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Tsukuba, Japan - Cardiovascular disease is the leading cause of death in humans. Worldwide, as the population ages, the burden of treating heart failure is increasing; opportunities for heart transplantation cannot keep pace. As adult cardiomyocytes (heart muscle cells) are terminally differentiated and do not proliferate, regeneration may be the answer. Support cells like fibroblasts can be directly reprogrammed in vitro, but these induced cardiomyocytes (iCMs) are less mature than those in vivo. Now, researchers at the University of Tsukuba have identified the roles of matrix stiffness and mechanotransduction in cardiac reprogramming, showing that matrices with softness comparable to native myocardium enhance the efficiency of this transformation by about 15%.

Mammalian myocardium is essentially incapable of regeneration following injury. Instead, a non-contractile fibrous scar forms to maintain structural integrity; compensatory hypertrophy is often inadequate to prevent eventual cardiac failure. Though cell transplantation holds potential, regeneration of damaged myocardium by direct reprogramming of cardiac fibroblasts, present in abundance, is a viable alternate strategy.

The researchers sought to investigate the signaling pathways for cardiac reprogramming as well as the underlying mechanotransductive processes (whereby cells convert physical stresses into electrochemical signals). They first prepared Matrigel-coated polystyrene dishes and Matrigel-based hydrogels to replicate extracellular matrices (ECM) with elasticities ranging from that of brain tissue to bone. These substrates were plated with transgenic mouse fibroblasts which were later transduced with four cardiac transcription factors, Gata4, Mef2c, Tbx5 and hand2 (GHMT), to generate iCMs.

"After four weeks, we found that soft substrates showed significantly more spontaneously beating iCMs, maximally on those matching native myocardium," says senior author, Professor Masaki Ieda. "Additionally, using innovative high-speed video microscopy and motion vector analysis, we demonstrated increased iCM contraction/relaxation velocities on those substrates, thus illustrating their functional maturation."

Further immunocytochemistry, western blot analysis, and fluorescence-activated cell sorting analysis helped elucidate the underlying mechanisms and signaling pathways. The researchers showed that soft ECM promotes cardiac reprogramming by inhibiting two related transcriptional co-activators, YAP and TAZ, thus suppressing fibroblast signatures. The upstream mechanotransduction pathway was also elucidated; suppression of YAP/TAZ was mediated by inhibition of integrins (transmembrane receptors that facilitate and signal ECM adhesion), Rho/ROCK (a kinase that modulates cell shape and movement), and actomyosin (a contractile protein-complex).

Professor Ieda explains the implications of their results: "Following a heart attack, the healing myocardium stiffens due to fibrosis. Understanding how matrix softness and mechanobiology affect cardiac reprogramming could inform clinical research. Direct reprogramming of cardiac fibroblasts may allow replacement of non-contractile scar by functional muscle in patients recovering from myocardial infarction."

Sophia Antipolis, France - 29 Aug 2020: The first recommendations on sports and physical activity in all types of heart disease are launched today by the European Society of Cardiology (ESC). The document is published online in European Heart Journal,1 and on the ESC website.2

"With rising levels of obesity and sedentary lifestyles, promoting physical activity is more crucial now than ever before," said Professor Antonio Pelliccia, Chairperson of the guidelines Task Force and chief of cardiology, Institute of Sports Medicine and Science, Rome, Italy. "Regular exercise not only prevents heart disease, but also reduces premature death in people with established heart disease."

"The chance of exercise triggering a cardiac arrest or heart attack is extremely low," said Professor Sanjay Sharma, Chairperson of the guidelines Task Force and professor of sports cardiology and inherited cardiac diseases, St. George's, University of London, UK. "People who are completely inactive and those with advanced heart disease should consult their doctor before taking up sports."

