Publisher Health

Scientists have decoded the physical process that takes place in the mouth when a piece of chocolate is eaten, as it changes from a solid into a smooth emulsion that many people find totally irresistible.
By analysing each of the steps, the interdisciplinary research team at the University of Leeds hope it will lead to the development of a new generation of luxury chocolates that will have the same feel and texture but will be healthier to consume.
During the moments it is in the mouth, the chocolate sensation arises from the way the chocolate is lubricated, either from ingredients in the chocolate itself or from saliva or a combination of the two.
Fat plays a key function almost immediately when a piece of chocolate is in contact with the tongue. After that, solid cocoa particles are released and they become important in terms of the tactile sensation, so fat deeper inside the chocolate plays a rather limited role and could be reduced without having an impact on the feel or sensation of chocolate.
Anwesha Sarkar, Professor of Colloids and Surfaces in the School of Food Science and Nutrition at Leeds, said: “Lubrication science gives mechanistic insights into how food actually feels in the mouth. You can use that knowledge to design food with better taste, texture or health benefits.
“If a chocolate has 5% fat or 50% fat it will still form droplets in the mouth and that gives you the chocolate sensation. However, it is the location of the fat in the make-up of the chocolate which matters in each stage of lubrication, and that has been rarely researched.

“We are showing that the fat layer needs to be on the outer layer of the chocolate, this matters the most, followed by effective coating of the cocoa particles by fat, these help to make chocolate feel so good.”
The study — published in the scientific journal ACS Applied Materials and Interface — did not investigate the question of how chocolate tastes. Instead, the investigation focused on its feel and texture.
Tests were conducted using a luxury brand of dark chocolate on an artificial 3D tongue-like surface that was designed at the University of Leeds. The researchers used analytical techniques from a field of engineering called tribology to conduct the study, which included in situ imaging.
Tribology is about how surfaces and fluids interact, the levels of friction between them and the role of lubrication: in this case, saliva or liquids from the chocolate. Those mechanisms are all happening in the mouth when chocolate is eaten.
When chocolate is in contact with the tongue, it releases a fatty film that coats the tongue and other surfaces in the mouth. It is this fatty film that makes the chocolate feel smooth throughout the entire time it is in the mouth.

Dr Siavash Soltanahmadi, from the School of Food Science and Nutrition at Leeds and the lead researcher in the study, said: “With the understanding of the physical mechanisms that happen as people eat chocolate, we believe that a next generation of chocolate can be developed that offers the feel and sensation of high-fat chocolate yet is a healthier choice.
“Our research opens the possibility that manufacturers can intelligently design dark chocolate to reduce the overall fat content.
“We believe dark chocolate can be produced in a gradient-layered architecture with fat covering the surface of chocolates and particles to offer the sought after self-indulging experience without adding too much fat inside the body of the chocolate.”
Revenue from chocolate sales in the UK is forecast to grow over the next five years, according to research from the business intelligence agency MINTEL. Sales are expected to grow 13% between 2022 and 2027 to reach £6.6 billion.
The researchers believe the physical techniques used in the study could be applied to the investigation of other foodstuffs that undergo a phase change, where a substance is transformed from a solid to a liquid, such as ice-cream, margarine or cheese.
This project received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme.

A new study of domestic and hospital drinking water systems found Legionella in 41% of samples — with Flinders University researchers making a key connection between the pathogen’s co-existence with a ‘host’ microorganism in all samples tested.
The study found Legionella bacteria “infect the amoeba host and then once inside these hosts are protected from disinfection strategies,” says Flinders University Associate Professor of Environmental Health Harriet Whiley, a co-author of the new journal article in Water Research.
Researchers tested for Legionella and its likely amoebae hosts in 140 samples of water or biofilm (the slime found on showerheads and end of faucets) to understand how the potentially dangerous bacterium colonises andproliferates in both domestic and hospital plumbing and poses a threat to human health.
Legionnaires’ disease is a severe pneumonia-like infection that can be fatal. Globally the number of Legionnaires’ disease cases is increasing, with elderly and immunocompromised people at the highest risk.
“It is vital that we strive to improve the management of our water distribution systems, particularly in high risk setting such as hospitals, to protect vulnerable populations,” says Associate Professor Whiley, from the Flinders College of Science and Engineering.
“Having a better understanding of the relationships between these amoebae and Legionella is an important step in improving future water treatment processes aimed at controlling Legionella and preventing Legionnaires disease.”
L. pneumophilia is the main cause of Legionnaires’ disease and is not transmitted from person to person but caused by inhalation or aspiration of contaminated water.

