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Severe childhood restrictive cardiomyopathy is a condition that causes the muscles in the walls of the heart to become stiff, so that the heart is unable to fill properly with blood. A mutation in a protein called BAG3 is known to result in restrictive cardiomyopathy, muscle weakness, difficulty taking in enough oxygen, and damage to multiple peripheral nerves, often shortening the patient’s lifespan significantly. Until now there has been no successful model for the disease, making it extremely difficult to study.
However, researchers in Japan and Germany have now created a mouse model that mimics the human pathology, allowing the disease to be studied more easily. The team’s data suggest that the restrictive cardiomyopathy caused by BAG3 mutation changes the process by which damaged proteins are broken down and removed. This causes proteins to build up in the cells, disrupting the cardiac muscle.
The team was able to express a human version of the mutant BAG3 protein in mouse cardiomyocytes, the cells that make up the heart muscle. “Our mouse model successfully mimicked the human disease,” says lead author Assistant Professor Kenichi Kimura. “The mice had increasingly severe symptoms of heart failure and growth retardation starting shortly after birth, and only survived for around five weeks.”
The team studied the heart tissue of the mice expressing the mutant human BAG3 protein, and uncovered changes to the protein quality control system, which ensures proteins are correctly folded, alongside increased levels of autophagy, a process by which damaged cells are removed and recycled. BAG3 is involved in the breakdown of proteins that have become damaged due to mechanical stress. The mutation that causes restrictive cardiomyopathy involves the alteration of just a single base in the DNA, leading to a leucine amino acid in the mutant BAG3 protein where there should be a proline.
The team showed that this leads to the mutant protein having reduced solubility and mobility, causing it to build up in the muscle cells. This causes fibrosis, or scarring, and results in the heart muscle stiffening and losing the ability to fully relax, meaning that the heart is unable to properly fill with blood. Moreover, in preliminary investigations using a technique to knockdown and reduce the mutant protein expression, the researchers were able to mitigate the disease symptoms in the mouse model.
Childhood restrictive cardiomyopathy is a rare but very serious disease. Hopefully, the knowledge provided in this study, and the establishment of a mouse model of the disease to support further research, will bring about the development of better treatments for children with this condition.
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Materials provided by University of Tsukuba. Note: Content may be edited for style and length.

Ocean currents sometimes pinch off sections that create circular currents of water called “eddies.” This “whirlpool” motion moves nutrients to the water’s surface, playing a significant role in the health of the Florida Keys coral reef ecosystem.
Using a numerical model that simulates ocean currents, researchers from Florida Atlantic University’s Harbor Branch Oceanographic Institute and collaborators from the Alfred-Wegener-Institute in Germany and the Institut Universitaire Europeen De La Mer/Laboratoire d’Océonographie Physique et Spatiale in France are shedding light on this important “motion of the ocean.” They have conducted a first-of-its-kind study identifying the mechanisms behind the formation of sub-mesoscale eddies in the Straits of Florida, which have important environmental implications.
Despite the swift flow of the Florida Current, which flows in the Straits of Florida and connects the Loop Current in the Gulf of Mexico to the Gulf Stream in the Western Atlantic Ocean, eddies provide a mechanism for the retention of marine organisms such as fish and coral larvae. Since they trap the nutrient rich West Florida Shelf waters, they provide habitat to many reef and pelagic species within the region of the Florida Keys Reef Track, which sustains the very high productivity of this region.
Moreover, despite the tendency of the West Florida Shelf to overflow into the Straits of Florida, the formation of eddies provides a mechanism that limits the cross shelf transport of nutrient-laden waters. As a result, the formation of eddies stops the export of the West Florida Shelf waters across the Straits of Florida, preventing events such as red tides from crossing over to Cuba or the Bahamas. Conversely, toxic red tide waters emanating from the shelf remain longer in the vicinity of the Florida Keys Reef Tract coral reef ecosystem, adversely affecting the ecosystem’s health.
These small-scale frontal eddies are frequently observed and present a wide variety of numbers, shapes, and sizes, which suggest different origins and formation mechanisms. Their journey through the Straits of Florida is at time characterized by the formation and presence of mesoscale, but mostly sub-mesoscale frontal eddies on the cyclonic side of the current.
The study, published in the Journal of Physical Oceanography, provides a comprehensive overview and understanding of the Straits of Florida shelf slope dynamics based on a realistic two-way nested high-resolution Regional Oceanic Modeling System (ROMS) simulation of the South Florida oceanic region. The full two-way nesting allowed the interaction of multiscale dynamics across the nest boundaries.
