Culture

People with bipolar disorder may not take their medication because of side effects, fear of addiction and a preference for alternative treatment - according to research from Norfolk and Suffolk NHS Foundation Trust (NSFT) and the University of East Anglia (UEA).

Nearly half of people with bipolar disorder do not take their medication as prescribed leading to relapse, hospitalisation, and increased risk of suicide.

A new study, published today, reveals six key factors that stop people taking their medication as prescribed.

These include whether they are experiencing side effects, difficulties in remembering to take medication and a lack of support from family, friends and healthcare professionals.

A patient's own beliefs and knowledge about bipolar disorder and its treatment was also found to affect whether or not they take their meds, as well as fear of addiction, and a preference for alternative treatment.

The new study comes from a team of pharmacists, psychiatrists, and experts in behavioural science from NSFT, UEA, Devon Partnership Trust, and the University of Lyon.

Asta Ratna Prajapati, consultant pharmacist at NSFT and a post-graduate researcher at UEA's School of Pharmacy, led the research. The study was funded by a Health Education England (HEE) / National Institute for Health Research Clinical Doctoral Research Fellowship.

He said: "Bipolar disorder is a mental health condition that causes extreme mood swings that include emotional highs, known as mania or hypomania, and depressive lows.

"Around half of people with bipolar disorder don't take their medication which can lead to a relapse of symptoms. And this can have a knock-on impact with problems at work, strained relationships with family and friends, hospitalisation, and an increased risk of suicide.

"We wanted to better understand what stops people from taking their medication."

The research team looked at the evidence for what hinders people taking their medication for bipolar disorder. The research team carried out a systematic review and included 57 studies, mostly surveys and interviews, involving 32894 patients and healthcare professionals. The majority (79 per cent) of the studies were conducted in the USA and Europe.

"We found six key factors that affect whether people take their medication. The main reason being what the medication is like, whether there are side effects, and whether it works," said Prajapati.

"Secondly, we found that a patient's beliefs and knowledge about bipolar disorder and its treatment could stop them taking medication.

"We also found that how patients felt taking their medication had an impact - for example a fear of addiction or worry about negative side effects.

"Other factors included a lack of support, difficulty remembering taking medication and not wanting to take it for reasons including preferring alternative treatment.

"We recommend that the prescribers talk to patients about their thoughts and experiences of the medications they take, paying particular attention to these issues which may stop patients taking their meds."

The research team are now developing a tool to identify people who struggle to take their medication and their individual reasons. They hope it will help prescribers and patients work together and offer bespoke support to make medication taking easier.

'Mapping modifiable determinants of medication adherence in bipolar disorder (BD) to the theoretical domains framework (TDF): a systematic review is published in the Psychological Medicine Journal on May 19, 2021.

Researchers at the University of Eastern Finland have found a potential neuroprotective effect of a protein modification that could be a therapeutic target in early Alzheimer's disease. The new study investigated the role of MECP2, a regulator of gene expression, in Alzheimer's disease related processes in brain cells. The study found that phosphorylation of MECP2 protein at a specific amino acid decreases in the brain as Alzheimer's disease is progressing. Abolishing this phosphorylation of MECP2 in cultured mouse neurons upon inflammatory stimulation enhanced their viability and increased the expression of important genes in the maintenance and protection of neurons. The results obtained in the study call attention to modifications of MECP2 as potential targets for developing specific therapies against AD and other neurodegenerative diseases. The study was recently published in the Cells journal.

Alzheimer's disease is the most common form of dementia with more than 40 million people living with the disease worldwide. No therapies currently exist for the effective prevention or treatment of the disease. Long before severe symptoms of Alzheimer's disease, such as memory loss and confusion occur, connections between neurons are lost and neurons are dying in the brain. Neurons are not the only cell type that contributes to Alzheimer's disease progression. Microglia, the immune cells of the brain, have been shown to contribute to neuronal damage and loss. While mildly activated microglia can protect neurons by removing harmful substances and cell debris, their chronic activation can lead to secretion of neurotoxic factors and engulfment of healthy neurons.

"The function of MECP2 phosphorylation has been almost exclusively studied in neurons. As it has become evident that microglia are involved in the pathogenesis of many neurodegenerative diseases, we chose to focus on microglial cells and co-cultures of neurons with microglia. To additionally model the activation of microglia, we induced inflammation through treatment with different compounds", says Early Stage Researcher Rebekka Wittrahm.

In post-mortem brain samples from different stages of Alzheimer's disease, this study found that phosphorylation of the MECP2 protein decreased at the amino acid serine 423 in the early stages of Alzheimer's disease. Accordingly, the question arose whether MECP2 unphosphorylated at serine 423 would change cellular processes when expressed in cultured microglia or neuron-microglia co-cultures. To study this question, both wild type MECP2 and a variant where serine 423 was mutated to prevent phosphorylation were expressed in the different cell culture models. In microglia cells, the researchers found that overexpression of wildtype MECP2 led to a decrease in phagocytic uptake of particles. Upon activation of the microglia, expression of wildtype MECP2 enhanced their inflammatory response to stimulation. For most of the analyzed parameters, blocked phosphorylation of MECP2 serine 423 did not lead to major changes as compared to the wild type protein.

