The findings are published June 27 in PLOS Biology.

Mutations in Gjb2 cause more than a quarter of all hereditary forms of hearing loss at birth in people, according to some estimates. The connexin 26 protein coded by the gene is in a family of proteins known as GAP junctions, because these proteins span the tiny gap between cells and form a kind of tube that connects two cells to trade ions, metabolites and other molecules that communicate or maintain an equilibrium.

This unexpected finding, according to investigators, suggests a molecular mechanism for the observation that people with this hereditary mutation respond well to cochlear implants, the electronic devices that are designed to mimic sound conduction in the inner ear and can improve hearing in those with severe hearing loss. According to the National Institutes of Health, about 118,100 cochlear implants were implanted in adults and 65,000 in children between December 2019 and March 2021.

The connexin 26 protein in the cochlea, the spiral-like structure in the inner ear, is highly enriched in supportive cells, which, like their name implies, provide structural and nutritional help to surrounding hair cells and auditory neurons.

Previous studies have shown that, without connexin 26, the cochlea fails to develop its normal shape and is incapable of amplifying sound-induced vibrations necessary for efficient sound detection. Despite this disruption to the cochlear structure, this research shows the cochlea is still capable of producing the “spontaneous” activity needed to shape brain development.

“Supportive cells are extremely important for tissues and organs,” says neuroscientist Dwight Bergles, Ph.D., the Diana Sylvestre and Charles Homcy Professor at the Johns Hopkins University School of Medicine. “The new study shows how critical they are for training the auditory system and getting it ready to process sound.”

For the study, Bergles and Calvin Kersbergen, an M.D./Ph.D. candidate in Johns Hopkins’ Medical Scientist Training Program, created a mouse model that lacked connexin 26 specifically in supportive cells in the cochlea.

By using external electrodes to measure electrical responses in the auditory nerve in response to tones or clicks, they found that mice lacking connexin 26 only in supportive cells of the cochlea were, indeed, deaf, demonstrating the crucial role of these intercellular channels in hearing.

However, Bergles and Kersbergen wondered if this change in supportive cells and shape of the cochlea would also disrupt spontaneous activity in younger mice, less than 2 weeks old, before their ear canal opens.

The researchers found that mice without connexin 26 still exhibit bursts of electrical activity in auditory neurons at nearly the same levels as young mice with intact connexin 26. Further investigation revealed that spontaneous activity in supportive cells was able to activate sensory hair cells in the inner ear, leading to normal neuronal activity in sound-processing areas of the brain.

“Even in the absence of connexin 26, we still find robust spontaneous activity in the cochlea in these young mice,” says Bergles.

Bergles says there is now evidence that the role of supportive cells in this early period is to “train” the auditory system to respond to sound at certain frequencies. Since the ear canal isn’t open yet, supportive cells generate their own activity spontaneously to stimulate the mechanically sensitive hair cells in the fluid-filled cochlea.

“It’s as if the cochlea is producing its own ‘sounds’ at this stage of development,” Bergles says. “This practice may help the auditory neurons and circuits in the brain mature before the ear canal opens.”

“It’s like a baseball player in a batting cage, learning the basics of their swing and preparing to face the unpredictability of a real pitcher,” says Bergles.

Finally, the researchers found that spontaneous activity in supportive cells of deaf mice halts once the ear canal opens. At the same time, because the mice can’t process sound, their auditory neurons actually increase their sensitivity to sound.

This hypersensitivity to sound is similar to the phenomenon of hyperacusis, in which normal levels of sound can be painful. In humans, this hearing loss-induced hypersensitivity can also lead to constant ringing of the ears, called tinnitus.

Bergles says the research also suggests a molecular mechanism for why people with this hereditary mutation who receive cochlear implants early on tend to do better than those who receive them later.

“Spontaneous activity in supportive cells in the cochlea may provide the molecular evidence for empirical data showing better outcomes among people who have cochlear implants placed earlier in life,” says Bergles.

