Researchers from the University of Kent’s School of Biosciences have combined computational and microbiology laboratory approaches to identify existing drugs that can be repurposed to combat antibiotic-resistant bacterial infections, instead of developing new ones.
This research, which has been published in the Journal of Infectious Diseases, revealed that a class of steroid drugs currently used in hormone replacement therapy (HRT) can also stop the growth of antibiotic-resistant E. coli and effectively kill MRSA.
These drugs are particularly good at binding to a protein complex, cytochrome bd, which is important for the growth and survival of a range of disease-causing bacterial species. The researchers made an in silico screening for drugs that could inhibit bd activity, and identified quinestrol, ethinyl estradiol and mestranol, then evaluated their effectiveness in vitro.
The steroid drugs ethinyl estradiol and quinestrol inhibited E. coli bd-I activity. The IC50 of quinestrol for inhibiting oxygen consumption in E. coli bd-I-only membranes as 0.2µg/mL, although residual activity remained at around 20% at higher concentrations Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli.
It is expected that steroids may provide an alternative to conventional antibiotics that are becoming increasingly ineffective.
Dr Mark Shepherd, Reader in Microbial Biochemistry at Kent and the corresponding author on the paper, said: “These exciting developments will help to advance research into new antimicrobials, and we are enthusiastic to use our powerful experimental approach to discover drugs that can target other bacterial proteins and combat a wide range of antibiotic-resistant infections.”
A team of scientists has developed the first 3D-printed brain tissue that can grow and function like typical brain tissue. This has important implications for scientists studying the brain and working on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimer’s and Parkinson’s disease.
“This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans,” says Su-Chun Zhang, professor of neuroscience and neurology at UW-Madison’s Waisman Center. “It could change the way we look at stem cell biology, neuroscience, and the pathogenesis of many neurological and psychiatric disorders.”
Printing methods have limited the success of previous attempts to print brain tissue, according to Zhang and Yuanwei Yan, a scientist in Zhang’s lab. The group behind the new 3D-printing process described their method today in the journal Cell Stem Cell.
Instead of using the traditional 3D-printing approach, stacking layers vertically, the researchers went horizontally. They situated brain cells, neurons grown from induced pluripotent stem cells, in a softer “bio-ink” gel than previous attempts had employed.
“The tissue still has enough structure to hold together but it is soft enough to allow the neurons to grow into each other and start talking to each other,” Zhang says.
The cells are laid next to each other like pencils laid next to each other on a tabletop.
“Our tissue stays relatively thin and this makes it easy for the neurons to get enough oxygen and enough nutrients from the growth media,” Yan says.
The results speak for themselves – which is to say, the cells can speak to each other. The printed cells reach through the medium to form connections inside each printed layer as well as across layers, forming networks comparable to human brains. The neurons communicate, send signals, interact with each other through neurotransmitters, and even form proper networks with support cells that were added to the printed tissue.
“We printed the cerebral cortex and the striatum and what we found was quite striking,” Zhang says. “Even when we printed different cells belonging to different parts of the brain, they were still able to talk to each other in a very special and specific way.”
The printing technique offers precision – control over the types and arrangement of cells – not found in brain organoids, miniature organs used to study brains. The organoids grow with less organisation and control.
“Our lab is very special in that we are able to produce pretty much any type of neurons at any time. Then we can piece them together at almost any time and in whatever way we like,” Zhang says. “Because we can print the tissue by design, we can have a defined system to look at how our human brain network operates. We can look very specifically at how the nerve cells talk to each other under certain conditions because we can print exactly what we want.”
That specificity provides flexibility. The printed brain tissue could be used to study signaling between cells in Down syndrome, interactions between healthy tissue and neighboring tissue affected by Alzheimer’s, testing new drug candidates, or even watching the brain grow.