Results showed that the formation of the sub-mesoscale frontal eddies in the Straits of Florida are associated with the sloshing of the Florida Current, which consists of the oscillation of the distance of the current core from the shelf. When the Florida Current core is pushed up against the shelf, the shear on the shelf increases and sub-mesoscale frontal eddies can be formed by barotropic instability. When this position is relaxed, baroclinic instability instead is likely to form sub-mesoscale eddies. Unlike barotropic instability, which is shear driven, baroclinic instability is driven by changes in density anomalies.
“In the Straits of Florida, eddies smaller than their open ocean relative are formed. Those eddies, called sub-mesoscale eddies, are common and can be easily observed in ocean color imagery,” said Laurent Chérubin, Ph.D., senior author and an associate research professor, FAU Harbor Branch. “Unlike the larger open ocean mesoscale eddies, they are not in geostrophic balance, meaning that their circulation is not sustained by the balance between the pressure gradient and the Coriolis forces. Instead, some of the frontal eddies in the Straits of Florida are in gradient wind balance, which indicates that a third force, the centrifugal force, is large enough to modify the geostrophic balance.”
The Florida Current is part of the western branch of the wind driven north Atlantic anti-cyclonic gyre, which is intensified on the western side of the North Atlantic basin in comparison to its eastern side. Similar types of currents also are found on the western side of ocean basins such as the Agulhas current in the southern Indian Ocean or the Kuroshio in the northern Pacific Ocean. They are called boundary currents because they impinge on the continental shelf and as such, they undergo a significant amount of friction on the ocean floor. This friction, which acts vertically and horizontally on the boundary current, contributes to the formation of a sheared boundary layer.
“Our study shows that this shear layer can become unstable and form eddies. This process is in fact a pathway for the dissipation of wind energy injected in the ocean. Therefore, in the Straits of Florida, eddies smaller than their open ocean relative are formed,” said Chérubin.
In addition to sub-mesoscale eddies formed locally in the Straits of Florida, there are incoming mesoscale eddies that transit in the Straits of Florida, such as the Tortugas Gyre.
“Findings from our research also show that mesoscale eddies can be squeezed on the shelf and transformed into sub-mesoscale eddies when the Florida Current is in its protracted position or remains relatively unaffected if the Florida Current is retracted from the shelf,” said Chérubin.

Scientists have identified key molecular events in the developing human embryo between days 7 and 14 — one of the most mysterious, yet critical, stages of our development.
The second week of gestation represents a critical stage of embryo development, or embryogenesis. Failure of development during this time is one of the major causes of early pregnancy loss. Understanding more about it will help scientists to understand how it can go wrong, and take steps towards being able to fix problems.
The pre-implantation period, before the developing embryo implants into the mother’s womb, has been studied extensively in human embryos in the lab. On the seventh day the embryo must implant into the womb to survive and develop. Very little is known about the development of the human embryo once it implants, because it becomes inaccessible for study.
Pioneering work by Professor Magdalena Zernicka-Goetz and her team developed a technique, reported in 2016, to culture human embryos outside the body of the mother beyond implantation. This enabled human embryos to be studied up to day 14 of development for the first time.
In a new study, the team collaborated with colleagues at the Wellcome Sanger Institute to reveal what happens at the molecular level during this early stage of embryogenesis. Their findings provide the first evidence that a group of cells outside the embryo, known as the hypoblast, send a message to the embryo that initiates the development of the head-to-tail body axis.
When the body axis begins to form, the symmetrical structure of the embryo starts to change. One end becomes committed to developing into the head end, and the other the ‘tail’.
The new results, published today in the journal Nature Communications, reveal that the molecular signals involved in the formation of the body axis show similarities to those in animals, despite significant differences in the positioning and organisation of the cells.
“We have revealed the patterns of gene expression in the developing embryo just after it implants in the womb, which reflect the multiple conversations going on between different cell types as the embryo develops through these early stages,” said Professor Magdalena Zernicka-Goetz in the University of Cambridge’s Department of Physiology, Development and Neuroscience, and senior author of the report.
She added: “We were looking for the gene conversation that will allow the head to start developing in the embryo, and found that it was initiated by cells in the hypoblast — a disc of cells outside the embryo. They send the message to adjoining embryo cells, which respond by saying ‘OK, now we’ll set ourselves aside to develop into the head end.'”
