The circadian rhythm is coordinated by the brain at a general level, but each organ or tissue is also subjected to specific regulation, adjusting to time to optimise their processes. However it was not known how the liver “knows” whether it is day or night.
The liver’s main role is digestion, mainly of fats and sugars: the brain is the main consumer of sugar while skeletal muscle is the main consumer of fat.
Scientists at IRB Barcelona discovered a surprising relationship: that it is skeletal muscle which regulates liver function and determines fat metabolism. Skeletal muscle accomplishes this by secreting a that is transported to the liver through serum is responsible for modulating around 35% of the metabolic functions of the liver. The remaining basal functions of this organ and others related to carbohydrate metabolism are independent of muscle activity and are regulated by the basal circadian rhythm from the brain.
“It’s a very nice discovery because it is the first demonstration of the need for communication between the circadian clocks of tissues and organs outside the brain, and we can see that this communication between muscle and liver is altered by aging,” said study leader Dr Salvador Aznar-Benitah at IRB Barcelona. “When we get older, cells stop obeying the biological clock and begin to perform functions in a non-optimal manner, leading to errors that cause tissues to age.”
The researcher’s results show that the liver does not independently regulate the metabolism of fats and that it is muscle that sends the message that it is time to switch on fatty acid metabolism and how it should go about this. “We didn’t expect to find this connection between the liver and muscle because it wasn’t known previously, but, on second thought, it makes complete sense that fat management is coordinated by one of its main consumers,” said Dr Aznar-Benitah. Carbohydrate metabolism meanwhile is dependent on the basal coordination exercised by the brain.
Researchers have identified specific drug targets within memory-encoding neural circuits, opening up possibilities for new treatments of a range of brain disorders.
Memory loss is a main feature of a number of neurological and psychiatric disorders including Alzheimer’s disease and schizophrenia. Presently, there are few, very limited memory loss treatments and the search for safe and effective drug therapies has, until now, borne little fruit.
The research was done in collaboration with colleagues at the international biopharmaceutical company Sosei Heptares. The findings, published in Nature Communications, identify specific receptors for the neurotransmitter acetylcholine that re-route information flowing through memory circuits in the hippocampus. Acetylcholine is released in the brain during learning and is critical for the acquisition of new memories. Until now, the only effective treatment for the symptoms of cognitive or memory impairment seen in diseases such as Alzheimer’s is using drugs that broadly boost acetylcholine. However, this leads to multiple adverse side effects. The discovery of specific receptor targets that have the potential to provide the positive effects whilst avoiding the negative ones is promising.
Lead author Professor Jack Mellor from the University of Bristol’s Center for Synaptic Plasticity, said: “These findings are about the fundamental processes that occur in the brain during the encoding of memory and how they may be regulated by brain state or drugs targeting specific receptor proteins. In the long-term, the discovery of these specific targets opens up avenues and opportunities for the development of new treatments for the symptoms of Alzheimer’s disease and other conditions with prominent cognitive impairments. The academic-industry partnership is important for these discoveries and we hope to continue working together on these projects.”
Dr Miles Congreve, Chief Scientific Officer at Sosei Heptares, added: “These important studies have helped us to design and select new, exquisitely targeted therapeutic agents that mimic the effects of acetylcholine at specific muscarinic receptors, without triggering the unwanted side effects of earlier and less-well targeted treatments. This approach has the exciting potential to improve memory and cognitive function in patients with Alzheimer’s and other neurological diseases.”
“It is fascinating how the brain prioritises different bits of information, working out what is important to encode in memory and what can be discarded. We know there must be mechanisms to pull out the things that are important to us but we know very little about how these processes work. Our future program of work aims to reveal how the brain does this using acetylcholine in tandem with other neurotransmitters such as dopamine, serotonin and noradrenaline,” said Professor Mellor.
Researchers believe that antibacterial properties of sugars in human breast milk could be harnessed for new antimicrobial therapies.