“In the past, we have often looked at one thing at a time, which means we often miss some critical components. Our brain operates in networks. We want to print brain tissue this way because cells do not operate by themselves. They talk to each other. This is how our brain works and it has to be studied all together like this to truly understand it,” Zhang says. “Our brain tissue could be used to study almost every major aspect of what many people at the Waisman Center are working on. It can be used to look at the molecular mechanisms underlying brain development, human development, developmental disabilities, neurodegenerative disorders, and more.”
The new printing technique should also be accessible to many labs. It does not require special bio-printing equipment or culturing methods to keep the tissue healthy, and can be studied in depth with microscopes, standard imaging techniques and electrodes already common in the field.
The researchers would like to explore the potential of specialization, though, further improving their bio-ink and refining their equipment to allow for specific orientations of cells within their printed tissue..
“Right now, our printer is a benchtop commercialised one,” Yan says. “We can make some specialised improvements to help us print specific types of brain tissue on-demand.”
Colourised electron micrograph image of a macrophage. Credit: NIH
A new study reveals that immune cells in the liver react to high cholesterol levels and eat up excess cholesterol that can otherwise cause damage to arteries. The findings, published in Nature Cardiovascular Research, suggest that the response to the onset of atherosclerosis begins in the liver.
Immediate response from the liver
In the current study, researchers from Karolinska Institutet wanted to understand how different tissues in the body react to high levels of LDL, commonly called ‘bad cholesterol’, in the blood.
To test this, they created a system where they could quickly increase the cholesterol in the blood of mice.
“Essentially, we wanted to detonate a cholesterol bomb and see what happened next,” says Stephen Malin, lead author of the study and principal researcher at the Department of Medicine, Solna, Karolinska Institutet.
“We found that the liver responded almost immediately and removed some of the excess cholesterol.”
However, it wasn’t the typical liver cells that responded, but a type of immune cell called Kupffer cells that are known for recognising foreign or harmful substances and eating them up. The discovery made in mice was also validated in human tissue samples.
“We were surprised to see that the liver seems to be the first line of defence against excess cholesterol and that the Kupffer cells were the ones doing the job,” says Stephen Malin.
“This shows that the liver immune system is an active player in regulating cholesterol levels, and suggests that atherosclerosis is a systemic disease that affects multiple organs and not just the arteries.”
Several organs could be involved
The researchers hope that by understanding how the liver and other tissues communicate with each other after being exposed to high cholesterol, they can find new ways to prevent or treat cardiovascular and liver diseases.
“Our next step is to look at how other organs respond to excess cholesterol, and how they interact with the liver and the blood vessels in atherosclerosis,” says Stephen Malin. “This could help us develop more holistic and effective strategies to combat this common and deadly disease.”
University of Michigan researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. The findings, published in Nature Neuroscience, could help unravel how we sense and suffer from cold temperature in the winter, and why some patients experience cold differently under particular disease conditions.
“The field started uncovering these temperature sensors over 20 years ago, with the discovery of a heat-sensing protein called TRPV1,” said neuroscientist Shawn Xu, a professor at the U-M Life Sciences Institute and a senior author of the new research.
“Various studies have found the proteins that sense hot, warm, even cool temperatures – but we’ve been unable to confirm what senses temperatures below about 60 degrees Fahrenheit (15.5°C).”
In a 2019 study, researchers in Xu’s lab discovered the first cold-sensing receptor protein in Caenorhabditis elegans, a species of millimetre-long worms that the lab studies as a model system for understanding sensory responses.
Because the gene that encodes the C. elegans protein is evolutionarily conserved across many species, including mice and humans, that finding provided a starting point for verifying the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2).
For this latest study, a team of researchers from the Life Sciences Institute and the U-M College of Literature, Science, and the Arts tested their hypothesis in mice that were missing the GluK2 gene, and thus could not produce any GluK2 proteins. Through a series of experiments to test the animals’ behavioural reactions to temperature and other mechanical stimuli, the team found that the mice responded normally to hot, warm and cool temperatures, but showed no response to noxious cold.
GluK2 is primarily found on neurons in the brain, where it receives chemical signals to facilitate communication between neurons. But it is also expressed in sensory neurons in the peripheral nervous system.
