Publishing in the Proceedings of the National Academy of Sciences, Yasir Suhail, a postdoctoral researcher working alongside Kshitiz, assistant professor in the Department of Biomedical Engineering, uncovered regulatory sequences in the genomes of mammals including cows, pigs, horses, and humans that explain how endometrium is invaded by the placenta, and how normal tissue is invaded by cancer.

Suhail and Kshitiz were joined in their efforts by Gunter Wagner, professor in evolutionary biology and ecology at Yale University.

In many mammals including humans, the placenta invades the wall of the uterus during pregnancy in the same way that cancer cells invade surrounding tissues.

“When you look at a picture of placentation, it looks eerily similar to cancer in any other part of the body,” says Kshitiz, “Even the molecular mechanisms are quite similar. This is quite a contrast from cows and horses, where the placenta does not invade into the mother. In these mammals, cancer cells also do not invade into their surroundings as they do in humans.”

Kshitiz, along with Gunter Wagner and Andre Levchenko at Yale first drew the comparison between cancer metastasizing in cows and humans in a seminal finding in Nature Ecology & Evolution. Looking at cells from the endometrium of various species, Kshitiz found that in order to resist invasion of the placenta, certain species have evolved over time to make their stromal cells — the connective tissue cells in an organ — highly resistant to any invasion.

The latest research is a deeper dive into the comparative genetics between mammals, which shows how changes in genetic regulation informs this resistance in cows and horses and makes humans vulnerable to cancer malignancy. With comparative data generated by Wagner and Jamie Maziarz at Yale, Suhail developed a model to identify how the binding of transcription factors — the proteins that regulate the expression of genes — explain changes in resistance to invasion across different species of mammals.

“Our new framework identifies key transcription factors and examines how their targets differ from cows, pigs, and horses to humans,” says Suhail. “What we learned from other species has direct applications in advancing our understanding of human cancer.”

Suhail used the genomic sequences and gene expression information to predict specific signaling proteins that drive the expression of genes that decrease the susceptibility of invasion in human cells. Using a custom fabricated bio chip, the researchers were able to confirm that these predicted proteins did in fact decrease the invasion of both cancer and placental cells. Evolutionary predictions across species are difficult to test experimentally, so confirmation of the theory experimentally is very satisfying to the researchers.

“We all think about human cancers are an outcome of cancer cells themselves. But what we’ve proposed is that mammals have very different mechanisms to resist cancer spread, and that these mechanisms have actually been derived to resist fetal invasion into the mother,” Kshitiz says. “To be vulnerable to malignancy may partly be an evolutionary compromise to allow an invasive pregnancy.”

While other researchers are targeting cancer and immune cells, Kshitiz’s lab focuses on how healthy cells limit cancer growth around them. This approach can help us rethink the way we approach cancer therapies.

“This study identifies specific genetic regulatory mechanisms which explain these differences, and point us towards many directions to rethink about anti-cancer therapy, from those that kill cancer to creating new therapies which “contain” cancer within its boundaries.”

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Materials provided by University of Connecticut. Original written by Courtney Chandler. Note: Content may be edited for style and length.

NAFLD is a condition where excess fat builds up in liver tissue for reasons unrelated to alcohol consumption. If untreated, the excess fat can lead to inflammation, scarring and increased risk of liver cancer. The incidence of NAFLD is increasing among children and adolescents, with 10% of children in the U.S. currently affected. This number is expected to increase within the next decade.

“We know that development of NAFLD is partly to do with diet and lack of exercise, but there is an environmental component that primes an infant’s liver to develop it as well; specifically, the metabolic state of the mother,” says Michael Cowley, associate professor of biology at NC State and corresponding author of the work.

Metabolic syndrome, or MetS, is a catchall term for a number of health issues including high blood sugar, obesity and elevated blood pressure. Previous studies had shown a link between MetS in mothers and increased NAFLD susceptibility in infants.

“We wanted to look specifically at mothers with MetS to see whether infants are affected pre- or post-natally, and tease out what is happening on the molecular level to trigger the disease,” Cowley says.