Group B Streptococcus (GBS) bacteria are a common cause of blood infections, meningitis and stillbirth in newborns, and are becoming resistant to antibiotics. Researchers have now discovered that human milk oligosaccharides (HMOs), short strings of sugar molecules abundant in breast milk, can help prevent GBS infections in human cells and tissues and in mice. This might yield new antibiotic treatments, the researchers believe.
“Our lab has previously shown that mixtures of HMOs isolated from the milk of several different donor mothers have antimicrobial and antibiofilm activity against GBS,” says Rebecca Moore, who is presenting the work at a meeting of the American Chemical Society (ACS). “We wanted to jump from these in vitro studies to see whether HMOs could prevent infections in cells and tissues from a pregnant woman, and in pregnant mice.” Moore is a graduate student in the labs of Steven Townsend, PhD, at Vanderbilt University and Jennifer Gaddy, PhD, at Vanderbilt University Medical Center.
According to the US Centers for Disease Control and Prevention, about 2000 babies in the U.S. get GBS each year, with 4-6% of them dying from it. The bacteria are often transferred from mother to baby during labour and delivery. An expectant mother who tests positive for GBS is usually given intravenous antibiotics during labor to help prevent early-onset infections, which occur during the first week of life. Notably, late-onset infections (which happen from one week to three months after birth) are more common in formula-fed than breastfed infants, suggesting breast milk has factors which could help protect against GBS. If so, the sugars could be a replacement for current antibiotics which are steadily becoming less effective.
The researchers studied the effects of combined HMOs from several mothers on GBS infection of placental macrophages and of the gestational membrane. “We found that HMOs were able to completely inhibit bacterial growth in both the macrophages and the membranes, so we very quickly turned to looking at a mouse model,” Moore says. They examined whether HMOs could prevent a GBS infection from spreading through the reproductive tract of pregnant mice. “In five different parts of the reproductive tract, we saw significantly decreased GBS infection with HMO treatment,” Moore notes.
To determine which HMOs and other oligosaccharides have these antimicrobial effects and why, the researchers made an artificial two-species microbiome with GBS and the beneficial Streptococcus salivarius species growing in a tissue culture plate, separated by a semi-permeable membrane. Then, the researchers added oligosaccharides that are commonly added to infant formula, called galacto-oligosaccharides (GOS), which are derived from plants. In the absence of the sugar, GBS suppressed the growth of the “good” bacteria, but GOS helped this beneficial species grow. “We concluded that GBS is producing lactic acid that inhibits growth, and then when we add the oligosaccharide, the beneficial species can use it as a food source to overcome this suppression,” Moore explained. The first HMOs tested did not have this effect, but Townsend says it’s likely that one or more of the over 200 unique sugars in human milk will show activity in the artificial microbiome assay. There are likely two reasons why HMOs can treat and prevent GBS infection: they prevent pathogens from sticking to tissue surfaces and forming a biofilm, and they could also act as a prebiotic by promoting good bacteria growth.
“HMOs have been around as long as humans have, and bacteria have not figured them out. Presumably, that’s because there are so many in milk, and they’re constantly changing during a baby’s development,” Townsend said. “But if we could learn more about how they work, it’s possible that we could treat different types of infections with mixtures of HMOs, and maybe one day this could be a substitute for antibiotics in adults, as well as babies.”
There is an urgent need for more standardised and detailed reporting of research on mammalian cells, and for greater control over and measurement of the environmental conditions of cell cultures, according to a recent study. This will improve the precision of human physiology models and contribute to the reproducibility of research.
Researchers analysed 810 randomly selected papers on mammalian cell lines. Fewer than 700 of those, involving 1749 individual cell culture experiments, included relevant data on the environmental conditions of the media in which the cells were cultured. The analysis suggests that the relevance and reproducibility of this type of research needs significant improvement.
“Mammalian cell cultures are fundamental to manufacturing viral vaccines and other biotechnologies,” explained marine scientist, Shannon Klein. “They are used to study basic cell biology, replicate disease mechanisms and investigate the toxicity of novel drug compounds before they are tested on animals and humans.”
