a child is eventually diagnosed with autism, they are clustering sounds within one vocal category at a time,” Su said. “While one cannot rule out the possibility that some patterns may be mimicry, these are not just imitations; they are doing this with and without the presence of a parent, even in the first month of life. This process of learning to produce sounds is more endogenous, more spontaneous than previously understood.

“We tend to think babies are passive recipients of input. And certainly, parents are their best teachers. But at the same time, they’re doing a lot of things on their own.”

Su has received a three-year grant from the National Institute on Deafness and Other Communication Disorders (NIDCD) to study parents’ use of “parentese” — or baby talk — with autistic children. Parentese is an exaggerated style of speech often containing high-pitched elongated words and singsong diction.

Parentese is portrayed in the literature as a type of optimal input for typically developing children, who tend to pay better attention and respond to it more than they do to normal speech. It also helps children learn to segment words. But is it also ideal for autistic children?

“One hypothesis of why parentese works is that it encourages social interaction by being very animated,” Su said. “Autistic children have differences in social communication and responses to sensory stimuli. Would they also find parentese engaging? Could it be too loud or extreme? This new grant will allow me to examine whether parentese facilitates word learning for autistic children compared to a more standard adult-directed register.”

Other researchers who contributed to both articles include co-lead author Dr. Hyunjoo Yoo of The University of Alabama; Dr. Edina Bene from The University of Memphis; Dr. Helen Long of Case Western Reserve University; and Dr. Gordon Ramsay from the Emory University School of Medicine. Additional researchers from the Marcus Autism Center contributed to the Journal of Autism and Developmental Disorders study.

The research was funded by grants from the NIDCD (R01DC015108) and the National Institute of Mental Health (P50MH100029), both components of the National Institutes of Health.