In a mouse model of MetS, Cowley and his colleagues compared offspring of mice with MetS to those from control mice, or mice without MetS. They studied four groups: offspring of control mice nursed by control mice, offspring of MetS mice nursed by MetS mice, and cross-fostered offspring from both groups. Cross-fostered means that the offspring of one group were nursed by mothers from the other group. They compared offspring at birth and at three weeks after birth, just before weaning.

They found that mice born to MetS mothers and nursed by control mice did not develop NAFLD, whereas most mice from both control and MetS groups nursed by MetS mothers did.

Using RNA sequencing, the researchers found that the imprinted gene network (IGN), including its regulator, an imprinted gene called Zac1, was upregulated, or more active, in mice nursed by the MetS mothers.

Imprinted genes are a small set of genes which are expressed from a single parental allele. Most genes consist of two copies (one inherited from each parent) which activate and influence inherited traits. Imprinted genes are expressed by a single active copy, and have been shown to be susceptible to changes in environmental factors.

“Zac1 is acting as the master switch here,” Cowley says. “It was activated in pups that nursed from MetS mothers, and this has downstream effects in the IGN that lead to an increased susceptibility to NAFLD.

“Researchers have proposed that imprinted genes play a role in this process — we’re showing here that they do,” Cowley continues. “The work also confirms the post-natal environment is more important to the development of the disease than pre-natal exposure. Our next steps will involve looking at what happens once potential environmental stressors such as the mother’s milk are removed. Can Zac1 be switched off again?”

The research appears in Hepatology and was supported by the National Institutes of Health (grant numbers K22ES027510, R01ES031596, P30ES025128 and P30DK034987) and by Oak Ridge Associated Universities through a Ralph E. Powe Junior Faculty Enhancement Award. Marine Baptissart, former postdoctoral researcher at NC State, is first author.

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Materials provided by North Carolina State University. Original written by Tracey Peake. Note: Content may be edited for style and length.

The survival rate for children with ALL has increased impressively to over 80% over the last several decades. However, the prognosis for children whose cancer recurs remains unfavorable. Therefore, minimal residual disease (MRD) monitoring is an important prognostic factor for treatment response and patient stratification. MRD monitoring uses highly sensitive real-time PCR to measure the amount of cancer cells among normal cells.

“MRD markers can disappear during treatment, which can lead to false-negative results and poor decision-making in personalized treatments,” explains Principal investigator Cornelia Eckert, PhD, Department of Pediatric Oncology/Hematology, Charité — Universitätsmedizin Berlin, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ). Consequently, monitoring at least two independent markers per patient is recommended. Dr. Eckert continues, “The current gold standard EuroMRD consortium guidelines call for amplification using singleplex real-time PCR quantification, making testing additional markers more laborious and expensive. They also lead to a higher consumption of patient material.”

To overcome these limitations, Dr. Eckert and co-investigators established the personalized MP PCR, an iterative workflow and guidelines for designing multiplex real-time PCRs to monitor up to four MRD markers for ALL simultaneously in one assay. When tested on DNA in bone marrow samples from patients with ALL, the MP PCRs met the EuroMRD gold standard guidelines and level of sensitivity for clinical decision-making.

Co-investigator Michael Lehnert, PhD, Hahn-Schickard Freiburg, states, “Multiplexing can significantly improve personalized MRD monitoring of patients, because a higher number of MRD markers per patient can be analyzed at the same time. Even though these patient-specific sequences of cancer cells only differ in a few DNA nucleotides from healthy cells, our multiplex assay can still distinguish between these DNA sequences. Therefore, a broader range of patient-specific sequences can be included in the assay.”

The MRD-MP guidelines are simple and may allow assay standardization across different laboratories. To demonstrate the potential transfer of the duplex MP PCR into a routine diagnostic setting, the new assay was applied in a prospectively assessed patient case in comparison with the gold standard singleplex test. Both fulfilled the EuroMRD guidelines and led to a similar quantitative range and sensitivity.

