By analyzing measurements of the cranial vault — the part of the skull that forms the rounded top of the head and protects the brain — the team identified 30 regions of the genome associated with different aspects of head shape, 29 of which have not been reported previously.

“Anthropologists have speculated and debated the genetics of cranial vault shape since the early 20^th century,” said co-senior author Seth Weinberg, Ph.D., professor of oral and craniofacial sciences in the Pitt School of Dental Medicine and co-director of the Center for Craniofacial and Dental Genetics. “We knew from certain rare human conditions and animal experiments that genes play an important role in vault size and shape, but very little was known about the genetic basis for typical features we see in the general population, such as what makes someone’s head long and narrow versus short and wide. This study reveals some of the key genes driving variation in this part of the human body.”

According to the researchers, one application of better understanding the factors that drive natural variation in human head shape is informing paleoanthropology studies, potentially shedding light on the early development of modern humans.

Weinberg and colleagues used magnetic resonance (MR) scans from more than 6,000 adolescents to extract 3D surfaces corresponding to the cranial vault. After dividing the 3D vault surfaces into incrementally smaller anatomical subparts and quantifying the shape of these subparts, they tested more than 10 million genetic variants for evidence of statistical association with measures of vault shape.

“Previous genetic studies of the cranial vault involved a small number of relatively simple measures,” added Weinberg. “While such measures are often easy to obtain, they may fail to capture features that are biologically relevant. Our analysis used an innovative approach capable of describing 3D vault shape in much more comprehensive and nuanced ways. This approach increased our ability to find genetic associations.”

An important discovery was that many of the strong associations are near genes that play key roles in the early formation of the head and face and regulation of bone development. For example, variants in and near the gene RUNX2, a major player in coordinating development of the skull, were associated with multiple aspects of vault shape.

While some genes, including RUNX2, had global effects involving the entire vault, others showed more localized effects that only impacted a specific portion of the vault, such as the central forehead.

When the researchers compared the 30 genomic regions associated with head shape across participants with European, African and Indigenous American ancestry, they found that the majority of genetic associations were shared across these different ancestral groups.

Although the study focused on healthy participants, the findings may reveal important clues about the biological basis of diseases involving the cranial vault, according to Weinberg.

One of these conditions is craniosynostosis, which occurs when the bones of the skull fuse too early while the brain is still growing rapidly. Without neurosurgery, craniosynostosis can cause permanent disfigurement, brain damage, blindness and even death. The team showed that variants near three genes associated with vault shape, BMP2, BBS9 and ZIC2, were also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease.

“This kind of study is possible due to the availability of publicly funded resources,” said Weinberg. “The original study that generated these MR scans is focused on understanding brain development and behavior. By creatively leveraging these resources, we have managed to advance discovery beyond that original scope.”

Other authors on the study were Seppe Goovaerts, Hanne Hoskens, Ph.D., Meng Yuan, Dirk Vandermeulen, Ph.D., all of KU Leuven; Ryan J. Eller, Ph.D., Noah Herrick, Ph.D., and Susan Walsh, Ph.D., all of Indiana University-Purdue University Indianapolis; Anthony M. Musolf, Ph.D., and Cristina M. Justice, Ph.D., both of the National Human Genome Research Institute; Sahin Naqvi, Ph.D., and Joanna Wysocka, Ph.D., both of Stanford University; Myoung Keun Lee, Heather L. Szabo-Rogers, Ph.D., Mary L. Marazita, Ph.D., and John R. Shaffer, Ph.D., all of Pitt; Paul A. Romitti, Ph.D., of the University of Iowa; Simeon A. Boyadjiev, M.D., of the University of California, Davis; Mark D. Shriver, Ph.D., of Penn State University; and Peter Claes, Ph.D., of KU Leuven and Murdoch Children’s Research Institute.

This research was supported by the National Institute of Dental and Craniofacial Research (R01DE027023, R01DE016886, R03DE031061 and X01HL14053) and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health

Scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) and the Joint BioEnergy Institute (JBEI) are collaborating with X — the moonshot incubator led by Alphabet, Google’s parent company — to not only skip the problematic separation step, but also make the final product better for the planet.

The team has invented a simple “one pot” process to break down mixtures of petroleum-based and bio-based plastics using naturally derived salt solutions paired with specialized microbes. In a single vat, the salts act as a catalyst to break the materials down from polymers, large structures of repeating molecules bonded together, into the individual molecules called monomers, which the microbes then ferment into a new type of biodegradable polymer that can be made into fresh commodity products. The process is described in a One Earth paper published November 17.