The study identified the gene conversations in the developing embryo by sequencing the code in the thousands of messenger RNA molecules made by individual cells. They captured the evolving molecular profile of the developing embryo after implantation in the womb, revealing the progressive loss of pluripotency (the ability of the embryonic cells to give rise to any cell type of the future organism) as the fates of different cells are determined.
“Our goal has always been to enable insights to very early human embryo development in a dish, to understand how our lives start. By combining our new technology with advanced sequencing methods we have delved deeper into the key changes that take place at this incredible stage of human development, when so many pregnancies unfortunately fail,” said Zernicka-Goetz.
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Materials provided by University of Cambridge. The original story is licensed under a Creative Commons License. Note: Content may be edited for style and length.

People living with obesity who attended a non-judgemental and personalised lifestyle modification programme improved their cardiovascular and mental health during just 10 weeks, according to a study presented today at EuroHeartCare — ACNAP Congress 2021, an online scientific congress of the European Society of Cardiology (ESC).1 Participants lost weight and achieved benefits in anxiety and depression and physical measurements including blood pressure.
“We focus on changing behaviours and improving people’s relationship with food,” said study author Ms. Aisling Harris, cardiac and weight management dietitian, Croi Heart and Stroke Centre, Galway, Ireland. “Many participants have tried diets with strict rules and have fears about foods they can’t eat. Our programme has no diet or meal plan, and no foods are excluded. Each person sets their own goals, which are reviewed weekly, and our approach is non-judgemental, which builds rapport and gains trust.”
“Obesity develops for multiple reasons and blaming someone for their weight can stop them from getting healthcare and advice,” said Ms. Harris. “It can lead to emotional eating and feeling too self-conscious to exercise. By identifying each person’s triggers, we can develop alternative coping strategies, all within the context of their job, caring responsibilities, external stresses, and so on. For some people, coming to a group like this might be the only social contact that they’ve had in the week or that they’ve had in years. People share experiences and support their peers.”
Both overweight and obesity are associated with an increased risk of dying from cardiovascular disease.2 Weight loss is recommended to reduce blood pressure, blood lipids, and the risk of developing type 2 diabetes, and thus lower the likelihood of heart disease. This study analysed the impact of a community-based, lifestyle modification programme on the physical and mental health of people living with obesity referred from a specialist bariatric service at Galway University Hospital. The researchers reviewed data from 1,122 participants between 2013 and 2019.
The 10-week Croí CLANN (Changing Lifestyle with Activity and Nutrition) programme started with an assessment by a nurse, dietitian and physiotherapist and baseline measurements of weight, blood pressure, cholesterol, blood glucose, fitness, and levels of anxiety and depression. Personalised goals and a management plan were agreed in collaboration with each patient.
Participants attended a 2.5-hour session each week for 8 weeks. The first 30 minutes were devoted to one-to-one goal setting. Next was a 1-hour exercise class led by the physiotherapist. A 1-hour health promotion talk followed on topics such as healthy eating, portion sizes, reading food labels, emotional versus physical hunger, stress management techniques (e.g. meditation), physical activity, sedentary behaviour, cardiovascular risk factors, and making and maintaining changes. Participants used activity trackers and kept food diaries to identify triggers for emotional eating.
In the last week patients had an end of programme assessment with the nurse, dietitian and physiotherapist to look at outcomes. They were then referred back to the hospital.
At baseline, the average body mass index (BMI) was 47.0 kg/m2 and 56.4% of participants had a BMI above 45 kg/m2. In addition, 26.7% had type 2 diabetes, and 31.4% had a history of depression.
More than three-quarters of participants (78%) completed the programme. Psychosocial health was assessed using the 21-point Hospital Anxiety and Depression Scale (HADS), where 0-7 is normal, 8-10 is mild, 11-15 is moderate, and 16-21 is severe. Anxiety and depression scores decreased by 1.5 and 2.2 points, respectively, over the course of the programme. The proportion with an anxiety score greater than 11 at the start was 30.8% and reduced to 19.9%; for depression the corresponding proportions were 21.8%, falling to 9.5%.
The average reduction in body weight was 2.0 kg overall, with 27.2% of participants losing more than 3% of their initial weight. The proportion achieving recommended physical activity levels rose by 31%. There were significant reductions in total cholesterol, low-density lipoprotein (LDL) cholesterol, and blood pressure. The proportion with high blood pressure fell from 37.4% at baseline to 31.1% at 10 weeks. In those with type 2 diabetes, the proportion achieving the recommended blood sugar target rose from 47.6% to 57.4%.