In contrast to the results from microglial monocultures, the expression of the proteins in neurons co-cultured with microglia cells revealed several differences between wild type and the mutated MECP2. RNA sequencing analysis revealed that blocking of the serine 423 phosphorylation upon microglial activation increased the expression of several neuronal genes that are known to contribute to maintenance and protection of the cells.

"More extensive experiments are needed but it is conceivable that the dephosphorylation of MECP2 at serine 423 might be a mechanism of the cells to mediate neuroprotection in the early stages of Alzheimer's disease," Rebekka Wittrahm considers.

In summary, the results of this study suggest that MECP2 serine 423 is an essential phosphorylation site that might play a role in regulating neuronal gene expression upon neuroinflammation. The study calls attention to the idea that modification sites of MECP2 are potential targets for developing specific therapies against Alzheimer's disease and other neurodegenerative diseases in the future.

The latest findings show that with clever science, a single fingerprint left at a crime scene could be used to determine whether someone has touched or ingested class A drugs.

In a paper published in Royal Society of Chemistry's Analyst journal, a team of researchers at the University of Surrey, in collaboration with the National Centre of Excellence in Mass Spectrometry Imaging at the National Physical Laboratory (NPL) and Ionoptika Ltd reveal how they have been able to identify the differences between the fingerprints of people who touched cocaine compared with those who have ingested the drug - even if the hands are not washed. The smart science behind the advance is the mass spectrometry imaging tools applied to the detection of cocaine and its metabolites in fingerprints.

This is a step up from research previously conducted by the University. In 2020 Surrey researchers were able to determine the difference between touch and ingestion if someone had washed their hands prior to giving a sample. Given that a suspect at a crime scene is unlikely to wash their hands before leaving fingerprints, these new findings are a significant advantage to crime forensics.

The Surrey team have continued to use their world-leading experimental fingerprint drug testing approach based on high resolution mass spectrometry. Cocaine and its primary metabolite - benzoylecgonine*, can be imaged in fingerprints produced after either ingestion or contact with cocaine using these techniques. By analysing the images of cocaine and its metabolite in a fingerprint, and exploring the relationship between these molecules and the fingerprint ridges, it is possible to tell the difference between a person who has ingested a drug, and someone who has only touched it.

Dr Melanie Bailey, Reader in Forensic and Analytical Science and EPSRC Fellow at the University of Surrey, said: "Over the decades, fingerprinting technology has provided forensics with a great deal of information about gender and medication. Now, these new findings will inform forensics further when it comes to determining the use of class A drugs.

"In forensic science being able to understand more about the circumstances under which a fingerprint was deposited at a crime scene is important. This gives us the opportunity to reconstruct more detailed information from crime scenes in the future. The new research demonstrates that this is possible for the first time using high resolution mass spectrometry techniques."

Dr Allen Bellew, Applications & Marketing Manager at Ionoptika, commented: "To image these metabolites excreted through the skin requires very powerful analytical tools such as the unique Water Cluster Source that Ionoptika has been developing for over a decade. It's clear that this new technique will be important for forensic science in the future, and as a small business in the UK it's very exciting to see the role that our J105 SIMS instrument has played in its development."

Dr Chelsea Nikula, Higher Research Scientist, NPL said: "This novel application of three different techniques illustrates the capabilities of mass spectrometry imaging to enable next generation forensics analyses. It is great to see that the work we do here at NPL and the facilities we have available to us at the National Centre of Excellence in Mass Spectrometry Imaging helped support this research."

*Benzoylecgonine is a molecule produced in the body when cocaine is ingested, and it is essential in distinguishing those who have consumed the class A drug from those who have handled it.

A pioneering new study led by UCL scientists has revealed, for the first time, a layer of genetic material involved in controlling the production of tau; a protein which plays a critical role in serious degenerative conditions, such as Parkinson's and Alzheimer's disease.

The international research, conducted in mice and cells, also revealed this material is part of a larger family of non-coding genes* which control and regulate other similar brain proteins, such as beta-amyloid associated with Alzheimer's and alpha-synuclein implicated in Parkinson's disease and Lewy body dementia.

Researchers say the breakthrough findings, published in Nature, shed an important new light on how proteins linked to neurological conditions are produced and controlled, and could pave the way for new treatments for a wide range of dementia related diseases.

Lead author, Dr Roberto Simone (UCL Queen Square Institute of Neurology), said: "Tau plays a vital role inside our brain cells: It helps to stabilise and maintain the cytoskeletal structures that allow different materials to be transported to where they need to be. We know that too much tau is detrimental - the excess unused tau converts into toxic species that may be responsible for damaging cells and driving the spread and progression of degenerative disease. However, despite the fact that tau has been studied for more than three decades, until now we did not know how tau protein production is controlled."

For the laboratory-based study, researchers identified a section of genetic material known as 'antisense long non-coding RNA' (lncRNA). They discovered this material does not make tau directly but helps to regulate, fine-tune and repress the production of the protein inside brain cells. This precision provided by antisense lncRNA in tau regulation could be crucial for smooth functioning of the brain's nerve cells.