“It’s sort of ironic because the purpose of using bio-based plastics is to be more sustainable, but it’s causing problems,” said first author Chang Dou, a senior scientific engineering associate at the Advanced Biofuels and Bioproducts Process Development Unit (ABPDU) at Berkeley Lab. Dou was recently named as one of the American Institute of Chemical Engineer’s 35 Under 35. “Our project is trying to get around the separation issue and make it so you don’t have to worry about whether you mix your recycling bin. You can put all the plastic in one bucket.”

In addition to streamlining recycling, the team’s approach could enable bio-based manufacturing of other valuable products using the same bacteria that are happily munching on plastic monomers. Imagine a world where biofuels or even medicines could be made from plastic waste — of which there is about 8.3 billion tons sitting around in landfills.

“There is an open discussion on whether we can use waste plastics as a carbon source for biomanufacturing. It is a very advanced idea. But we proved that using waste plastics, we can feed microbes. With more genetic engineering tools, microbes might be able to grow on multiple types of plastics at the same time. We foresee the potential to continue this study where we can replace the sugars, traditional carbon sources for microbes, with the processed hard-to-recycle mixed plastics that can be converted to valuable products through fermentation,” said Zilong Wang, a UC Berkeley postdoctoral researcher working at JBEI.

The Berkeley Lab scientists’ next step is to experiment with other organic salt catalysts to try to find one that is both highly effective at breaking polymers down and can be reused in multiple batches to lower costs. They are also modeling how the process would work at the large scales of real-world recycling facilities.

In their recent paper, the scientists demonstrated the potential of their approach in laboratory bench-scale experiments with mixtures of polyethylene terephthalate (PET) — the most common petroleum-based plastic, used in things like water bottles and spun into polyester fibers — and PLA, the most common bio-based plastic.

They used an amino-acid-based salt catalyst previously developed by colleagues at JBEI and a strain of Pseudomonas putida engineered by scientists at Oak Ridge National Laboratory. This combination successfully broke down 95% of the PET/PLA mixture and converted the molecules into a type of polyhydroxyalkanoate (PHA) polymer. PHAs are a new class of biodegradable plastic substitutes designed to efficiently break down in a variety of natural environments, unlike petroleum-based plastics.

Team member Hemant Choudhary noted that although their chemical recycling process is currently only proven for PET plastics contaminated with biodegradable PLA, it would still be beneficial for the diverse plastic streams encountered in real recycling facilities. “It can be completely integrated with existing plastic sources,” said Choudhary, a Sandia National Laboratories staff scientist working at JBEI. Most commercial products are not just one kind of plastic, but a handful of different kinds combined, he explained. For example, a fleece jacket is made with PET-based polyesters alongside polyolefins or polyamides. “We can throw it in our one-pot process and easily process the polyester component from that mixture and convert it into a bioplastic. These monomers are soluble in water, but the leftover parts, the polyolefins or polyamides, are not.” The leftovers can be easily removed by simple filtration and then sent off for a traditional mechanical recycling process where the material is shredded and melted, said Choudhary.

“Chemical recycling has been a hot topic, but it’s difficult to make it happen at the commercial scale because all the separation steps are so expensive,” said Ning Sun, a staff scientist at the ABPDU, lead author, and principal investigator of this project. “But by using a biocompatible catalyst in water, the microbes can directly convert the depolymerized plastics without extra separation steps. These results are very exciting, although we acknowledge that a number of improvements are still needed to realize the economic viability of the developed process.”

Co-authors Nawa R. Baral and Corinne Scown, experts in technoeconomic analysis in JBEI and Berkeley Lab’s Biosciences Area, also demonstrated that once optimized with a reusable salt solution, the process could reduce the cost and carbon footprint of PHAs by 62% and 29%, respectively, compared with today’s commercial PHA production.

JBEI is a Department of Energy (DOE) Bioenergy Research Center managed by Berkeley Lab. The ABPDU is a collaboration facility supported by the DOE BioEnergy Technologies Office.

The capsule, which is about the size of a multivitamin, uses an accelerometer to measure the patient’s breathing rate and heart rate. In addition to diagnosing sleep apnea, the device could also be useful for detecting opioid overdoses in people at high risk, the researchers say.

“It’s an exciting intervention to help people be diagnosed and then receive the appropriate treatment if they suffer from obstructive sleep apnea,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “The device also has the potential for early detection of changes in respiratory status, whether it’s a result of opiates or other conditions that could be monitored, like asthma or chronic obstructive pulmonary disease (COPD).”

In a study of 10 human volunteers, the researchers showed that the capsule can be used to monitor vital signs and to detect sleep apnea episodes, which occur when the patient repeatedly stops and starts breathing during sleep. The patients did not show any adverse effects from the capsule, which passed harmlessly through the digestive tract.

Traverso is one of the senior authors of the study, along with Robert Langer, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; Victor Finomore, director of the Human Performance and Applied Neuroscience Research Center at the West Virginia University School of Medicine; and Ali Rezai, director of the Rockefeller Neuroscience Institute at the West Virginia University School of Medicine. The paper appears today in the journal Device.