The research team plans to study whether they can tap into the spontaneous activity pathway in supportive cells to treat tinnitus and other auditory conditions.

Scientists Travis Babola and Patrick Kanold also contributed to this research.

Funding was provided by the National Institutes of Health (F30DC018711, F32DC019842, U19NS107464, R01DC009607, R01DC008860, P30NS050274).

The catastrophic destruction triggered by the asteroid hitting the Earth resulted in the death of all non-avian dinosaurs in an event termed the Cretaceous-Paleogene (K-Pg) mass extinction. Debate has long raged among researchers over whether placental mammals were present alongside the dinosaurs before the mass extinction, or whether they only evolved after the dinosaurs were done away with. Fossils of placental mammals are only found in rocks younger than 66 million years old, which is when the asteroid hit Earth, suggesting that the group evolved after the mass extinction. However, molecular data has long suggested an older age for placental mammals.

In a new paper published in the journal Current Biology, a team of palaeobiologists from the University of Bristol and the University of Fribourg used statistical analysis of the fossil record to determine that placental mammals originated before the mass extinction, meaning they co-existed with dinosaurs for a short time. However, it was only after the asteroid impact that modern lineages of placental mammals began to evolve, suggesting that they were better able to diversify once the dinosaurs were gone.

The researchers collected extensive fossil data from placental mammal groups extending all the way back to the mass extinction 66 million years ago.

Lead author Emily Carlisle of Bristol’s School of Earth Sciences said: “We pulled together thousands of fossils of placental mammals and were able to see the patterns of origination and extinction of the different groups. Based on this, we could estimate when placental mammals evolved.”

Co-author Daniele Silvestro (University of Fribourg) explained: “The model we used estimates origination ages based on when lineages first appear in the fossil record and the pattern of species diversity through time for the lineage. It can also estimate extinction ages based on last appearances when the group is extinct.”

Co-author Professor Phil Donoghue, also from Bristol, added: “By examining both origins and extinctions, we can more clearly see the impact of events such as the K-Pg mass extinction or the Paleocene-Eocene Thermal Maximum (PETM).”

Primates, the group that includes the human lineage, as well as Lagomorpha (rabbits and hares) and Carnivora (dogs and cats) were shown to have evolved just before the K-Pg mass extinction, which means their ancestors were mingling with dinosaurs. After they survived the asteroid impact, placental mammals rapidly diversified, perhaps spurred on by the loss of competition from the dinosaurs.

Published today in the journal Nature, this embryo model is an organised three-dimensional structure derived from pluripotent stem cells that replicate some developmental processes that occur in early human embryos.

Use of such models allows experimental modelling of embryonic development during the second week of pregnancy. They can help researchers gain basic knowledge of the developmental origins of organs and specialised cells such as sperm and eggs, and facilitate understanding of early pregnancy loss.

“Our human embryo-like model, created entirely from human stem cells, gives us access to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother’s womb,” said Professor Magdalena Zernicka-Goetz in the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the work.

She added: “This exciting development allows us to manipulate genes to understand their developmental roles in a model system. This will let us test the function of specific factors, which is difficult to do in the natural embryo.”

In natural human development, the second week of development is an important time when the embryo implants into the uterus. This is the time when many pregnancies are lost.

The new advance enables scientists to peer into the mysterious ‘black box’ period of human development — usually following implantation of the embryo in the uterus — to observe processes never directly observed before.

Understanding these early developmental processes holds the potential to reveal some of the causes of human birth defects and diseases, and to develop tests for these in pregnant women.

Until now, the processes could only be observed in animal models, using cells from zebrafish and mice, for example.

Legal restrictions in the UK currently prevent the culture of natural human embryos in the lab beyond day 14 of development: this time limit was set to correspond to the stage where the embryo can no longer form a twin.

Until now, scientists have only been able to study this period of human development using donated human embryos. This advance could reduce the need for donated human embryos in research.

