The new research, recently published in the journal PLOS ONE, will help wildlife conservationists better understand the complex relationship between these two species and promote the management of both species. The project was made possible thanks to funding from the Wild Sheep Foundation and support from the Texas Parks & Wildlife Department.

Aoudad (pronounced “AH-dad”) originated in North Africa and were introduced to Texas for hunting opportunities in the late 1950s. Some wildlife experts estimate that there could be as many as 40,000 living in the state.

“There isn’t much research about disease transmission between Texas aoudad and native species like bighorn sheep. This makes it difficult for wildlife experts to monitor diseases and preserve animal populations,” said Dr. Logan Thomas, an assistant professor at Kansas State University and former postdoctoral researcher under Dr. Walter Cook, a clinical associate professor in the VMBS’ Department of Veterinary Pathobiology.

“If we can measure the disease exposure in both species, we can start to understand how they might affect each other,” he said. “By analyzing samples from both kinds of animals, we were ultimately able to determine that they too can carry and transmit the same respiratory illnesses.”

It Takes Two

Both aoudad and bighorn sheep are important animals for Texas wildlife conservation and the state’s economy. In West Texas, both animals are hunted as game, and some landowners make a significant portion of their income by charging hunters a fee to hunt on their land.

“Aoudad, in particular, are economically valuable for hunting opportunities,” Thomas said. “Since they’re a non-native species, there are no season or bag limits, which is very attractive to hunters.”

While bighorn sheep are also a favorite game animal among hunters, they require intensive management in Texas to keep their population numbers sustainable.

The respiratory diseases, including pneumonia, that both species can share have already wreaked havoc on bighorn populations, raising concerns among experts about what these diseases could do to aoudad, in addition to worsening the situation for bighorns.

“When there are outbreaks of these diseases in bighorn sheep, we usually see two waves of population decline,” Thomas said. “There’s a decline in all age groups when the outbreak first happens. Then there’s another wave after the lambs are born — many of them don’t survive because they haven’t been exposed to the disease and therefore lack an immune response like the older bighorns have.”

Complicating the problem is that some adult bighorns will carry the disease for several years after the initial outbreak, which means that the population may never have a chance to recover its numbers.

“We’ve known about this cycle in bighorn sheep for a while now, but no one had studied whether the same thing could happen in aoudad or if the two species could spread these pathogens back and forth,” he said. “We don’t suspect that it will be a significant health problem for aoudad, but we aim to learn more as we continue our research.”

Keeping A Close Watch

Now that the researchers have confirmed that aoudad can carry the same respiratory pathogens as bighorn sheep, wildlife experts can start to monitor disease transmission within and between those populations.

“Based on previous reports about this family of diseases, it’s also possible that they could spread to mule deer, which would complicate things further,” Thomas said. “We’re very interested in studying that in the future as well as how these diseases affect aoudad populations, since they haven’t received as much research attention on this as native species.

“Ultimately, we want all of these animal populations to thrive within a well-managed balance in Texas,” Thomas said. “Disease monitoring is one way we can take steps to make that happen.”

However, purifying these critical metals from ores with complex mixtures is a nasty business involving strong acids and hazardous solvents, and is primarily conducted in China. Over the past three years, a team of researchers from Sandia National Laboratories has been pioneering an environmentally friendly method to separate these rare-earth elements from watery mixtures.

Initially, the team made and modified tinker-toy-like molecules called metal-organic frameworks or MOFs to test their ability to adsorb these vital metals. They then used computer simulations and X-ray-based experiments to investigate how the rare-earth elements interact with the synthesized “sponges.” The team’s ultimate goal is to design sponges that selectively absorb one rare earth metal while excluding others. Their findings were recently published in a series of scientific papers, including one in the scientific journal ACS Applied Materials and Interfaces on August 26.

“We synthesized MOFs with variable surface chemistry and were able to show through adsorption experiments that these MOFs can pick out rare-earth elements from a mixture of other metals,” said Anastasia Ilgen, a Sandia geochemist and project lead. “They are more selective for the rare earths — that’s good. Importantly, we illustrated that their ability to pick out metals can be fine-tuned by adding chemical groups on their surfaces.”

Synthesizing stable sponges

The researchers selected two zirconium-based tinker-toy-like MOFs for the project. These MOFs are highly stable in water and easily adjustable, according to Dorina Sava Gallis, a Sandia materials chemist involved in the project.