Ms. Harris concluded: “Nearly eight in ten people finished the programme which suggests that the content and format were acceptable. We observed improvements across all psychosocial and health outcomes during a relatively short period indicating that this could be a model of service delivery for other centres.”

Many people likely lost sleep over COVID-19. A study of twins led by Washington State University researchers found that stress, anxiety and depression during the first few weeks of the pandemic were associated with less and lower quality sleep.
In a survey of more than 900 twins taken shortly after COVID-19 lockdown measures began, about half of the respondents reported no change in their sleep patterns, but around a third, 32.9%, reported decreased sleep. Another 29.8% reported sleeping more. In the analysis, the researchers found that any change in sleep was connected to self-reported mental health issues, though it was more strongly associated with decreased sleep.
“The results show that deviations from your typical sleep behavior may be associated with depression, anxiety and stress,” said Siny Tsang, lead author on the study published in Frontiers in Neuroscience.
Tsang, a staff scientist with the WSU Elson S. Floyd College of Medicine, emphasized that this showed a connection, not a cause, but the study supports previous research that has found a two-way relationship between disrupted sleep patterns and poor mental health. In other words, when people don’t sleep well, they are more likely to feel stress, anxiety and depression, and when they are dealing with those same problems, they are more likely to sleep less — and sometimes more — than the typical six to nine hours a night.
This study analyzes survey responses collected between March 26 and April 5, 2020 from participants in the Washington State Twin Registry. Since then, the same group has answered three more waves of survey questions. Researchers are particularly interested in studying twins, so they can investigate whether associations are mediated by genetic factors, shared environment, or both. The pandemic also offered an opportunity for a natural experiment to see how a stressful situation affects sleep amount and quality among individuals in the community, Tsang said.
The research relies on the self-reported perception of sleep length and quality, but the researcher said that when it comes to mental health, perception can matter more than the real amount of sleep.
“Even if your cell phone says you consistently sleep eight hours every day, you may feel that you slept less or slept poorly, and that may be linked to stressful or anxious feelings,” Tsang said. “It may not matter whether or not the actual number has changed. It’s how you are feeling that is associated with your mental health.”
WSU researchers have also conducted twin-studies on COVID-19 lockdown effects on alcohol use and pandemic stress and exercise. These have all been initial studies taken at the early stages of the pandemic and associated social distancing measures. The scientists are still analyzing results of later surveys, but they are starting to see a common theme.
“A pattern that is consistent across these three studies is that people who reported change in physical exercise, alcohol use or sleep are more stressed, anxious and depressed than those who had said that they have had no change,” Tsang said.
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Materials provided by Washington State University. Original written by Sara Zaske. Note: Content may be edited for style and length.

The coronavirus pandemic has exposed economic and social fault lines around the globe, but Covid-19 vaccines have made the divides even starker: While some poor countries are pleading for doses to save their people, a few rich ones are awash in shots and lacking takers.A handful of U.S. states, for example, have tried incentives to get more people vaccinated. But in Moscow, as Covid hospitalizations surged this week, the city government took a harder line, mandating vaccinations for many workers in public-facing jobs.Some other governments have also attempted to require vaccines. A province in Pakistan has said it will stop paying the salaries of civil servants who are not inoculated, starting next month. And Britain, which is seeing a surge attributed to the spread of the Delta variant of the virus, is weighing whether to make shots obligatory for all health care workers.The Moscow Times quoted the city’s mayor, Sergei S. Sobyanin, as saying on Wednesday, “When you go out and come into contact with other people, you are an accomplice of the epidemiological process — a chain in the link spreading this dangerous virus.” The mandate he announced focuses on the education, entertainment, health care, and hospitality sectors and will continue until at least 60 percent of employees have been vaccinated, the newspaper reported.In Britain, officials said that requiring health care workers to be vaccinated would help stop the spread of the virus in hospitals. Nadhim Zahawi, the British vaccine minister, said that there was a precedent for such a requirement. “Obviously, surgeons get vaccinated for hepatitis B, so it’s something that we are absolutely thinking about,” he told Sky News last month.Many universities in the United States now require at least some students and employees to be vaccinated, and federal officials have repeatedly made clear that most companies with at least 15 employees have the right to require that workers are inoculated.But vaccine requirements continue to face resistance from some.In 15 American states, not a single college had announced any type of vaccine requirement as of last month. Days ago, 178 employees of Houston Methodist Hospital who refused to get a coronavirus shot were suspended. And on Saturday, protesters are expected at the offices of the New York State Bar Association in Albany, where officials will be discussing a report that recommends mandating a coronavirus vaccine for all New Yorkers, unless they are exempted by doctors.But for the undecided who are open to persuasion, incentives to get the vaccine remain common: There are lotteries in California, college scholarships in New York State and free drinks in New Jersey.The giveaways have spurred some to action. This week, both New York and California announced that they were lifting virtually all coronavirus restrictions on businesses and social gatherings.