Though cells are cultured in controlled incubators in line with standard protocols, cells grow and ‘breathe’ over time and exchange gases with their surrounding environment. This impacts their immediate environment, and even these small changes can affect parameters like culture acidity and dissolved oxygen and carbon dioxide. These changes in turn can affect cell function, causing different conditions to that found in a living human body.
The researchers found that around half of the papers analysed failed to report the temperature and carbon dioxide settings of their cell cultures. Less than 10 percent reported the atmospheric oxygen levels in the incubator and less than 0.01 percent reported the medium’s acidity. No papers reported the dissolved oxygen or carbon dioxide in their media.
“We were very surprised that researchers largely overlooked the maintenance of environmental factors, like culture acidity, at levels relevant to the physiological body over the full course of the cell cultures, despite it being well known that this is important for cell function,” said Ph.D. student Samhan Alsolami.
The team, led by KAUST’s marine ecologist Carlos Duarte and stem cell biologist Mo Li in collaboration with developmental biologist Juan Carlos Izpisua Belmonte from the Salk Institute, who is currently a visiting professor at KAUST, recommends that biomedical scientists develop standard reporting and control and measuring procedures, in addition to employing specialised instruments for controlling the culture environments of different cell types. Additionally, scientific journals should establish reporting standards and require adequate monitoring and control of culture medium acidity and dissolved oxygen and carbon dioxide.
“Better reporting, measurement and control of the environmental conditions of cell cultures should improve how well scientists can repeat and reproduce experimental results,” said Alsolami. “More careful attention could drive new discoveries and increase the relevance of preclinical research to the human body.”
A new study has helped researchers understand the experiences of people who withdraw from clinical cancer trials.
Cancer clinical trials (CCTs) provide patients with an opportunity to receive experimental drugs, tests, and/or procedures that may lead to remissions. Such opportunities can be a great benefit for those who took part, but there is little known of the experiences of participants who withdraw from CCTs.
To address this, a first-of-its-kind study from the University of Pennsylvania School of Nursing (Penn Nursing) was conducted to better understand the post-trial needs of these patients and define responsible transitions when patients exit CCTs.
“Understanding the post-trial needs of patients with cancer and their families represents a measure of ethical respect of the many contributions that patients with cancer make to advancing our scientific knowledge and finding treatments that save lives,” said the study’s lead researcher, Connie M Ulrich, the Lillian S Brunner Chair in Medical and Surgical Nursing, professor of nursing, professor of medical ethics and health policy.
The study revealed three important areas:
Patients exiting CCTs feel intense symptoms, emotions, and awareness that their life spans are short and options seem limited.
The limited discussions with patients who are exiting on their immediate post-trial care needs can result in many feeling that there is no clear path forward.
Good communication that deliberately includes attention to post-trial needs throughout the CCT is needed to help scared and disappointed patients navigate their next steps.
A small study has shown that a doctor’s presence during a blood pressure measurement skews the results, according to researchers who studied the effect by measuring nerve activity.
The phenomenon known as ‘white coat hypertension‘ is where the mere presence of a medical professional can raise blood pressure. Known about for decades, it occurs in about a third of patients.
In a small study published in the journal Hypertension, researchers probed the effect by measuring blood pressure, heart rate and nerve traffic in the skin and muscles with and without a doctor present.
The researchers found a “drastic reduction” in the body’s alarm response when a doctor was not present, said co-lead author Dr Guido Grassi, professor of internal medicine at the University of Milano-Bicocca.
Blood pressure and heart rate increases in response to a perceived threat, said Dr Meena Madhur, associate professor of medicine in the divisions of clinical pharmacology and cardiology at Vanderbilt University.
“If you’re out in the wild and a bear was charging after you, you’d want your blood vessels in your skin, for example, to constrict and the blood vessels in your muscles to dilate to provide more blood flow to those organs so that you can run really fast,” said Prof Madhur, who was not involved in the new research.