Maintenance and monitoring of water systems is a common preventive step to reduce public risk.
“To our knowledge, this is the first time the amoebae Allovahlkampfia and Stenamoeba have been demonstrated as hosts of L. pneumophila in Australian drinking water,” says Flinders University PhD candidate Muhammad Atif Nisar, who conducted the study.
The findings support the need further research to investigate the prevalence of Legionella as well as free-living amoebae in domestic and commercial water systems and to improve guidelines to better control water systems and safeguard the public health.
“Free-living amoebae are ubiquitous in the environment and cause both opportunistic and non-opportunistic infections in humans. Some amoebae are the natural reservoirs of opportunistic plumbing pathogens, such as Legionella pneumophila,” says Mr Atif Nisar.
“There is a need for future research to improve disinfection strategies against amoeba to reduce their colonisation within building drinking water systems.”
Up to 75% of the drinking water or biofilm samples tested positive for free-living amoebae. This included V. vermiformis which was present in 55% of samples and Acanthamoeba was present in 11%.

As well as being hosts for Legionella, Acanthamoeba and V. vermiformis are pathogens that can cause severe eye infections, with contact lens users and immunocompromised individuals at greatest risk.
The water samples were collected from showers and hand basins located in domestic houses and hospitals across New South Wales and South Australia.
These results demonstrate the importance of amoebae in engineered water systems, both as a pathogen and as a reservoir of Legionella.
“Future water management protocols should incorporate improved treatment strategies to control amoebae to reduce the risk to end-users,” adds Mr Atif Nisar.

Negative emotions, anxiety and depression are thought to promote the onset of neurodegenerative diseases and dementia. But what is their impact on the brain and can their deleterious effects be limited? Neuroscientists at the University of Geneva (UNIGE) observed the activation of the brains of young and older adults when confronted with the psychological suffering of others. The neuronal connections of the older adults show significant emotional inertia: negative emotions modify them excessively and over a long period of time, particularly in the posterior cingulate cortex and the amygdala, two brain regions strongly involved in the management of emotions and autobiographical memory. These results, to be published in Nature Aging, indicate that a better management of these emotions — through meditation for example — could help limit neurodegeneration.
For the past 20 years, neuroscientists have been looking at how the brain reacts to emotions. ”We are beginning to understand what happens at the moment of perception of an emotional stimulus,” explains Dr Olga Klimecki, a researcher at the UNIGE’s Swiss Centre for Affective Sciences and at the Deutsches Zentrum für Neurodegenerative Erkrankungen, who is last author of this study carried out as part of a European research project co-directed by the UNIGE. ”However, what happens afterwards remains a mystery. How does the brain switch from one emotion to another? How does it return to its initial state? Does emotional variability change with age? What are the consequences for the brain of mismanagement of emotions?”
Previous studies in psychology have shown that an ability to change emotions quickly is beneficial for mental health. Conversely, people who are unable to regulate their emotions and remain in the same emotional state for a long time are at higher risks of depression. ”Our aim was to determine what cerebral trace remains after the viewing of emotional scenes, in order to evaluate the brain’s reaction, and, above all, its recovery mechanisms. We focused on the older adults, in order to identify possible differences between normal and pathological ageing,” says Patrik Vuilleumier, professor in the Department of Basic Neurosciences at the Faculty of Medicine and at the Swiss Centre for Affective Sciences at the UNIGE, who co-directed this work.
Not all brains are created equal
The scientists showed volunteers short television clips showing people in a state of emotional suffering — during a natural disaster or distress situation for example — as well as videos with neutral emotional content, in order to observe their brain activity using functional MRI. First, the team compared a group of 27 people over 65 years of age with a group of 29 people aged around 25 years. The same experiment was then repeated with 127 older adults.
”Older people generally show a different pattern of brain activity and connectivity from younger people,” says Sebastian Baez Lugo, a researcher in Patrik Vuilleumier’s laboratory and the first author of this work. ”This is particularly noticeable in the level of activation of the default mode network, a brain network that is highly activated in resting state. Its activity is frequently disrupted by depression or anxiety, suggesting that it is involved in the regulation of emotions. In the older adults, part of this network, the posterior cingulate cortex, which processes autobiographical memory, shows an increase in its connections with the amygdala, which processes important emotional stimuli. These connections are stronger in subjects with high anxiety scores, with rumination, or with negative thoughts.”
Empathy and ageing
However, older people tend to regulate their emotions better than younger people, and focus more easily on positive details, even during a negative event. But changes in connectivity between the posterior cingulate cortex and the amygdala could indicate a deviation from the normal ageing phenomenon, accentuated in people who show more anxiety, rumination and negative emotions. The posterior cingulate cortex is one of the regions most affected by dementia, suggesting that the presence of these symptoms could increase the risk of neurodegenerative disease.
”Is it poor emotional regulation and anxiety that increases the risk of dementia or the other way around? We still don’t know,” says Sebastian Baez Lugo. ”Our hypothesis is that more anxious people would have no or less capacity for emotional distancing. The mechanism of emotional inertia in the context of ageing would then be explained by the fact that the brain of these people remains ‘frozen’ in a negative state by relating the suffering of others to their own emotional memories.”
Could meditation be a solution?
Could it be possible to prevent dementia by acting on the mechanism of emotional inertia? The research team is currently conducting an 18-month interventional study to evaluate the effects of foreign language learning on the one hand, and meditation practice on the other. ”In order to further refine our results, we will also compare the effects of two types of meditation: mindfulness, which consists of anchoring oneself in the present in order to concentrate on one’s own feelings, and what is known as ‘compassionate’ meditation, which aims to actively increase positive emotions towards others,” the authors add.
This research is part of a large European study, MEDIT-AGEING, which aims to evaluate the impact of non-pharmacological interventions for better ageing.