Research group leader, Professor Rohan de Silva (UCL Queen Square Institute of Neurology) said: "Excitingly, we found that the lncRNA that controls tau is not unique. Other key proteins we know to be involved in neurological conditions, including alpha-synuclein in Parkinson's disease and beta-amyloid in Alzheimer's disease, are controlled by very similar lncRNAs. This means we may have found the key to regulating the production of a whole range of proteins involved in brain function and the development of these devastating conditions.

"It's early days but we hope that these exciting new insights will lead to the development of drugs that can keep tau and other proteins under control, and that these therapies could be life-changing for degenerative brain conditions that as yet, have no treatments to halt, let alone slow their progression."

Other neurological conditions associated with the tau protein include corticobasal degeneration and progressive supranuclear palsy.

Targeting tau to create new treatments

Professor de Silva said: "Genetic studies have previously shown that people who have a particular form of the tau gene - called H1 - are more likely to get Parkinson's disease, corticobasal degeneration and progressive supranuclear palsy. We know that people with the H1 form of the gene produce more tau. We also know the lncRNA we've identified helps to limit tau production, and that studies using post-mortem brain tissue show this lncRNA may be reduced in people with Parkinson's disease.

"So, if we can find a way to boost the levels of this lncRNA, we might be able to reduce the production of tau protein which could help to slow or stop the damage to cells inside the brain."

He added: "That's exactly what we are working on now. Specifically, we are developing a gene therapy to deliver this lncRNA to brain cells and we're currently testing whether this approach can reduce tau levels in mice and other animal models. If it's successful, we hope to take this approach forward to be developed as a new therapy that can one day be tested in people."

Professor David Dexter, Associate Director of Research at Parkinson's UK, said: "This important research provides fantastic new insights into how tau production is controlled inside brain cells, and presents an exciting new opportunity for developing therapies that target this. It's especially exciting to see that similar mechanisms may be involved in controlling the production of many other key proteins implicated in other neurological conditions, as it suggests strategies targeting these mechanisms could be effective across many conditions."

This research has involved collaborations within UCL and with research groups at the Francis Crick Institute, UK Dementia Research Institute, St George's University of London, Karolinska Institute, Sweden and the University of Trento, Italy.

Funding for this study came from Reta Lila Weston Trust, Wellcome Trust, Medical Research Council (MRC), Parkinson's UK, CBD Solutions, PSP Association and CurePSP.

* Non-coding DNA: Our genome contains coding genes, the parts of our DNA that contain instructions for making proteins, the building blocks of our bodies. However, these coding genes make up only a small part of our genome - a mere 3% of the 3 billion letters (the nucleotides) of our genetic material. Until recently, the remainder of the genome (non-coding) was regarded as junk DNA, without known function. However, it is now clear that the DNA that lies in-between the coding genes is emerging as crucially important not only in human evolution but also in regulating function of cells and influencing the way coding genes produce proteins.

Research has found that strict lockdowns to reduce the spread of COVID-19 might be responsible for delaying normal cardiorespiratory development in children.

The study, the first to examine the topic, is published in the European Journal of Pediatrics. It was carried out by Dr Lee Smith of Anglia Ruskin University (ARU) and a team of academics from Spain, led by Dr Ruben Lopez-Bueno of the University of Zaragoza.

The research involved a group of 89 children from a school in north-eastern Spain. The country introduced a strict six-week lockdown in spring 2020, during which under-15s were unable to leave their homes except for medical reasons.

The children, aged 12-14, took part in fitness tests to measure their maximal oxygen uptake (VO2 max) in November 2019, before the start of the COVID-19 pandemic, and repeated the fitness tests in November 2020.

VO2 max is a well-known cardiorespiratory fitness indicator and levels increase during adolescence, in line with physical growth and development.

The study found that in November 2020, boys and girls in each age group showed lower levels of cardiorespiratory fitness than would be expected with normal VO2 max rate development. Healthy Fitness Zone (HFZ) levels - a standard measure of health based on age and sex - also fell by 3.4% over the 12-month period.

Senior author Dr Lee Smith, Reader in Physical Activity and Public Health at Anglia Ruskin University (ARU), said: "We know that sedentary behaviour has a negative effect on cardiorespiratory fitness and health, but we're unable to say to what extent the delay in development of VO2 max levels we found was caused by COVID-19 restrictions.

"In normal conditions, VO2 max levels tend to increase in adolescents up to a certain age. In our study, each age and sex subgroup showed lower levels in relation to normal VO2 max rate development and specific subgroups, such as boys aged 12 and girls aged 14, displayed reductions in their actual VO2 max levels, which could underscore a higher vulnerability in these groups.

"Our results are perhaps not as pronounced as might have been predicted. This could be because Spain relaxed their lockdown entering the summer. The children were able to take part in physical activity again, helping them to regain cardiorespiratory fitness, and we did not test the group again until November.

"Regardless, if further lockdowns are necessary in future, maintaining access to open spaces such as parks and sports facilities should certainly be considered, particularly for vulnerable groups such as adolescents."

Base editing is a novel gene editing approach that can precisely change individual building blocks in a DNA sequence. By installing such a point mutation in a specific gene, an international research team led by the University of Zurich has succeeded in sustainably lowering high LDL cholesterol levels in the blood of mice and macaques. This opens up the possibility of curing patients with inherited metabolic liver diseases.