Zernicka-Goetz says the while these models can mimic aspects of the development of human embryos, they cannot and will not develop to the equivalent of postnatal stage humans.

Over the past decade, Zernicka-Goetz’s group in Cambridge has been studying the earliest stages of pregnancy, in order to understand why some pregnancies fail and some succeed.

In 2021 and then in 2022 her team announced in Developmental Cell, Nature and Cell Stem Cell journals that they had finally created model embryos from mouse stem cells that can develop to form a brain-like structure, a beating heart, and the foundations of all other organs of the body.

The new models derived from human stem cells do not have a brain or beating heart, but they include cells that would typically go on to form the embryo, placenta and yolk sac, and develop to form the precursors of germ cells (that will form sperm and eggs).

Many pregnancies fail at the point when these three types of cells orchestrate implantation into the uterus begin to send mechanical and chemical signals to each other, which tell the embryo how to develop properly.

There are clear regulations governing stem cell-based models of human embryos and all researchers doing embryo modelling work must first be approved by ethics committees. Journals require proof of this ethics review before they accept scientific papers for publication. Zernicka-Goetz’s laboratory holds these approvals.

“It is against the law and FDA regulations to transfer any embryo-like models into a woman for reproductive aims. These are highly manipulated human cells and their attempted reproductive use would be extremely dangerous,” said Dr Insoo Hyun, Director of the Center for Life Sciences and Public Learning at Boston’s Museum of Science and a member of Harvard Medical School’s Center for Bioethics.

Zernicka-Goetz also holds position at the California Institute of Technology and is NOMIS Distinguished Scientist and Scholar Awardee.

The research was funded by the Wellcome Trust and Open Philanthropy.

Lean body mass is defined in the study — published in the journal Alcohol Clinical and Experimental Research — as one’s total body weight minus fat.

“We believe the strong relationship we found between participants’ lean body mass and their alcohol elimination rate is due to the association that exists between lean body mass and lean liver tissue — the part of the liver responsible for metabolizing alcohol,” said research group leader M. Yanina Pepino, a professor of food science and human nutrition at the University of Illinois Urbana-Champaign.

To explore links between body composition and alcohol elimination rates, the team conducted a secondary analysis of data from a study performed at the U. of I and another at Indiana University, Indianapolis. Both projects used similar methods to estimate the rate at which alcohol is broken down in the body.

The combined sample from the studies used in the analysis included 143 women who ranged in age from 21 to 64 and represented a wide range of body mass indices — from healthy weights to severe obesity. Among these were 19 women who had undergone different types of bariatric surgery.

In a subsample of 102 of these women, the researchers had measured the proportions of lean and fat tissue in their bodies and calculated their body mass indices. Based on their BMI, those in the subsample were divided into three groups: normal weight, which included women with BMI ranging from 18.5-24.9; overweight, those with BMI ranging from 25-29.9; and obese, participants with BMI above 30.

As the researchers expected, women with higher BMI had not only more fat mass than women of healthy weights, they also had more lean mass. On average, the group with obesity had 52.3 kg of lean mass, compared with 47.5 kg for the normal weight group.

The two studies both used an alcohol clamp technique, where participants received an intravenous infusion of alcohol at a rate controlled by a computer-assisted system. The system calculated personalized infusion rates based upon each participant’s age, height, weight and gender and was programmed so they would reach a target blood alcohol concentration of .06 percent within 15 minutes and maintain that level for about two hours

Using a breathalyzer, breath samples were collected at regular intervals throughout the experiments to estimate participants’ blood alcohol concentration and provide feedback to the system.

“We found that having a higher fat-free body mass was associated with a faster alcohol elimination rate, particularly in women in the oldest subgroups,” said Neda Seyedsadjadi, a postdoctoral fellow at the university and the first author of the study.