In order to deal with challenges inherent to multiplex PCR, the researchers developed an efficient iterative workflow for PCR design and optimization. DNA primer titration is only involved and extended if the assay performance is not sufficient in the first step, so that the number of iterations is minimized.

“There is a vast variety of DNA marker sequences unique to each leukemia,” adds first author Elena Kipf, PhD, Hahn-Schickard Freiburg. “The MRD-multiplex workflow provides a systematic and reliable way of effective MRD-MP PCR design and optimization and helps the standardization of personal diagnostics.”

While their work demonstrates that multiplex MP PCR has the potential to set a new standard in personalized MRD monitoring, the researchers note it must be clinically validated in a representative cohort of ALL patients. “Cancer is a fatal disease from which not every patient can be cured,” Dr. Eckert stresses. “After successful clinical validation, patients could benefit from extended MRD monitoring, leading to more precise predictions of therapy response and better patient stratification and outcomes.”

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Materials provided by Elsevier. Note: Content may be edited for style and length.

With the growing importance of these resonators, scientists need a reliable and efficient way to make sure the devices are working properly. That’s best accomplished by carefully studying the acoustic waves that the resonators generate.

Now, researchers at the National Institute of Standards and Technology (NIST) and their colleagues have developed an instrument to image these acoustic waves over a wide range of frequencies and produce “movies” of them with unprecedented detail.

The researchers measured acoustic vibrations as rapid as 12 gigahertz (GHz, or billions of cycles per second) and may be able to extend those measurements to 25 GHz, providing the necessary frequency coverage for 5G communications as well as for potentially powerful future applications in quantum information.

The challenge of measuring these acoustic vibrations is likely to increase as 5G networks dominate wireless communications, generating even tinier acoustic waves.

The new NIST instrument captures these waves in action by relying on a device known as an optical interferometer. The illumination source for this interferometer, ordinarily a steady beam of laser light, is in this case a laser that pulses 50 million times a second, which is significantly slower than the vibrations being measured.

The laser interferometer compares two pulses of laser light that travel along different paths. One pulse travels through a microscope that focuses the laser light on a vibrating micromechanical resonator and is then reflected back. The other pulse acts as a reference, traveling along a path that is continually adjusted so that its length is within a micrometer (one millionth of a meter) of the distance traveled by the first pulse.

When the two pulses meet, the light waves from each pulse overlap, creating an interference pattern — a set of dark and light fringes where the waves cancel or reinforce one another. As subsequent laser pulses enter the interferometer, the interference pattern changes as the microresonator vibrates up and down. From the changing pattern of the fringes, researchers can measure the height (amplitude) and phase of the vibrations at the location of the laser spot on the micromechanical resonator.

NIST researcher Jason Gorman and his colleagues deliberately chose a reference laser that pulses between 20 and 250 times more slowly than the frequency at which the micromechanical resonator vibrates. That strategy enabled the laser pulses illuminating the resonator to, in effect, slow down the acoustic vibrations, similar to the way that a strobe light appears to slow down dancers in a nightclub.

The slowdown, which converts acoustic vibrations that oscillate at GHz frequencies to megahertz (MHz, millions of cycles per second), is important because the light detectors used by the NIST team operate much more precisely, with less noise, at these lower frequencies.

“Moving to lower frequencies removes interference from communication signals typically found at microwave frequencies and allows us to use photodetectors with lower electrical noise,” said Gorman.

Each pulse lasts only 120 femtoseconds (quadrillionths of a second), providing highly precise moment-to-moment information on the vibrations. The laser scans across the micromechanical resonator so that the amplitude and phase of the vibrations can be sampled across the entire surface of the vibrating device, producing high-resolution images over a wide range of microwave frequencies.

By combining these measurements, averaged over many samples, the researchers can create three-dimensional movies of a microresonator’s vibrational modes. Two types of microresonators were used in the study; one had dimensions of 12 micrometers (millionths of a meter) by 65 micrometers; the other measured 75 micrometers on a side — about the width of a human hair.

Not only can the images and movies reveal whether a micromechanical resonator is operating as expected, they can also indicate problem areas, such as places where acoustic energy is leaking out of the resonator. The leaks make resonators less efficient and lead to loss of information in quantum acoustic systems. By pinpointing problematic areas, the technique gives scientists the information they need to improve resonator design.