Hearing loss cases are climbing globally — 1 in 5 adults are affected — along with a growing number of older workers who are more likely to experience hearing loss. A new study from researchers at Portland State, Oregon State and York universities sheds light on how the severity of an employee’s hearing loss can impact their experience at work — and the steps managers and employers can take to create a more inclusive environment for deaf or hard-of-hearing employees.
The study builds on prior research that says employees with hearing loss experience isolation at work, which can be detrimental to their career outcomes, and finds that tailored support can counter those experiences.
The results suggest that the severity of an employee’s hearing loss influences the degree to which they rely on professional connections for their sense of self, which then has downstream consequences for career outcomes. This is especially true among employees who have an unsupportive supervisor.
The study found that employees with more severe hearing loss tend to fare better, in large part because they tend to disengage from relationships with others at work. The researchers suggest that employees with more severe hearing loss are more likely to experience awkward, anxious and frustrating interactions with co-workers and have a harder time building and maintaining professional connections. Those workers often protect themselves by putting less importance on professional connections. When they care less and are less sensitive to fewer professional connections, their sense of isolation is not as high.
“We are not recommending that managers and supervisors stop worrying about supporting employees with more severe hearing loss; we’re suggesting they offer tailored support,” said Liu-Qin Yang, a professor of industrial-organizational psychology at PSU. She said that even if self-isolation is an effective coping mechanism, those employees ultimately have worse career outcomes in the areas of attitudes, commitment, satisfaction and salary levels.
Yang’s co-authors Brent Lyons of York University and David Baldridge of Oregon State, who are both hard of hearing, offered insights into what that tailored support could look like.

Lyons, whose hearing loss fluctuates from severe to profound to moderate, says his needs vary and it’s helpful when supervisors create a sense of openness for him to request certain accommodations. In one meeting, he might need to be seated next to the speaker; in another, he might need closed captions on the screen.
“That might not always be the case for me and my needs may change,” Lyons said. “But I really appreciate when supervisors are open and touch base on a regular basis: ‘How are things going? What can we do to make sure that you can fully participate?'”
Baldridge, who has experienced full hearing, deafness and now restored hearing with cochlear implants, said flexibility — focusing on the results and not how the work is done — is also important.
When it comes to facilitating professional connections, Baldridge said that organizing a one-on-one meeting or lunch in a quiet location would be more effective for an employee with hearing loss than trying to introduce them to people at a cocktail party. Supervisors can also connect them with employee resource groups or organizations such as the Hearing Loss Association of America (HLAA) and the Association of Late Deafened Adults (ALDA).
Lyons also said that it’s important for supervisors to create a culture of respect and understanding among all of their employees.
“They can advocate on my behalf so co-workers don’t start to think negatively about me if I don’t attend a loud, busy event,” he said. “That could lead to fewer opportunities, which would negatively affect my career.”
The researchers are clear that, regardless of the severity of an employee’s hearing loss, managers can play a critical role in making them feel included by working to understand their abilities, perceptions and limitations and helping them build professional connections that will be helpful throughout their careers.
The study was published in the Journal of Management. Camellia Bryan, a Ph.D. student at York University, is also a co-author.