“We now know that this protein serves a totally different function in the peripheral nervous system, processing temperature cues instead of chemical signals to sense cold,” said Bo Duan, U-M associate professor of molecular, cellular, and developmental biology and co-senior author of the study.
While GluK2 is best known for its role in the brain, Xu speculates that this temperature-sensing role may have been one of the protein’s original purposes. The GluK2 gene has relatives across the evolutionary tree, going all the way back to single-cell bacteria.
“A bacterium has no brain, so why would it evolve a way to receive chemical signals from other neurons? But it would have great need to sense its environment, and perhaps both temperature and chemicals,” said Xu, who is also a professor of molecular and integrative physiology at the U-M Medical School. “So I think temperature sensing may be an ancient function, at least for some of these glutamate receptors, that was eventually co-opted as organisms evolved more complex nervous systems.”
In addition to filling a gap in the temperature-sensing puzzle, Xu believes the new finding could have implications for human health and well-being. Cancer patients receiving chemotherapy, for example, often experience painful reactions to cold.
“This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated,” Xu said.
Viral infections trigger more cases of intussusception in young children than previously thought, according to a new study. The research, led by Murdoch Children’s Research Institute (MCRI) and published in Clinical Infectious Diseases, found that during the COVID lockdowns, hospital admissions for intussusception, a medical emergency involving obstruction of the intestine, among young children significantly decreased.
For the study, 12 years of data was analysed across Victoria, NSW and Queensland. A total of 5589 intussusception cases were recorded between January, 2010 and April, 2022. Of those, 3179 were children under the age of two.
During the lockdown periods, Victoria and NSW experienced a decline in hospital admissions for intussusception among children under two by 62.7% and 40.1%, respectively. The rate of intussusception cases has now returned to normal levels.
MCRI and Monash University researcher Dr Ben Townley said the magnitude of the decline supported that common respiratory diseases such as colds, the flu and respiratory syncytial virus (RSV), were behind a significant proportion of intussusception cases.
“Reductions in intussusception hospital admissions were seen in all age groups, however most occurred in children less than two years of age,” he said.
“Intussusception is the leading cause of acute bowel obstruction in infants and young children and without prompt diagnosis and management, can be fatal.
“Countries with prolonged COVID lockdowns and suppression strategies saw reductions in common respiratory viruses, which influenced the drop in intussusception admissions.”
Victoria experienced the greatest lockdown duration, with Melbourne having six lockdown periods, for a total of 263 days. Greater Sydney had 159 days and Brisbane had 18 days in lockdown.
MCRI Professor Jim Buttery said the decrease in intussusception cases was greater than expected given previous research into the causes of the condition.
“Our analysis found commons viruses play a larger role than previously recognised in triggering intussusception,” he said.
Professor Buttery said the findings raised the possibility that emerging vaccines like the new RSV vaccines may help prevent intussusception.
“When a new vaccine against common childhood respiratory viruses is introduced, we may find there are some unexpected benefits, like protecting more children from intussusception,” he said.
Researchers from Sydney Children’s Hospital Network, University of Melbourne and Queensland Health also contributed to the findings.
Research into the link between disordered sleep and disease show an outsized burden on the most vulnerable. It’s sounding alarms for sleep equity to have a place on the public health agenda, reports Ufrieda Ho.
Scientists are increasingly connecting the dots on how a lack of sleep places a disproportionate health burden on at-risk population groups, including people living with HIV, women, informal workers, the elderly and the poor.
This year’s World Sleep Day on 15 March focuses on sleep equity. Researchers say that tackling sleep inequity and raising awareness for the importance of sleep as a pillar of good health could help stave off several looming public health pressures.
The lack of healthy sleep is linked to cardiovascular disease, obesity, hypertension, diabetes, mental health conditions and dementia. In South Africa, understanding the connection between sleep and HIV is also key to managing the health of the large ageing population of people living with the disease.