Lipoproteins are complex particles that deliver fat molecules to all tissues of the body through the blood system, supplying energy to the cells. One such lipoprotein, the low-density lipoprotein (LDL), can transport thousands of fat molecules, such as cholesterol, per particle. High levels of LDL in the blood are clinically associated with an increased risk of cardiovascular diseases. Since LDL can also carry cholesterol into smaller vessels and thus supply more distant tissues, it can increasingly block the artery lumen, which leads to atherosclerosis.

Introducing a single gene mutation blocks an enzyme

An international research team led by the University of Zurich (UZH) has now demonstrated that a novel precise gene editing approach can reduce high LDL cholesterol levels - substantially and sustainably. The scientists introduced a single point mutation in the gene encoding for an enzyme called PCSK9. This protein is involved in the uptake of LDL cholesterol from the blood into the cells. "The genetic change we induced in mice and macaques successfully blocked PCSK9, which led to a significant reduction of the LDL cholesterol concentrations in the blood. This provides a potential therapy for patients suffering from familial hypercholesterolemia, an inherited form of high cholesterol levels," says study leader Gerald Schwank, professor at the Institute for Pharmacology and Toxicology of UZH.

Adaption of RNA technology used in COVID-19 vaccines

The gene editing technology applied by the researchers uses what are known as base editors. These proteins can change individual bases of the DNA molecule - a single "letter" of a genetic "text" - into another. Adenine base editors, for example, convert an adenine (A) into a guanine (G). And base editors do this much more precisely than previous CRISPR-Cas nucleases, which function as molecular scissors. To control the delivery of the base editor tool into the liver of animals, the researchers adapted the RNA technology used in COVID-19 vaccines. However, instead of encapsulating an RNA encoding the spike protein of SARS-CoV2 into lipid nanoparticles, they encapsulated an RNA encoding for the adenine base editor.

Accurate, efficient and safe

The RNA-lipid nanoparticles formulations were introduced into the animals intravenously, leading to liver-specific uptake and transient production of the base editor tool by the cell machinery. "Up to two-thirds of PCSK9 genes were edited in the mice and up to one-third in the non-human primates, leading to a significant reduction in LDL cholesterol levels," says Schwank. In addition, the scientists carefully assessed whether unspecific editing at undesired locations occurred, but found no indications of such off-target events.

RNA-based therapies for metabolic liver diseases

"Our study shows the feasibility of installing single nucleotide base changes in the liver of non-human primates with high efficiency and accuracy. Approximately 30 percent of all disease-causing hereditary mutations are single base mutations that can, in principle, be corrected with base editors," says Schwank. The new approach could therefore be used to treat a large number of patients suffering from inherited metabolic liver diseases, such as hypercholesterolemia, phenylketonuria or urea cycle disorders. Compared to conventional drugs, genome editing has the advantage that induced changes are sustainable. Thus, if a mutation is repaired in a sufficient number of cells, the patient will be permanently cured.

World-leading eye experts have made a breakthrough that could potentially change the way cataracts are treated - with potential for drug therapy to replace surgery.

Cataract is a clouding of the eye lens that develops over time and affects the quality of vision. It is caused by an accumulation of protein in the lens that reduce the transmission of light to the retina. Previous research led by ARU found that cataracts account for almost half of global cases of blindness.

A significantly developed cataract can only currently be treated by a surgical procedure to remove the cloudy lens and insert an artificial replacement.

A team of international scientists, led by Professor Barbara Pierscionek of Anglia Ruskin University (ARU), has published peer-reviewed research that shows the sophisticated optics of the lens develops much earlier in gestation than has previously been thought possible. They also found how a particular protein (aquaporin) responsible for water passage in the lens disrupts the optical development, leading to cataract formation.

The scientists have spent more than a decade conducting the most precise measurements on optics of the lens at SPring-8, the world's largest and most powerful synchrotron, in Japan.

The synchrotron is a particle accelerator that produces powerful X-rays by accelerating electrons to the speed of light. The X-rays allow measurements to be taken with the highest accuracy yet on optical properties of the eye.

The project team is the first in the world to have measured how the optics in the eye lens develop. Their research was presented earlier this month at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting.

Professor Pierscionek, Deputy Dean (Research and Innovation) for the Faculty of Health, Education, Medicine and Social Care and member of the Medical Technology Research Centre at ARU, said: "Cataracts are one of the main causes of vision loss and blindness worldwide, yet for many people surgery is inaccessible for various reasons.

"Our findings indicate the role of the aquaporin proteins and the crucial importance of this for the lens to work correctly and the eye to see clearly.

"Further research in this area is planned, but this discovery, together with our research on nanotechnologies that indicate drug therapy for cataract is possible, could potentially revolutionise the way cataract is treated, opening up the field for drug-based therapy rather than surgery. This would have exciting implications for public health."

Wednesday 19 May 2021 - New research published today sheds important light on how the production of a key protein in the brain is controlled, which could pave the way for new treatments for a wide range of neurological conditions.

In a study part-funded by Parkinson's UK, researchers investigated a section of genetic material known as antisense long non-coding RNA (lncRNA), which helps fine-tune the production of the protein tau inside brain cells. This precision in tau regulation is crucial for smooth functioning of the nerve cells.