Vital sign measurements

Over the past decade, Traverso and Langer have developed a range of ingestible sensors that could be used to monitor vital signs and diagnose disorders of the GI tract, such as gastrointestinal slowdown and inflammatory bowel diseases.

This new study focused on measuring vital signs, using a capsule developed by Celero Systems that includes an accelerometer that detects slight movements generated by the beating of the heart and the expansion of the lungs. The capsule also contains two small batteries and a wireless antenna that transmits data to an external device such as a laptop.

In tests in an animal model, the researchers found that this capsule could accurately measure breathing rate and heart rate. In one experiment, they showed that the sensor could detect the depression of breathing rate that resulted from a large dose of fentanyl, an opioid drug.

Building on those results, the researchers decided to further test the capsule in a clinical trial at the West Virginia University Rockefeller Neuroscience Institute. Ten patients who enrolled in the study were monitored using the ingestible capsule, and these patients were also connected to the sensors typically used to monitor sleep, so the researchers could compare measurements from both types of sensors.

The researchers found that their ingestible sensor was able to accurately measure both breathing rate and heart rate, and it also detected a sleep apnea episode that one of the patients experienced.

“What we were able to show is that using the capsule, we could capture data that matched what the traditional transdermal sensors would capture,” Traverso says. “We also observed that the capsule could detect apnea, and that was confirmed with standard monitoring systems that are available in the sleep lab.”

In this study, the researchers monitored signals emitted by the capsule while it was in the stomach, but in a previous study, they showed that vital signs can also be measured from other parts of the GI tract.

“The stomach generally offers some of the best signals, mainly because it’s close to the heart and the lungs, but we know that we can also sense them elsewhere,” Traverso says.

None of the patients reported any discomfort or harm from the capsule. Radiographic imaging performed 14 days after the capsules were ingested revealed that all of them had passed through the patients’ bodies. The research team’s previous work has shown that objects of similar size usually move through the digestive tract in a little more than a day.

Close monitoring

The researchers envision that this kind of sensor could be used to diagnose sleep apnea in a less intrusive way than the skin-based sensors that are now used. It could also be used to monitor patients when they begin treatment for apnea, to make sure that the treatments are effective.

Celero Systems, a company founded by Traverso, Langer, Jeremy Ruskin, a professor of medicine at Harvard Medical School, and Benjamin Pless, now CEO of the company, is now working on sensors that could be used to detect sleep apnea or opioid overdose.

“We know that people who have had an overdose are at higher risk of recurrence, so those individuals could be monitored more closely so that in the event of another overdose, someone could help them,” Traverso says.

In future work, the researchers hope to incorporate an overdose reversal agent such as nalmefene into the device, so that drug release would be triggered when the person’s breathing rate slowed or stopped. They are also working on strategies to lengthen the amount of time that the capsules could remain in the stomach.

The research was funded by the Karl van Tassel Career Professorship, MIT’s Department of Mechanical Engineering, and Celero Systems.

Authors of the paper also include Pless, James Mahoney, Justin Kupec, Robert Stansbury, Daniel Bacher, Shannon Schuetz, and Alison Hayward.

The study in mice, published in Neuron, is the first to show how hunger hormones can directly impact activity of the brain’s hippocampus when an animal is considering food.

Lead author Dr Andrew MacAskill (UCL Neuroscience, Physiology & Pharmacology) said: “We all know our decisions can be deeply influenced by our hunger, as food has a different meaning depending on whether we are hungry or full. Just think of how much you might buy when grocery shopping on an empty stomach. But what may seem like a simple concept is actually very complicated in reality; it requires the ability to use what’s called ‘contextual learning’.

“We found that a part of the brain that is crucial for decision-making is surprisingly sensitive to the levels of hunger hormones produced in our gut, which we believe is helping our brains to contextualise our eating choices.”

For the study, the researchers put mice in an arena that had some food, and looked at how the mice acted when they were hungry or full, while imaging their brains in real time to investigate neural activity. All of the mice spent time investigating the food, but only the hungry animals would then begin eating.

The researchers were focusing on brain activity in the ventral hippocampus (the underside of the hippocampus), a decision-making part of the brain which is understood to help us form and use memories to guide our behaviour.

The scientists found that activity in a subset of brain cells in the ventral hippocampus increased when animals approached food, and this activity inhibited the animal from eating.

But if the mouse was hungry, there was less neural activity in this area, so the hippocampus no longer stopped the animal from eating. The researchers found this corresponded to high levels of the hunger hormone ghrelin circulating in the blood.

Adding further clarity, the UCL researchers were able to experimentally make mice behave as if they were full, by activating these ventral hippocampal neurons, leading animals to stop eating even if they were hungry. The scientists achieved this result again by removing the receptors for the hunger hormone ghrelin from these neurons.