The study included 18 people, 14 of them men, with untreated mild to moderate hypertension. Each participant was examined in a lab, where an electrode measured nerve activity in the skin and muscles. Readings were taken twice in the presence of a doctor and twice without.
Both blood pressure and heart rate rose when the doctor was present, with nerve traffic patterns to the skin and skeletal muscle suggesting a classic fight or flight reaction.
Without the doctor’s presence, cardiovascular and neural responses were “strikingly different,” the researchers wrote. Fight or flight response indications were “entirely absent”.
Peak systolic blood pressure was an average of 14 points lower when the participant was alone than when a doctor was present, and peak heart rate was lowered by nearly 11 beats per minute.
This was the first study to actually measure sympathetic nervous system responses to doctors supervising a blood pressure measurement, the researchers wrote.
The study’s findings illustrated the complexity of blood pressure measurement and how it is affected by involuntary nervous system reactions, Grassi said. “Measurements without the doctor’s presence may better reflect true blood pressure values.”
White coat hypertension is not a new concept, Prof Madhur said, “this just drives home the fact that we should be more conscious of how the blood pressure is taken in the clinic.”
Last year, the American Medical Association and AHA issued a joint report endorsing more blood pressure measurement at home.
Limitations included the small study size due to the complexity of the measurements, the researchers said. Subsequent research would need to examine blood pressure medication as they could affect the fight or flight response, said Orof Madhur.
The work needs to be repeated with more women to examine possible sex differences. And she’d be interested in seeing whether people have the same response to nurses and other medical professionals as they did to doctors in this study.
Previous work shows that when nurses take blood pressure measurements, the white coat effect is reduced.
This latest research emphasises the need for people to handle blood pressure measurements with care, Prof Madhur said.
“I always tell my patients that we really can’t rely on a single office blood pressure measurement, because that’s just a random point in time,” she said.
Prof Madhur said that to take an accurate reading at home, a patient should sit still, with their back straight and supported and feet on the floor, waiting at least a few minutes before recording blood pressure. They should take multiple readings at the same time of day over the course of a week, and bring that log to their doctor’s appointment. Those at-home readings should be the ones used for planning treatment, she said.
“But,” Prof Madhur added, “if we are going to do an office blood pressure reading, it should be taken with the doctor not in the room.”
A group of newly discovered bacteriophages named after the UK village of Colney could help combat C. difficile infections.
Clostridioides difficile, or C. diff, is a species of bacteria that infects the human gut. It can become a major problem when our normal gut microbes are impaired, most commonly during a course of antibiotics. This leads to an overgrowth of C. diff, with toxins it produces causing diarrhoea and severe inflammation.
Treatment involves further courses of antibiotics, but relapse and recurrent infections are common. The strains are becoming more resistant to antibiotics and causing more severe illness.
This prompted researchers in Norwich to look for the bacteria’s natural enemy, bacteriophages. They screened 27 different C. diff strains for any bacteriophages, finding one, which they called ΦCD27 (phiCD27). Genome sequencing confirmed this phage had not been discovered before. In fact, the members of the International Committee on Taxonomy of Viruses (ICTV) decided it was genetically distinct enough to form a new group, or genus of phages.
The ICTV decided to name the new genus Colneyvirus, the Colney parish address of the Institute of Food Research (IFR, now part of Quadram Institute), where it was first discovered.
Like normal viruses, phages reproduce by injecting their genetic material into bacteria, making viral copies using the host’s own machinery. Using enzymes called endolysins, they destroy the bacterial cell wall and escape.
The researchers extracted the gene for ΦCD27’s endolysin and put it into another bacterium, E. coli so that they could produce and purify the endolysin. It was proven active against 30 different C. diff strains, including hypervirulent strains behind the current epidemic. It also didn’t affect other common bacterial species in the human gut microbiome.
”This phage and the endolysin encoded by its genome can provide a targeted approach to combat C. diff infections, in contrast to use of broad spectrum antibiotics that cause collateral damage by inhibiting other members of the gut bacterial population” said Professor Arjan Narbad, Group Leader at the Quadram Institute.