Reaching out to support a person when they’re under stress is always a good idea. But a new study suggests that support could be especially important for someone whose genetic makeup makes them more likely to develop depression.
The study shows the importance of social support in buffering the risk of developing depression symptoms in general, using data from two very different groups of people under stress: new doctors in the most intense year of training, and older adults whose spouses recently died.
But the largest effect was seen in those who had the most genetic variation that raised the risk of depression.
The paper uses a measure of genetic risk called a polygenic risk score, which is based on decades of research about what tiny variations in specific genes are linked to depression risk.
Compared to individuals in the study who had low depression polygenic risk scores, the doctors and widows with higher risk scores had higher rates of depression after they lost social support, but also had lower rates of depression when they gained social support during stressful times.
The study, published in the American Journal of Psychiatry by a University of Michigan team, suggests that more could be done to target social support to those who can most benefit.

Genes, stress and social connection
“Our data show wide variability in the level of social support individuals received during these stressful times, and how it changed over time,” said first author Jennifer Cleary, M.S., a psychology doctoral student at U-M who is doing her research with senior author Srijan Sen, M.D., Ph.D., of the U-M Medical School. “We hope these findings, which incorporate genetic risk scores as well as measures of social support and depressive symptoms, illuminate the gene-environment interactions and specifically the importance of social connection in depression risk.”
Sen, who is the director of the Eisenberg Family Depression Center and a professor of psychiatry and neuroscience, adds that even as genetic research reveals more of the DNA variation related to depression vulnerability, learning how that variation leads to depression is crucial.
“Further understanding the different genetic profiles associated with sensitivity to loss of social support, insufficient sleep, excessive work stress and other risk factors could help us develop personalized guidance for depression prevention,” he said. “In the meantime, these findings reaffirm how important social connections, social support and individual sensitivity to the social environment are as factors in wellbeing and preventing depression.”
Different populations, similar patterns
The new study used data from two long-term studies that both capture genetic, mood, environment and other data from populations of participating individuals.