Understanding the mechanism which helps regulate tau production could be the key to developing better treatments for conditions including Parkinson's, Alzheimer's, corticobasal degeneration and progressive supranuclear palsy.

The team's findings, published in Nature, show that tau, along with other key proteins involved in brain function, are controlled by very similar lncRNAs. This insight could help scientists develop the ability to control the production of these proteins and in turn, the development of certain neurological conditions.

The international team comprised of researchers from University College London (UCL), the Francis Crick Institute, University of Trento, Italy and the Karolinska Institute in Stockholm, Sweden.

Lead investigators Professor Rohan de Silva and Dr Roberto Simone from University College London (UCL), said:

"Tau plays a really vital role inside our brain cells. It helps to stabilise and maintain the cytoskeletal structures that allow different materials to be transported to where they are needed. We know that too much tau is detrimental - the excess, unused tau converts into toxic species that may be responsible for damaging cells and driving the spread and progression of disease. However, despite the fact that tau has been studied for more than three decades, until now we did not know how neuronal cells exactly control tau protein production.

"Excitingly, we found that the lncRNA that controls tau is not unique. Other key proteins we know to be involved in neurological conditions, including alpha-synuclein in Parkinson's and beta-amyloid in Alzheimer's, could be controlled by very similar lncRNAs. This means we may have found the key to regulating the production of a whole range of proteins involved in brain function and the development of these devastating conditions.

"It's early days but we hope that these exciting new insights will lead to the development of drugs that can keep tau and other proteins under control, and that these therapies could be life-changing for degenerative brain conditions that as yet, we cannot slow or stop."

Professor David Dexter, Associate Director of Research at Parkinson's UK, said:

"Tau is emerging as one of the key determinants of different rates of progression in Parkinson's so understanding how this protein is regulated may be vital to finding better treatments and a cure for Parkinson's.

"This important research provides fantastic new insights into how tau production is controlled inside brain cells, and presents an exciting new opportunity for developing therapies that target this. It's especially exciting to see that similar mechanisms may be involved in controlling the production of many other key proteins implicated in other neurological conditions, as it suggests strategies targeting these mechanisms could be effective across many conditions."

Brazil is the world leader in sweet orange production, but citrus cultivation in the region faces constant threats concerning the availability of water and the outbreak of diseases. New research published in the Journal of Applied Microbiology indicates that a fatty acid called hexanoic acid may help protect against one such problem: citrus canker, a bacterial infection that causes brownish eruptive lesions on the leaves, stems, and fruit of citrus trees.

Hexanoic acid might be a suitable substitute for chemicals used to protect citrus from bacterial infections. Investigators examined several mechanisms that might explain how hexanoic acid exerts its effects.

"The world population needs food, and agriculture based on chemical protection has guaranteed food in unimaginable amounts. More recently, people want safer food," said senior author Henrique Ferreira, DPhil, of the Sao Paulo State University, in Brazil. "Therefore, we are working hard to deliver safer alternatives to protect plants and minimize the impacts of old-school chemical defenses."

NEW YORK, NY (May 19, 2021)--A new study from Columbia University and an international team of researchers identifies multiple ways to achieve the same health benefits from exercise--as long as the exercise "cocktail" includes plenty of light physical activity.

"For decades, we've been telling people that the way to stay healthy is to get at least 30 minutes of exercise five days a week," says Keith Diaz, PhD, assistant professor of behavioral medicine and director of the exercise testing laboratory at the Center for Behavioral Cardiovascular Health at Columbia University Vagelos College of Physicians and Surgeons.

"But even if you're one of the few adults who can stick to this advice, 30 minutes represents just 2% of your entire day," says Diaz. "Is it really possible that our activity habits for just 2% of the day is all that matters when it comes to health?"

Diaz says that the recommendation about how much exercise to do may be insufficient depending on how individuals spend the rest of their waking day.

Previous studies tended to look at the impact of one type of activity or another in isolation. But each activity has either harmful or beneficial effects on health. "What we don't know is the best combination, or cocktail, of ingredients needed to prolong life," Diaz says.

Only through recent cheap and easy-to-use activity monitors, which can be worn by study participants throughout the day, have researchers been able to address the question.

With data from six studies that included more than 130,000 adults in the United Kingdom, United States, and Sweden, the authors used a technique called compositional analysis to determine how different combinations of activities--including moderate-to-vigorous exercise (such as brisk walking, running, or other activities that increase heart rate), light physical activity (such as housework or casual walking), and sedentary behavior--affect mortality.

Here are the main take-aways:

The benefits of 30 minutes of moderate-to-vigorous exercise depends on how you spend the rest of the day.

Although the current recommendation of 30 minutes per day of moderate-to-vigorous physical activity reduced the odds of an earlier death by up to 80% for some--those who sat for less than 7 hours--it did not reduce mortality risk for individuals who were very sedentary (over 11 to 12 hours per day), the researchers found.

"In other words, it is not as simple as checking off that 'exercise' box on your to-do list," says Diaz. "A healthy movement profile requires more than 30 minutes of daily exercise. Moving around and not remaining sedentary all day also matters."