However, to be effective the endolysins need to be delivered into the gut, so the team also put the gene into a strain of lactic acid bacteria that has previously been used to deliver proteins and vaccines to the gut.
The research team believes this could serve as the basis for future new treatments C. diff. The system needs more work, but in the battle against this bacterial pandemic, the colneyvirus could be a vital ally.
After 60 years of fruitless searches by scientists, researchers from the University of Virginia have finally determined the location of our bodies’ natural blood-pressure sensors.
These cellular sensors monitor blood pressure and adjust hormone levels to keep it in check. Scientists have long suspected that these ‘baroreceptors’, may exist in or around specialised kidney cells called renin cells, but no one has been able to locate the baroreceptors within the cell until now.
The new findings, from UVA Health’s Dr Maria Luisa S Sequeira-Lopez and colleagues, finally reveal where the barometers are located, how they work and how they help prevent hypertension or hypotension. The study was published in Circulation Research.
“It was exhilarating to find that the elusive pressure-sensing mechanism, the baroreceptor, was intrinsic to the renin cell, which has the ability to sense and react, both within the same cell,” said Dr Sequeira-Lopez. “So the renin cells are sensors and responders.”
Back in 1957, it was first proposed that a pressure sensor existed inside renin cells because the cells had to know when to release renin, a hormone that helps regulate blood pressure. Though the baroreceptors had to exist, scientists couldn’t tell what it was and whether it was located in renin cells or surrounding cells.
To tackle this decades-old mystery, the study’s researchers used a combination of innovative lab models and determined that the baroreceptor was a ‘mechanotransducer’ inside renin cells. This mechanotransducer detects pressure changes outside the cell, then transmits these mechanical signals to the cell nucleus, akin to how the cochlea turns sound vibrations into nerve impulses.
Through in vitro tests, the researchers found that applying pressure to renin cells triggered changes within the cells and decreased activity of the renin gene, Ren1. The scientists also compared differences in gene activity in kidneys exposed to lower pressure and those exposed to higher pressure.
Ultimately, when the baroreceptors detect excess pressure outside the renin cell, renin production is cut back, while low blood pressure prompts more renin production.
Dr Sequeira-Lopez said she is looking forward to the work to “unravel the signaling and controlling mechanisms of this mechanotransducer and how we can use the information to develop therapies for hypertension.”
Researchers from Japan have found a protein that promotes the development of the early stages of emphysema, which could prove to be a target for treatment of the serious disease.
Chronic obstructive pulmonary disease (COPD) causes illness and death worldwide, and is characterised by destruction of the alveolar walls in the lungs, known as emphysema, resulting in lung function declining and to date little is known about how it develops. The Global Initiative for chronic obstructive lung disease (GOLD) has defined COPD as “a common, preventable, and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”
It is known that COPD can be triggered by certain environmental factors, such as cigarette smoking, which result in lung inflammation. The development of inflammation involves the movement of molecules inside cells, and this “intracellular trafficking” is known to play a part in some diseases. The team searched for COPD-related proteins that are involved in trafficking and identified a protein called FCHSD1, which not known to have any lung function but is associated with some diseases.
The researchers deleted the FCHSD1 protein in mice and studied these mice against normal mice when emphysema was induced. In normal mice, a large increase was seen in FCHSD1 after treatment, while mice lacking FCHSD1 were protected from the development of emphysema. These mice showed less airspace expansion from damaged air sacs, and had less inflammation and reduced apoptosis.
The researchers went on to investigate the molecular mechanism by which FCHSD1 acts. In response to stress, a protein called NRF2 moves into the nucleus to protect it. However, FCHSD1 binds to NRF2, stopping it from moving to the nucleus. “Mice with a FCHSD1 deficiency showed enhanced nuclear translocation of NRF2 and a smaller reduction in SIRT1 levels, which is seen to occur as emphysema develops,” explained lead author Takahiro Kawasaki, “and this reduced inflammation and apoptosis of lung cells.”