MOFs consist of metal “hubs” and carbon-based linker “rods,” which can be interchanged to create nanosized “sponges” with different properties. Also, chemists can add different chemical groups within MOFs to modify their properties or engineer structures with missing rods, Sava Gallis said.

In their study, published in the scientific journal Chemical Communications, Sava Gallis and her team experimented with two types of MOFs featuring zirconium hubs. They attached new chemical groups to the linkers in one MOF building block, while attaching them to the metal hub in another.

The team found that the MOFs with missing linkers bound more of the two rare-earth elements compared to those without missing linkers, as expected. The addition of an amino group to the linker had minimal impact on the adsorption of any of the metals. However, incorporating a negatively charged chemical group called phosphonate into the linker improved the adsorption of all the metals. Interestingly, in the MOF structure where the chemical groups were attached to the metal hubs, the additional chemical groups did not make much of a difference on the adsorption of the rare-earth elements. However, they greatly increased the selectivity for nickel over cobalt, Sava Gallis said.

“We are seeing that both approaches we implemented effectively tune the selectivity for different ions,” Sava Gallis said. “We’re looking into designing new materials, combining the knowledge we have gained from studying these two material systems, to intentionally tailor the adsorption selectivity for each metal of interest.”

Modeling molecular interactions

To further guide the design of MOFs selective for specific rare-earth metals, Sandia computational materials scientist Kevin Leung used two different computer modeling techniques. First, he conducted molecular dynamics simulations to understand the environment of rare-earth elements in water, with or without other chemicals, or within a MOF structure. Then he performed detailed density functional theory modeling to calculate the energy for 14 rare-earth elements from cerium to lutetium going from water to a binding site with various surface chemistries. These findings were published in Physical Chemistry Chemical Physics.

Consistent with the earlier experimental work, Leung found that rare-earth elements do not exhibit a preference for binding with amines over water. However, they do show a preference for negatively charged chemicals like sulfate or phosphate compared to water. Leung found this preference is stronger for heavier rare-earth elements such as lutetium compared to lighter elements like cerium and neodymium.

The goal was to find a chemical that would allow them to select one metal, but unfortunately everything modeled had a uniform trend, Leung said. He hypothesized that combining a slightly positively charged surface chemical with a negatively charged surface chemical would be able to select for one metal. However, this approach has not yet been attempted.

X-ray illumination and next steps

To see precisely how the rare-earth metals interact with MOFs, Ilgen used X-ray spectroscopy to examine the chemical environment of three rare-earth elements in zirconium-based MOFs and chromium-based MOFs. Using synchrotron-based X-ray absorption fine structure spectroscopy at Argonne National Laboratory, Ilgen observed that the rare-earth element chemically bonded to the metal hub in both zirconium and chromium MOFs. In the MOF with a phosphonate surface group, the rare-earth metals bound to the phosphonate instead of the metal hub.

“My spectroscopy work is the first to identify the surface complexes formed by rare-earth elements in MOFs,” Ilgen said. “No one had done X-ray spectroscopy before. Previous studies inferred surface complexes based on adsorption trends, but no one had ‘seen’ them. I saw them with my X-ray eyes.”

Ilgen also saw that the rare-earth element bound to the metal hub in the same manner in MOFs with missing linkers as in MOFs with all the linkers. This is significant because MOFs without defects are more stable and potentially more reusable than MOFs with missing linkers.

In the paper, Ilgen proposed that metal hubs with a mixture of metals could create MOF sponges that prefer to adsorb one rare-earth element over others, but she said this approach has not been attempted yet.

Armed with their extensive knowledge of rare-earth elements’ interactions with MOFs, the team has numerous avenues to explore in designing selective sponges.

“There are several possible design strategies for ion-selective MOFs, specifically for separating individual rare-earth elements from one another,” Ilgen said. “One strategy involves tuning the chemistry of the metal hub, potentially incorporating multiple types of metals to optimize the binding site for a specific rare earth. Another strategy focuses on surface group chemistry, where strong surface groups outcompete the metal hubs, creating ion-specific pockets associated with the surface groups. Lastly, the pore dimensions of the MOF itself can be adjusted, as nanosized pores alter local chemistry to favor specific elements.”

The project was funded by Sandia’s Laboratory Directed Research and Development program.

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.