"Getting 30 minutes of physical activity per day, or 150 minutes per week, is what's currently recommended, but you still have the potential to undo all that good work if you sit too long," says Sebastien Chastin, PhD, professor of health behaviour dynamics at Glasgow Caledonian University in Scotland and lead author of the study.

Light physical activity is more important than you think.

The research found that people who spent just a few minutes engaging in moderate-to-vigorous physical activity lowered their risk of early death by 30% as long as they also spent six hours engaging in light physical activity.

"Perhaps you're a parent with young kids and you simply can't get to the gym to exercise," Diaz says. "But you can still have a healthy movement profile as long as you move around a lot throughout the day as you tend to your everyday activities."

Sitting isn't as bad for your health as smoking, but it's still bad, Diaz says. "While there will always be sitting in our lives, as with most things in life, it's about sitting in moderation. The key is to find the right balance of sedentary time and physical activity."

A cocktail formula of 3 to 1 is best.

The researchers found that getting three minutes of moderate-to-vigorous activity or 12 minutes of light activity per hour of sitting was optimal for improving health and reducing the risk of early death.

"Our new formula gets at the right balance between moderate-to-vigorous exercise and sitting to help people lead a longer, healthier life," says Chastin. "The leftover hours should be spent moving around as much as possible and getting a good night's sleep."

Using this basic formula, the study found that multiple combinations of activities reduced the risk of early death by 30%:

55 minutes of exercise, 4 hours of light physical activity, and 11 hours of sitting

13 minutes of exercise, 5.5 hours of light physical activity, and 10.3 hours of sitting

3 minutes of exercise, 6 hours of light physical activity, and 9.7 hours of sitting

Although the researchers found that replacing sedentary time with just two minutes of moderate-to-vigorous exercise is more efficient than replacing it with light physical activity--two minutes of moderate-to-vigorous exercise is equivalent to four to 12 minutes of light physical activity--both have value.

"This is good news for people who may not have the time, ability, or desire to engage in formal exercise," Diaz says. "They can get health benefits from a lot of light physical activity and just a little moderate-to-vigorous activity."

"Our study shows that there is no one-size-fits-all approach to physical activity, and we get to choose which ones we like best," Diaz says. "It may be more important to mix a movement cocktail that includes a healthy dose of exercise and light activity to take the place of sitting."

Computed tomography -- CT scanning -- which combines a series of X-ray images taken from different angles around an organism and uses computer processing to create cross-sectional images of its bones, is providing new insight into an old initiative to characterize fishes in Africa's Lake Malawi.

The process, demonstrated in a new study using the high-resolution X-ray computer system in Penn State's Center for Quantitative X-Ray Imaging, is important because it will lead to the identification and management of more of the fish species in Africa's second largest lake, according to lead researcher Jay Stauffer Jr., distinguished professor of ichthyology in the College of Agricultural Sciences.

"Before they can effectively manage fish populations, they have to know what is there," he said.

Regarded by scientists as the most vibrant and diverse body of water in the world, Lake Malawi is home to between 800 and 1,000 species of colorful fish called cichlids; however, the lake is overfished by humans for food. As a result, about 10% of those species are believed to be endangered.

Located between Malawi, Tanzania and Mozambique, Lake Malawi is immense. It covers an area of more than 11,000 square miles and holds 7% of the world's available surface freshwater -- by comparison, appreciably more than Lake Erie.

"About half the species in the lake still haven't been described," said Stauffer, who has characterized, or discovered, more than 60 cichlid species himself. Since 1983, he has visited Lake Malawi for extended periods annually, collecting cichlid specimens while scuba diving.

After preservation, those specimens have been housed in the Penn State Fish Museum at Rock Springs, and approximately 35,000 are scheduled to be transferred to the National Research Institute of South Africa this year after COVID-19 restrictions are lifted. In the recent study, Stauffer and colleagues performed CT scans on selected specimens in the collection.

The entire head of each fish was scanned, and the researchers focused on the "morphology" -- analyzing the shape and profiles of the skulls and the structure and arrangement of teeth on the pharyngeal jaws and the oral jaws. This helps to determine a species' specialization to capitalize on certain food sources and to compete with other species.

"We chose species to scan that we knew had different feeding repertoires, and then we wanted to compare their head morphology with their species' feeding specializations to determine the relationships between morphology and behaviors," Stauffer said. "The purpose of this research was to show how observed behavioral traits of shallow-water species can be linked with morphological attributes using data collected from selected cichlids. Such associations can be used to predict behavior of deep-water or rare species, based on head morphology."

In findings recently published in Ecology and Evolution, the researchers reported that high-resolution CT scanning will enable scientists to infer life history and behavioral characteristics of rare or extinct fishes from a detailed examination of morphology and linkages between morphology and behavior observed in surviving species.

Stauffer and other scientists will use CT scanning as they continue to identify cichlids in Lake Malawi. The technology is nondestructive, he explained, so they can collect data from specimens in museum collections.

"High-resolution computed tomography permits us to view the internal morphology and examine areas that would otherwise be destroyed by dissection," he said. "It will be a great help to me because I'm going over there and spending four to six weeks a year at the institute, identifying fishes that are in its museum."