Increasing the activity of NRF2 to counteract FCHSD1 could therefore be a potential therapy for COPD. Treatments are currently available that target NRF2, and inhibiting FCHSD1 while targeting NRF2 could enhance these treatments and prevent systemic complications. “Our findings may also lead to a specific therapeutic strategy to ameliorate, or even halt, the progression of emphysema by inhibiting FCHSD1,” said Takashi Satoh, senior author of the paper.
A protein found in the venom of one of the world’s deadliest spiders has been shown to preserve heart cells, and could be developed into a potentially life-saving treatment for heart attack victims.
A drug candidate developed from a molecule found in the venom of the Fraser Island (K’gari) funnel web spider can prevent damage caused by a heart attack and extend the life of donor hearts used for organ transplants. This would not be the first investigation into a clinical application for spider venom, however. Tarantula spider venom has also been investigated as a potent anaesthetic.
The discovery was made by a team led by Dr Nathan Palpant and Professor Glenn King from The University of Queensland (UQ) and Professor Peter Macdonald from the Victor Chang Cardiac Research Institute.
Dr Palpant, from UQ’s Institute for Molecular Bioscience (IMB), said the drug candidate worked by stopping a ‘death signal’ sent from the heart in the wake of an attack.
“After a heart attack, blood flow to the heart is reduced, resulting in a lack of oxygen to heart muscle,” Dr Palpant said. “The lack of oxygen causes the cell environment to become acidic, which combine to send a message for heart cells to die.
“Despite decades of research, no one has been able to develop a drug that stops this death signal in heart cells, which is one of the reasons why heart disease continues to be the leading cause of death in the world.”
Using beating human heart cells exposed to heart attack stresses, Dr Palpant tested the drug candidate, a protein called Hi1a, to see if the drug improved the cells’ survival.
“The Hi1a protein from spider venom blocks acid-sensing ion channels in the heart, so the death message is blocked, cell death is reduced, and we see improved heart cell survival.”
At present, there are no drugs in clinical use that prevent the damage caused by heart attacks.
Professor Macdonald of Victor Chang Cardiac Research Institute said that this incredible result had been decades in the making.
“This will not only help the hundreds of thousands of people who have a heart attack every year around the world, it could also increase the number and quality of donor hearts, which will give hope to those waiting on the transplant list,” said Professor MacDonald, who is also a senior cardiologist at St Vincent’s Hospital in Sydney.
“The survival of heart cells is vital in heart transplants — treating hearts with Hi1a and reducing cell death will increase how far the heart can be transported and improve the likelihood of a successful transplant,” added Prof MacDonald. “Usually, if the donor heart has stopped beating for more than 30 minutes before retrieval, the heart can’t be used — even if we can buy an extra 10 minutes, that could make the difference between someone having a heart and someone missing out. For people who are literally on death’s door, this could be life-changing.”
The discovery builds on earlier work by Professor King, who identified a small protein in the venom of the Fraser Island (K’gari) funnel-web spider that was shown to markedly improve recovery from stroke.
“We discovered this small protein, Hi1a, amazingly reduces damage to the brain even when it is given up to eight hours after stroke onset,” Professor King said.
“It made sense to also test Hi1a on heart cells, because like the brain, the heart is one of the most sensitive organs in the body to the loss of blood flow and lack of oxygen.
“For heart attack victims, our vision for the future is that Hi1a could be administered by first responders in the ambulance, which would really change the health outcomes of heart disease.”
“This is particularly important in rural and remote parts of Australia where patients and treating hospitals can be long distances apart — and when every second counts.”
Also, this could help for the transfer of donor hearts for cardiac transplantation — allowing these donor hearts to be transported over longer distances and therefore increasing the network of available donors and recipients.
The protein has been tested in human heart cells, and the team are aiming for human clinical trials for both stroke and heart disease within 2-3 years.
Journal information: Meredith A. Redd, et al. Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation, 2021; DOI: 10.1161/CIRCULATIONAHA.121.054360
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