One is the Intern Health Study, which enrolls first-year medical residents (also called interns) around the United States and beyond, and which Sen directs.
The other is the Health and Retirement Study, based at the U-M Institute for Social Research and funded by the National Institute on Aging.
The data for the new paper came from 1,011 interns training at hospitals across the country, nearly half of whom were female, and from 435 recently widowed individuals, 71% of them women, who had data available from surveys conducted before and after their spouses died.
In the interns, as Sen and his team have shown in previous work, depressive symptoms increased dramatically (126%) during the stressful year of training that includes long and irregular work hours — often in environments far from friends and family.
In the widows and widowers, depressive symptoms increased 34% over their pre-widowhood scores. This correlates with past research showing loss of a spouse can be one of the biggest stressors in a person’s life, Cleary said.
A crossover effect
Then, the researchers factored together the depression symptom findings with each person’s polygenic risk score for depression, and their individual responses to questions about connections with friends, family and other social supporters.
Most of the interns lost social support from their pre-internship days — which fits well with the common experience of leaving the place where they attended medical school and going to a new environment where they may not know anyone.
Interns who had the highest polygenic risk scores and also lost social support had the highest scores on measures of depression symptoms later in the stressful intern year.
Those with the same high level of genetic risk who gained social support, though, had much lower depressive symptoms. In fact, it was lower than even their peers with low genetic risk, no matter what happened to their social support. The researchers call this a “crossover effect.”
Unlike the interns, some widowed individuals reported an increase in social support after the loss of their spouse, potentially as friends and family reached out to offer help or just a listening ear.
But the crossover effect was visible in them, too. Widows with high genetic risk for depression who gained social support showed a much smaller increase in depressive symptoms than their peers with similar genetic risk who lost social support after losing a spouse.
There were also some widows who lost social support or didn’t experience a change in support, and whose depressive symptoms didn’t change. Cleary notes that in future work, it will be important to look at this group’s history in light of any caregiving they may have done for a spouse with a long-term illness.
The team also hopes that other researchers will study this same interaction of genetic risk, stress and social support in other populations.
In the meantime, Cleary and Sen say, the message for anyone going through stressful times, or watching a friend or relative go through stressful times, is to reach out and maintain or strengthen social connections.
Doing so can have benefits both for the person under stress, and the person reaching out to them, they note.
Reducing the level of ongoing stress that the person is facing, whether it’s at work, school, after a personal loss or in family situations can be critical.
And even though the study did not examine the role of professional mental health help, individual and group therapy is an important option for those who have developed depression or other mental health concerns.
Note: The polygenic risk score used in the study is validated for use on people of mainly European ancestry, which limits the ability to generalize the findings to people of other backgrounds. Sen notes that additional work is being done using data from the Intern Health Study and Health & Retirement Study to develop polygenic risk scores based on depression-related genetic traits in other populations including people of East Asian and African descent.
In addition to Cleary and Sen, the study’s authors are Yu Fang, M.S.E., Laura B. Zahodne, Ph.D., Amy S.B. Bohnert, Ph.D., and Margit Burmeister, Ph.D., all of U-M. Zahodne, Bohnert and Burmeister are members of the Eisenberg Family Depression Center; Sen and Burmeister are members of the Michigan Neuroscience Institute; Sen and Bohnert are members of the U-M Institute for Healthcare Policy and Innovation.
The study was funded by the National Institute of Mental Health (MH101459) and the National Institute of Child Health and Development (HD007109).

Published48 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, MARK R CRISTINO/EPA-EFE/REX/ShutterstockBy Nicholas YongBBC NewsCovid cases will surge in rural China where healthcare is less accessible, a top Chinese epidemiologist has warned.Hundreds of millions of Chinese are travelling to their hometowns – many for the first time since the pandemic began – ahead of the lunar new year.The peak of China’s Covid wave is expected to last two to three months, added Zeng Guang, ex-head of the Chinese Center for Disease Control.China has stopped providing daily Covid statistics since abandoning zero-Covid.However hospitals in big cities – where healthcare facilities are better and more easily accessible – have become crowded with Covid patients as the virus has spread through the country.Speaking at an event earlier this month, Mr Zeng said it was “time to focus on the rural areas”, in remarks reported in the Caixin news outlet.Many elderly, sick and disabled in the countryside were already being left behind in terms of Covid treatment, he added.China’s central Henan province is the only province to have given details of infection rates – earlier this month a health official there said nearly 90% of the population had had Covid, with similar rates seen in urban and rural areas.However government officials say many provinces and cities have passed the peak of infections.The Lunar New Year holidays in China, which officially start from 21 January, involves the world’s largest annual migration of people.Some two billion trips are expected to be made in total and tens of millions of people have already travelled.Chinese hope lunar new year consigns Covid to pastYoung Chinese self-infect amid Covid fears for elderlyLast month, China abruptly abandoned its zero Covid policies. It also reopened its borders on Sunday.Official data shows five or fewer deaths a day over the past month, numbers which are inconsistent with the long queues seen at funeral homes and reports of deaths on social media.In December Chinese officials said they planned to issue monthly rather than daily updates on the Covid situation in the country.The World Health Organisation (WHO) said China, which stopped reporting Covid fatalities from Tuesday, was heavily under-reporting Covid deaths. In response, Foreign Ministry spokesman Wang Wenbin stressed again at a regular press briefing on Thursday that Beijing has been sharing Covid data in “a timely, open and transparent manner in accordance with the law”, having held technical exchanges with the WHO over the past month.International health experts have predicted at least a million Covid-related deaths in China this year. Beijing has officially reported just over 5,000 deaths since the pandemic began, one of the lowest death rates in the world.More on this storyJoy and long queues as China reopens borders4 days ago