Prior studies have shown that the hippocampus of animals, including non-human primates, has receptors for ghrelin, but there was scant evidence for how these receptors work.

This finding has demonstrated how ghrelin receptors in the brain are put to use, showing the hunger hormone can cross the blood-brain barrier (which strictly restricts many substances in the blood from reaching the brain) and directly impact the brain to drive activity, controlling a circuit in the brain that is likely to be the same or similar in humans.

Dr MacAskill added: “It appears that the hippocampus puts the brakes on an animal’s instinct to eat when it encounters food, to ensure that the animal does not overeat — but if the animal is indeed hungry, hormones will direct the brain to switch off the brakes, so the animal goes ahead and begins eating.”

The scientists are continuing their research by investigating whether hunger can impact learning or memory, by seeing if mice perform non-food-specific tasks differently depending on how hungry they are. They say additional research might also shed light on whether there are similar mechanisms at play for stress or thirst.

The researchers hope their findings could contribute to research into the mechanisms of eating disorders, to see if ghrelin receptors in the hippocampus might be implicated, as well as with other links between diet and other health outcomes such as risk of mental illnesses.

First author Dr Ryan Wee (UCL Neuroscience, Physiology & Pharmacology) said: “Being able to make decisions based on how hungry we are is very important. If this goes wrong it can lead to serious health problems. We hope that by improving our understanding of how this works in the brain, we might be able to aid in the prevention and treatment of eating disorders.”

“Depression affects millions of individuals worldwide, necessitating more effective treatments. Conventional methods, such as drug therapy with delayed onset of action and psychotherapy, have limitations in yielding satisfactory results for many patients. A pioneering advancement in treatment is urgently needed,” said Professor He Jufang, Wong Chun Hong Chair Professor in Translational Neuroscience at CityU.

Previous research found that stress leads to neural plasticity changes in brain’s valence-coding systems (“valence” refers to the degree to which something is pleasurable or aversive), which are strongly associated with depression, post-traumatic stress disorders and anxiety disorders. Also, some studies revealed that depression is correlated with the hyperactivated amygdala. “However, the neural mechanism that mediates depression in amygdala is still poorly understood,” said Professor He.

Over the years, Professor He’s research group has focused on memory formation and encoding studies. Previously, they discovered that cholecystokinin (CCK), a key neuromodulator, is crucial for inducing long-term potentiation (LTP) — a lasting increase in communication strength between neurons — to enable memory formation. They also found that the CCK and CCK-B receptors (CCKBR is one of three known types of CCK receptors in the central nervous system) mediate neuroplasticity, as well as visual and sound associative memory formation, in the auditory cortex, and trace fear memory formation in the amygdala. Other studies have found that CCKBR antagonist (which blocks the binding of the CCK and CCK-B receptors, thus inhibiting the effect of the binding) exhibited an anti-depressant effect in mice.

So Professor He’s group hypothesized that CCK might facilitate aversive memory formation by enabling LTP in the basolateral amygdala (BLA) — a brain region involved in processing emotional memories and thought to be dysregulated in depression, thus enhancing the development of depression.

In their latest study, they tested this hypothesis using various experimental methods, including in vitro electrophysiological recording, optogenetic manipulation, drug manipulation and behavioural analysis of mice, to examine the critical role of CCK and CCKBR in depression. They found that a CCKBR antagonist called YM022 had an anti-depressant-like effect by blocking neuroplasticity-caused aversive memory formation in mice.

The results of the in-vitro recording in the BLA showed that the YM022 significantly suppressed neuroplasticity. The neuroplasticity induction rate reached 72.3% in the control group; but it was only 10.2% in the drug-treated group.

Moreover, the team underwent a series of behavioural tests to determine the antagonist’s efficacy. The results showed that depressive behaviours in mice treated with a CCKBR antagonist was reduced.

“Remarkably, the YM022 shows anxiolytic effects with a dose of 3.0 ug/kg, which is 3,000 times lower than the required dosage of current antidepressants,” said Professor He. “These results indicate that CCKBR is a potential target for depression treatment, and that the selected antagonist, YM022, may be a good anti-depressant candidate due to its extremely small effective dose. This paves the way for targeted drug development that specifically addresses the abnormalities observed in the basolateral amygdala.” Next, the research team will focus on the precise mechanisms and potential side effects of CCKBR antagonists to set the stage for future clinical trials involving human subjects.

The research was supported by Hong Kong Research Grants Council, the Innovation and Technology Fund, the Health and Medical Research Fund, and the following charitable foundations: the Wong Chun Hong Endowed Chair Professorship, the Charlie Lee Charitable Foundation, and the Fong Shu Fook Tong Foundation.