Karine Scheuermaier is associate professor at the Wits University Brain Function Research Group. The country’s oldest sleep laboratory founded in 1982 is based at the university’s medical school in Parktown, Johannesburg.
“Society understands the role of exercise and diet in good health but somehow sleep has not had the same kind of awareness or priority, even if sleep is linked to how well your body functions and your chances of developing disease,” she says. “We do everything else at the expense of sleep. Sleep is somehow a symbol of laziness in a work-driven society and we need to change this thinking.”
Sleep inequity in SA
Sleep inequity is linked to socio-economic realities, she says. Sleep inequity might affect the person who lives in an environment where safety and security is neglected or where there is a high threat of gender-based violence. It could also be having to navigate apartheid city planning that forced black people to live far from job hubs. This legacy means today many workers still wake up early to face long work commutes daily. There could also be inequity in division of labour in households, when one person wakes up to take care of children or elderly family members in the home.
Living in overcrowded informal settlements also presents disturbances for good sleep, including high levels of noise and bright floodlights as street lighting. Those who work in unregulated or informal sectors, including shift work or digital platform workers, like e-hailing drivers, are prone to lose out on quality sleep.
clinic that does clinical work, research, and training. Chandiwana says homing in on the intersection of HIV and sleep is critical in a South African context.
“The average person living with HIV who has started antiretroviral treatment on time should live as long as a person who doesn’t have HIV. But what we know is that the person with HIV is on average, living 16 years less of good health. They are more likely to develop type II diabetes, mental health issues, obesity, and heart disease – and we know poor sleep is linked to this,” she says.
Chandiwana says sleep science is still a relatively new field of medicine and the nascent research is still looking to better understand how sleep deprivation triggers immune pathways and chronic inflammation in people living with HIV, even those who are healthy and respond positively on treatment.
A current study at the clinic is looking into the intersection of obesity, sleep apnoea, and women living with HIV. Chandiwana says because so much is unknown, the issue of sleep equity extends to support and funding for more locally appropriate sleep research. Medical school curricula needs to change and more avenues to train people in sleep research needs to be established, she says.
“We have very little African data on sleep disorders and disordered sleep,” she says. She argues we need better data on things like how many people are affected by poor sleep, a better understanding of what is causing it and what it means, and then we need to present these findings to public health authorities to look at it as a public health issue.
“We do have specific challenges in our country. If you are trying to explain to someone, who isn’t South African, how the impact of load-shedding affects sleep or how living in a shack affects sleep, it’s not always easy to do,” she says.
Chandiwana says countries in the global North are already counting insufficient quality sleep as an economic cost measured in loss of productivity, efficiency, safety and society’s well-being. They are also changing public health policies accordingly. South Africa and the rest of the continent stand to be left behind, she says.
How to get better sleep in SA
Chandiwana says: “There is no lab in South Africa that does sleep studies for people in the public sector and no place in the public sector for people to even be diagnosed for a sleep disorder – so services are extremely limited. With something like sleep apnoea, we can’t offer patients in the public sector the gold standard intervention of CPAP [continuous positive airway pressure, which is a device of a face mask, a nose piece, and a hose that delivers a steady flow of air pressure to keep airways open while someone sleeps] because this is financially out of reach. Instead, we have to work with patients to help them lose weight and do positional therapy like training them to sleep on their backs.”
Other ways to get better sleep without costly intervention or sleeping tablets, the two scientists say, include getting exercise, not having food, stimulants or alcohol two to three hours before bedtime, limiting screen time of all kinds in the hour around bedtime, getting exposure to the early morning sunlight each day, keeping sleeping areas dark, quiet and at a comfortable temperature, and developing fixed sleep routines and sleep time rituals – like brushing your teeth, putting on pyjamas, reading for a short period and then going to sleep.
Ultimately, Chandiwana suggests it all comes back to building awareness that healthy sleep is part of health rights.
“We have to fight for sleep equity and we need people to know that sleep is not elitist – it’s not just reserved for some,” she says, “and we should not be accepting poor sleep as the norm”.