Many of those older museum specimens are surprising him, noted Stauffer, who is 70 and has no plans to retire. "I'm finding a lot of species I've never seen before in more than 30 years of diving in Malawi. I think they're probably extinct. I'd like to describe these species, and the CT scans will help me to make accurate guesses about what their behavior was in the lake."

Adrianus Konings, ichthyologist, photographer, and founder and publisher of Cichlid Press in El Paso, Texas; and Joshua Wisor, doctoral degree student in wildlife and fisheries science, contributed to this research.

SARS-CoV-2 has evolved to acquire mutations on the spike protein--the part of the virus that protrudes from its surface and latches onto cells to infect them--that enhance the coronavirus' ability to bind to human cells or evade antibodies. A new study from the Centers for Genomics and Systems Biology at New York University and NYU Abu Dhabi uses computational modeling to assess the biological significance of spike protein mutations, uncovering versions of the virus that bind more tightly or resist antibodies and offering a promising public health surveillance tool.

The study, which appears in the Journal of Molecular Biology, also suggests that these mutations on the spike protein are a key reason for the virus' rapid spread in parts of the world.

New and more transmissible COVID-19 variants have emerged in recent months, fueling surges of cases in countries like India and Brazil. As a public health measure, rapid surveillance methods are needed to determine the biological effects of variants and to help anticipate emerging infectious viral strains. But monitoring new variants is no small task; genome sequencing shows that the SARS-CoV-2 spike protein alone, for example, has about 5,000 possible variants.

"Screening such a large set of variants poses a tremendous challenge for conventional experimental methods," said Hin Hark Gan, a senior research scientist at NYU's Center for Genomics and Systems Biology and the study's lead author. "An advantage of computer-based modeling is that a hundred mutations can be readily assessed in a few days."

Gan and his colleagues turned to a computational method that models how the SARS-CoV-2 spike protein recognizes the ACE2 receptor--a protein on the surface of many types of cells--to gain entry into host cells. Studies of coronaviruses indicate that spike-ACE2 recognition is the basis for infection.

The researchers focused on screening the mutations located where the spike protein and ACE2 receptor meet. They assessed 1,003 mutation combinations in the spike and ACE2 proteins, including those resulting in the fast-spreading spike variants that have originated in Brazil, South Africa, the U.K., and India.

Their systematic assessment of variants uncovered that spike mutations that bind tightly to the ACE2 receptor occur in two clusters or mutation "hotspots" on the binding interface. These hotspots are located in structurally flexible regions, indicating that mutations that increase binding effectively reprogrammed the spike conformation to enhance its recognition of the ACE2 receptor.

The researchers also looked at single, double, and triple mutations in the critical spike interface region, which make up some of the recently emerged infectious variants. Their modeling analysis suggests the spike variants S477N, N501Y, and S477N + E484K and E484K + N501Y--fast-spreading double mutants found in Brazil, South Africa, the U.S., and U.K.--have increased binding to the ACE2 receptor relative to the original coronavirus that emerged in Wuhan.

Gan and colleagues observed that the E484K and E484Q mutations found in some recent fast-spreading variants are not only predicted to bind more strongly to ACE2 but have also been shown to confer antibody resistance. Neutralizing antibodies are produced in response to viral infection and target different sites on the spike protein to prevent the virus from invading host cells. This prompted the researchers to look at another factor contributing to viral transmission: antibody resistance of individual spike mutations.

In particular, the variant circulating in India has two mutations in the spike interface region: L452R and E484Q. This variant is not predicted to bind to the ACE2 receptor more tightly than the virus that originated in Wuhan, likely because the individual mutations have opposing effects (the L452R mutation binds less easily while the E484Q mutation binds more easily). Strikingly, however, both of these mutations are strong antibody evaders, a scenario not found in other recent variants.

"As more of antibody target sites become resistant to antibodies due to viral mutations, the efficacy of existing antibodies and vaccines may diminish," added Gan. "This scenario is a likely cause for the rapid spread of the variant in India."

The study not only provides explanations for the coronavirus' rapid spread--both mutations that enhance binding to human cells and help evade antibodies--but also points to a promising predictive tool in the ongoing public health fight against SARS-CoV-2.

"Our computational modeling method can be used as a real-time surveillance tool to screen for emerging infectious COVID-19 variants. It allows for a more timely response to emerging outbreaks and could be used to guide the development of new vaccines," said Kristin C. Gunsalus, professor of biology at NYU, faculty director of bioinformatics at NYU Abu Dhabi, and the study's senior author.

Press release - ESE statement: COVID-19 and endocrine and metabolic diseases. An updated statement from the European Society of Endocrinology

New expert statement confirms strong links between our hormones and COVID-19

The endocrine system is strongly involved in SARS-Cov-2 infection - so much so that evidence of an "endocrine phenotype" of COVID-19 has emerged, according to a statement by the European Society of Endocrinology (ESE) published in the journal Endocrine in April 2021. Leading endocrinology researchers looked into the evidence that has accumulated over the past year since the pandemic emerged, and consistently found evidence for links across a variety of endocrine conditions. This statement constitutes an update of a March 2020 statement that was of the earliest and most read pieces delineating the involvement of the endocrine system in COVID-19.