“The average alcohol elimination rates were 6 grams per hour for the healthy weight group, 7 grams for the overweight group, and 9 grams for the group with obesity,” she said. “To put this in perspective, one standard drink is 14 grams of pure alcohol, which is found in 12 ounces of beer, 5 ounces of table wine or 1.5 ounces shot of distilled spirits.”

The interaction between participants’ age and lean body mass accounted for 72% of the variance in the time required to eliminate the alcohol from their system, the team found.

Pepino, who also holds an appointment as a health innovation professor at Carle Illinois College of Medicine, has conducted several studies on alcohol response in bariatric surgery patients.

The findings also shed light on alcohol metabolism and body composition in women who have undergone weight loss surgery. Researchers have long known that bariatric surgery alters women’s response to alcohol but were uncertain if it affected how quickly they cleared alcohol from their systems.

Some prior studies found that these patients metabolized alcohol more slowly after they had weight loss surgery. The new study’s findings indicate that these participants’ slower alcohol elimination rates can be explained by surgery-induced reductions in their lean body mass. Weight loss surgery itself had no independent effects on patients’ alcohol elimination rates, the team found.

Additional co-authors of the current study were Dr. Blair Rowitz, associate dean for clinical affairs with the Carle Illinois College of Medicine; Vijay A. Ramchandani, a senior investigator in the section on human psychopharmocology at the National Institute on Alcohol Abuse and Alcoholism; and psychiatry professors Dr. Martin H. Plawecki and Dr. Sean J. O’Connor, and scientist in neurology Ann E.K. Kosobud, all of the Indiana University School of Medicine.

Researchers from the University of Minnesota and Purdue University published their findings in Proceedings of the National Academy of Sciences. The team developed a first-of-its-kind, global earth-economy model to capture interactions between the economy and the environment. Crucially, these interactions include how nature benefits humans by pollinating crops, providing timber, storing carbon, and providing catch for marine fisheries, and how those benefits end up affecting the economy overall.

“We have long thought of the economy and the environment as working against each other,” said Justin Johnson, an assistant professor of Applied Economics at the University of Minnesota. “Investing in nature does not stifle the economy, it boosts the economy. But it has been difficult to model those interactions until recently.”

The researchers found:

• Policy options for investing in nature resulted in annual gains of $100-350 billion (2014 USD), with the largest percentage increases in GDP occurring in low-income countries. The policy options examined in this study include removing agricultural subsidies, financing research into improving crop yields and international payments from wealthy countries to poorer countries to support conservation.
• Continued trends in environmental degradation, on the other hand, would result in $75 billion losses annually, with the low-income countries suffering from 0.2% losses in GDP year on year.

The researchers combined a global general equilibrium economic model, GTAP (developed at Purdue University’s Center for Global Trade Analysis), with a suite of ecosystem service models, InVEST (developed at Stanford University’s Natural Capital Project). GTAP and InVEST are both widely used across the world by governments, non-governmental organizations and the private sector, but putting them together was a significant undertaking.

“Traditional economic models of this kind almost completely neglect the fact that the economy relies on nature,” said Tom Hertel, a distinguished professor of Agricultural Economics at Purdue University. “This new study required a detailed understanding of how and where land use patterns change as a result of economic activity, with enough spatial detail to understand environmental consequences of these changes. It is a huge achievement.”

The results from this research highlight how public goods and services provided by the environment are often most important for the world’s poorest, who have less access to alternative options when the environment is degraded. Consequently, investing in nature tends to make the world a more equitable place. This research only looks at a small subset of the ways in which the economy and the environment interact, nevertheless finding strikingly large effects.

“Of course nature provides much more than pollinators, timber, carbon and fish,” said Johnson. “Our future work will incorporate many more ecosystem services, leading to much more informed decision-making. This is just the beginning: we hope to make this kind of analysis a standard tool in a policy-maker’s toolbox.”

Financial support for the study came from the University of Minnesota, Purdue University and the National Science Foundation. Researchers from the World Bank and the University of Victoria also contributed to this study.