The role of people infected with malaria without showing symptoms presents a hidden risk to efforts to control the disease after they were found to be responsible for most infections in mosquitoes, according to a study published in The Lancet Infectious Diseases.
Researchers from the Infectious Diseases Research Collaboration (IDRC), London School of Hygiene & Tropical Medicine (LSHTM), Radboud university medical center and University of California, San Francisco, found asymptomatic children in the Uganda study were the biggest source of malaria parasites transmitted to mosquitoes. This could provide a new opportunity for control efforts by targeting this infectious reservoir.
Malaria presents a major health threat globally, with 94% of cases on the African continent alone, according to the WHO World Malaria Report 2020. The disease is passed to a human through the bite of an infected female Anopheles mosquito causing infection with the parasite. The predominant and most deadly parasite, Plasmodium falciparum, accounts for over 75% of mortality worldwide and is highly prevalent in Uganda.
Malarial parasites depend on a life cycle in which they constantly move back and forth between humans and mosquitoes. Successfully interrupting transmission of the disease can involve clearing parasites from human ‘hosts’ using anti-malaria drugs.
Nagongera sub-county (Tororo district) in eastern Uganda has historically very high malaria transmission but following intensive malaria control efforts, such as insecticide-treated bednets, indoor residual spraying (IRS) with insecticides and access to malaria drugs, infections — or at least symptomatic cases — have gone down remarkably.
The research team aimed to investigate patterns of malaria infection and understand more about transmission in the area. The study involved two years of regularly testing more than 500 people for evidence of malaria parasites. The genetic make-up of parasites was determined, as well as their ability to infect mosquitoes.

Researchers at the National Eye Institute (NEI) have determined how certain short protein fragments, called peptides, can protect neuronal cells found in the light-sensing retina layer at the back of the eye. The peptides might someday be used to treat degenerative retinal diseases, such as age-related macular degeneration (AMD). The study published today in the Journal of Neurochemistry. NEI is part of the National Institutes of Health.
A team led by Patricia Becerra, Ph.D., chief of the NEI Section on Protein Structure and Function, had previously derived these peptides from a protein called pigment epithelium-derived factor (PEDF), which is produced by retinal pigment epithelial cells that line the back of the eye.
“In the eye, PEDF protects neurons from dying. It prevents the invasion of blood vessels, it prevents inflammation, it has antioxidant properties — all these are beneficial properties,” said Becerra, the senior author of the study. Her studies suggest that PEDF is part of the eye’s natural mechanism for maintaining eye health. “PEDF may have a role for treating eye disease. If we want to exploit the protein for therapeutics, we need to separate out the regions responsible for its various properties and determine how each of them works.”
The team used a well-known cell culture model system where immature retinal cells are isolated from the eyes of newborn rats and grown in a dish with minimal nutrients. The system includes not only the retina’s light-sensing photoreceptors, but additional types of neurons that help the retina process and transmit visual information to the brain.
“Our model system — using cells isolated from the animal — lets us tease out the individual processes and mechanisms behind PEDF’s protective effects,” said Germán Michelis, graduate student and the study’s first author.
The PEDF protein has functionally distinct domains. The Becerra lab previously found that each domain can work independently. One area, which is called the 34-mer because it is formed by 34 amino acid building blocks, halts blood vessel growth. Aberrant blood vessel growth is central to retinal diseases such as AMD and diabetic retinopathy. The second PEDF domain, called the 44-mer, provides anti-death signals to retinal neurons. The 44-mer can also stimulate neurons to grow neurites, finger-like projections that help the neurons communicate with their neighbors. A shorter version of the 44-mer of only 17 amino acids (17-mer) has identical activities.