Published3 days agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesThe reason chocolate feels good to eat has been uncovered by researchers at the University of Leeds.Scientists analysed the process that takes place when the treat is eaten and focused on texture rather than taste.They claim that where the fat lies within the chocolate helps to create its smooth and enjoyable quality.Dr Siavash Soltanahmadi led the study and hopes the findings will lead to the development of a “next generation” of healthier chocolate.When chocolate is put in the mouth, the surface of the treat releases a fatty film that makes it feel smooth.But the researchers claim fat deeper inside the chocolate plays a more limited role and therefore the amount could be reduced without the feel or sensation of chocolate being affected.Prof Anwesha Sarkar, from the School of Food Science and Nutrition at Leeds, said it is the “location of the fat in the make-up of the chocolate which matters in each stage of lubrication, and that has been rarely researched”.Dr Soltanahmadi said: “Our research opens the possibility that manufacturers can intelligently design dark chocolate to reduce the overall fat content.”The team used an artificial “3D tongue-like surface” that was designed at the University of Leeds to carry out the study and researchers hope the same equipment could be used to investigate other foods that change texture, such as ice cream, margarine and cheese.Follow BBC Yorkshire on Facebook, Twitter and Instagram. Send your story ideas to yorkslincs.news@bbc.co.uk or send video here.More on this storyChocolate research to be revealed at exhibition5 July 2022Sweets at supermarket checkouts – good or bad idea?25 August 2021Related Internet LinksUniversity of LeedsThe BBC is not responsible for the content of external sites.

A team of volunteers are giving up their free time to help revellers in a town.The Hartlepool Ambulance charity patrols the streets at weekends doing what it can to help people who are involved in accidents, assaults and alcohol-related trouble.The volunteers are trained in first aid and aim to reduce pressure on the NHS by directing casualties to the appropriate services.The charity was formed 2017 and costs £25,000 a year to run, which comes from donations.BBC Radio Tees reporter Louise Hobson spent time with them.Follow BBC North East & Cumbria on Twitter, Facebook and Instagram. Send your story ideas to northeastandcumbria@bbc.co.uk.

In the continuing effort to improve upon opioid pain relievers, American and Chinese scientists used cryoEM technology to solve the detailed structures of the entire family of opioid receptors bound to their naturally occurring peptides. Subsequent structure-guided biochemical studies were then performed to better understand the mechanisms of peptide-receptor selectivity and signaling drugs.
This work, published in Cell, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain.
This work was spearheaded by the lab of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China, in collaboration with the lab of Bryan L. Roth, MD, PhD, at the UNC School of Medicine, where graduate student Jeff DiBerto led the pharmacological experiments to understand the receptors’ signaling mechanisms.
Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within our nervous symptoms. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe such as numbness, addiction, and respiratory depression, leading to overdose deaths.
Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors to no avail. One way scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.
Peptides are short chains of amino acids; think of them as short proteins. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief. Think of an analgesic like an anesthetic, except that analgesics do not “turn off” the nerves to numb the body or alter consciousness. So, the idea is to create a peptide drug that has a strong analgesic effect, without numbing nerves or altering consciousness or causing digestive, respiratory, or addiction issues.

“The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology. “We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”
Using cryogenic electron microscopy, or cryoEM, and a battery of biomechanistic experiments in cells, the Xu and Roth labs systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors. The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.
The cryoEM structures of agonist-bound receptors in complex with their G protein effectors (called their “active state”) represents what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions. The Roth lab used the structures solved by the Xu lab to guide the design of mutant receptors, and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling. Understanding these interactions can then be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.
“This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said DiBerto, first author and PhD candidate in the Roth lab. “We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”
Previous research showed the structure of opioid receptors in their inactive or active-like states, with active state structures only existing for the mu-opioid receptor subtype, the primary target of drugs like fentanyl and morphine. In the Cell paper, the authors show agonist-bound receptors in in complex with their G protein effectors, made possible through cryoEM technology that did not exist when currently used medications were being developed.
Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous symptom, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction. Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.
The thrust behind such research led by Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing.
“We are attempting to build a better kind of opioid,” Roth says, “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”
Co-first authors of the Cell paper are Yue Wang and Youwen Zhuang of the CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica in the Chinese Academy of Sciences. Other authors are Edward Zhou and Karsten Melcher of the Van Andel Research Institute in Grand Rapids, MI, Gavin Schmitz and Manish Jain at the UNC School of Medicine, and Qingning Yuan, Weiyi Liu, and Yi Jiant at the CAS Key Laboratory.