In the Feb. 4, 2022, edition of Nature Communications, the researchers reported that they could image acoustic vibrations that have an amplitude (height) as small as 55 femtometers (quadrillionths of a meter), about one-five-hundredth the diameter of a hydrogen atom.

Over the past decade, physicists have suggested that micromechanical resonators in this frequency range may also serve to store fragile quantum information and to transfer the data from one part of a quantum computer to another.

Establishing an imaging system that can routinely measure micromechanical resonators for these applications will require further research. But the current study is already a milestone in assessing the ability of micromechanical resonators to accurately perform at the high frequencies that will be required for effective communication and for quantum computing in the near future, Gorman said.

“It turns out prevention really is the best medicine,” said Stuart Pimm, Doris Duke Professor of Conservation Ecology at Duke University, who was co-lead author of the study. “We estimate we could greatly reduce the likelihood of another pandemic by investing as little as 1/20^th of the losses incurred so far from COVID into conservation measures designed to help stop the spread of these viruses from wildlife to humans in the first place.”

A smart place to start, the study shows, would be investing in programs to end tropical deforestation and international wildlife trafficking, stop the wild meat trade in China, and improve disease surveillance and control in wild and domestic animals worldwide.

COVID, SARS, HIV, Ebola and many other viruses that have emerged in the last century originated in wild places and wild animals before spreading to humans, the study’s authors note. Tropical forest edges where humans have cleared more than 25% of the trees for farming or other purposes are hotbeds for these animal-to-human virus transmissions, as are markets where wild animals, dead or alive, are sold.

“The bottom line is, if we don’t stop destroying the environment and selling wild species as pets, meat or medicine, these diseases are just going to keep coming. And as this current pandemic shows, controlling them is inordinately costly and difficult,” Pimm said. “It’s been two years since COVID emerged and the cure still isn’t working. Not enough people are vaccinated in the U.S, where shots are available and we can afford them, and not enough vaccines are going to other countries that can’t afford them.”

The new study, by epidemiologists, economists, ecologists, and conservation biologists at 21 institutions, calculates that by investing an amount equal to just 5% of the estimated annual economic losses associated with human deaths from COVID into environmental protection and early-stage disease surveillance, the risks of future zoonotic pandemics could be reduced by as much as half. That could help save around 1.6 million lives a year and reduce mortality costs by around $10 trillion annually.

“We’re talking about an investment of tens of billions of dollars a year. Government have that kind of money,” Pimm said.

One key recommendation of the new study is to use some of this money to train more veterinarians and wildlife disease biologists.

Another key recommendation is to create a global database of virus genomics that could be used to pinpoint the source of newly emerging pathogens early enough to slow or stop their spread, and, ultimately, speed the development of vaccines and diagnostic tests.

Aaron Bernstein of Boston Children’s Hospital and the Center for Climate, Health and the Global Environment at Harvard T.H. Chan School of Public Health, and Andrew Dobson of Princeton University were co-lead authors of the study with Pimm.

The need to put preventive measures in place as soon as possible is increasingly urgent, said Dobson. “Epidemics are occurring more frequently, they are getting larger, and spreading to more continents.”

“Prevention is much cheaper than cures,” noted Bernstein. Compared to the costs and social and economic disruptions associated with trying to control pathogens after they have already spread to humans, “preventing epidemics before they break out is the ultimate economic bargain.”

Researchers at 17 additional universities, medical centers, environmental nonprofits or government agencies in the United States, China, Brazil, South Africa, and Kenya coauthored the study.

The coauthors include Binbin V. Li, assistant professor of environmental science at Duke Kunshan University in China, who holds a secondary appointment at Duke’s Nicholas School of the Environment.

Funding for the study came from Johnson & Johnson; the U.S. Department of Agriculture; the Norwegian Agency for Development Cooperation; Brazil’s National Institute for Scientific and Technological Development; the U.S. Agency for International Development, and the National Natural Science Foundation of China.