Dr Manel Puig from the Universitat Autònoma de Barcelona in Spain and first author on the statement said "the evidence is clear. The effect on hormones cannot be ignored in the context of COVID-19". He added "we need to be aware of the endocrine consequences of COVID-19 for patients with a known endocrine condition such as diabetes, obesity or adrenal insufficiency, but also for people without a known condition. Vitamin D insufficiency for example is very common, and the knowledge that this condition has emerged frequently in the hospitalized COVID-19 population and may negatively impact outcomes should not be taken lightly".

Dr Puig, together with Profs Marazuela, Yildiz and Giustina based in Madrid, Ankara and Milano looked at the available evidence with respect to COVID-19 across a number of endocrine conditions and related factors: diabetes, obesity, nutrition, hypocalcemia, vitamin D insufficiency, vertebral fractures, adrenal insufficiency, as well as pituitary/thyroid issues and sex hormones.

Diabetes has emerged as one of the most frequent comorbidities associated with severity and mortality of COVID-19, according to a rapidly increasing amount of published data on the incidence of COVID-19 in patients over the last year. Mortality in type 1 or type 2 diabetes has consistently increased during the year of pandemic - and evidence is emerging that a bidirectional relationship between diabetes and COVID-19 may exist, both in terms of worsening existing conditions and new onset of diabetes.

The researchers identified similar trends for patients with obesity. Obesity increases susceptibility to SARS-CoV-2 and the risk for COVID-19 adverse outcomes. They posit that nutritional management is important both for patients with obesity or undernourishment in order to limit their increased susceptibility and severity of infection. Vitamin D, calcium and bone are other areas showing a growing body of evidence that better monitoring and solutions for patients are needed in the context of COVID-19.

With regard to vaccination, the statement concludes that available evidence suggests COVID-19 vaccination should not be handled differently in patients with stable endocrine diseases. However, patients with adrenal insufficiency may need adjusted glucocorticoid treatment to address side effects such as fever. The authors suggest data from the field should be collected in an international database in order to form firm conclusions on this matter. They also present a decalogue for endocrinologists and patients with endocrine and metabolic conditions in the conclusions of the statement.

This knowledge highlights the important role endocrinologists will need to play in future research on COVID-19 and other global health issues.

While the APP protein is well-known for its key role in Alzheimer's disease, its contribution to healthy brain function, by contrast, has remained largely unknown until now. Recently, an international research team, led by molecular biologist Prof. Dr Ulrike Müller from Heidelberg University, gained new insights on the physiological functions of the APP protein family by using a mouse model lacking APP. The absence of APP during brain development was shown to result in the malformation of important brain regions implicated in learning and memory. Consequently, these mice were severely impaired in their learning abilities and exhibited autistic-like behaviour.

Alzheimer's disease is triggered by insoluble protein deposits in the brain, which aggregate around nerve cells to form plaques. These plaques consist mainly of small β-amyloid peptides (Aβ), which are a cleavage product of the amyloid precursor protein (APP). Aβ peptides inflict damage on nerve cells and ultimately lead them to their death. While the detrimental effect of Aβ peptides on neurons has been recognised for many years, little is known about the natural physiological functions of APP. According to the researchers, this non-pathological perspective is worthy of investigation considering the fact that APP, as well as two other closely-related proteins, is produced by most nerve cells in the brain - particularly in critical regions for learning and memory formation.

To investigate the role of the APP protein family in the development and functionality of the nervous system, Prof. Müller's research group used mice as a model organism, which had been genetically engineered to block the production of all APP family proteins. Close examination of their brains revealed that the loss of APP during brain development led to malformations in the layered structure of the hippocampus - an essential brain region for memory formation. "We observed that the absence of APP led to impaired neuronal wiring and a decrease in the number of synaptic connections. It also greatly reduced communication between nerve cells and severely affected the animal's performance in behaviour tests that assess learning," says Ulrike Müller, who heads the department of Functional Genomics at the Institute of Pharmacy and Molecular Biotechnology of Heidelberg University.

According to Prof. Müller, the team was surprised to discover that these disruptions in brain development also gave rise to behavioural changes that resembled those occurring in autism spectrum disorder. The mice displayed the characteristic recurring movement patterns and lack of interest in social interactions with other mice. "Our findings suggest that the APP family plays a crucial role in the normal development of the nervous system, learning, memory formation and social communication," explains the scientist. "In the future, these understandings may aid the development of novel therapeutics for Alzheimer's disease."

Individuals are often prescribed increasing numbers of medications as they age, and while many of these prescriptions are justifiable, some may be inappropriate. A recent analysis published in the British Journal of Clinical Pharmacology examined the results of all studies investigating associations between potentially inappropriate prescribing--which includes prescribing medications that may not produce benefits relative to harm and not prescribing medications that are recommended--and outcomes of older adults.

Potentially inappropriate prescribing was significantly associated with a range of health-related and system-related outcomes, including functional decline, falls, and hospital admissions due to drug-related side effects.

"Several decision support tools for quality prescribing are available; however, our analysis highlights that medication-related harm due to inappropriate prescribing remains problematic," said lead author Alemayehu Mekonnen, PhD, of Deakin University, in Australia. "A comprehensive assessment of medication use, especially during care transitions such as at hospital discharge, is an important task to reduce medication-related harm and associated healthcare costs."