The document covers leisure exercise and competitive sports for people with heart disease and conditions which raise the risk of heart disease such as obesity and diabetes. Advice is also given on exercise during pregnancy, or in special settings such as at high altitude, in deep sea, in polluted areas, and at extreme temperatures. The document states that traffic fumes are unlikely to lessen the benefits of physical activity to heart health.

In common with healthy adults of all ages, people with heart disease should exercise on most days, totalling at least 150 minutes per week of moderate intensity exercise. Moderate intensity means increasing your heart rate and breathing rate but still being able to hold a conversation.

For people who are obese or have high blood pressure or diabetes, the guidelines recommend strength-building exercise (for example, lifting light weights) at least three times a week plus moderate or vigorous aerobic exercise, such as cycling, running, or swimming.

Coronary artery disease is the most common type of heart disease and is caused by build-up of fatty deposits on the inner walls of the arteries. If the arteries become completely blocked this can cause a heart attack. Most people with coronary artery disease can play competitive or amateur sports.

"People with long-standing coronary artery disease who wish to take up exercise for the first time should see their doctor first," said Professor Pelliccia. "The aim is to tailor the intensity of activity according to the individual risk of causing an acute event such as a heart attack."

Regular, moderate physical activity is recommended to prevent the most common heart rhythm disorder - called atrial fibrillation. People with atrial fibrillation who are taking anticoagulants to prevent stroke should avoid contact sports due to the risks of bleeding.

People with pacemakers should not be discouraged from playing sports (except collision sports) because of the device. However, they need to tailor their choice according to the underlying disease.

Professor Pelliccia noted that anyone experiencing chest pain for more than 15 minutes should call an ambulance. He added: "If you find that exercise brings on palpitations or unusual shortness of breath or chest discomfort, scale back your activity and make an appointment to see your health professional."

Professor Sharma said: "Physical activity is good for everyone with heart disease and even small amounts are beneficial. We hope these guidelines will help patients and their health professionals choose the best and most enjoyable activities for them."

Sophia Antipolis, France - 29 Aug 2020: One in five patients die within a year after the most common type of heart attack. European Society of Cardiology (ESC) treatment guidelines for non-ST-segment elevation acute coronary syndrome are published online today in European Heart Journal,1 and on the ESC website.2

Chest pain is the most common symptom, along with pain radiating to one or both arms, the neck, or jaw. Anyone experiencing these symptoms should call an ambulance immediately. Complications include potentially deadly heart rhythm disorders (arrhythmias), which are another reason to seek urgent medical help.

Treatment is aimed at the underlying cause. The main reason is fatty deposits (atherosclerosis) that become surrounded by a blood clot, narrowing the arteries supplying blood to the heart. In these cases, patients should receive blood thinners and stents to restore blood flow. For the first time, the guidelines recommend imaging to identify other causes such as a tear in a blood vessel leading to the heart.

Regarding diagnosis, there is no distinguishing change on the electrocardiogram (ECG), which may be normal. The key step is measuring a chemical in the blood called troponin. When blood flow to the heart is decreased or blocked, heart cells die, and troponin levels rise. If levels are normal, the measurement should be repeated one hour later to rule out the diagnosis. If elevated, hospital admission is recommended to further evaluate the severity of the disease and decide the treatment strategy.

Given that the main cause is related to atherosclerosis, there is a high risk of recurrence, which can also be deadly. Patients should be prescribed blood thinners and lipid lowering therapies. "Equally important is a healthy lifestyle including smoking cessation, exercise, and a diet emphasising vegetables, fruits and whole grains while limiting saturated fat and alcohol," said Professor Jean-Philippe Collet, Chairperson of the guidelines Task Force and professor of cardiology, Sorbonne University, Paris, France.

Behavioural change and adherence to medication are best achieved when patients are supported by a multidisciplinary team including cardiologists, general practitioners, nurses, dietitians, physiotherapists, psychologists, and pharmacists.

The likelihood of triggering another heart attack during sexual activity is low for most patients, and regular exercise decreases this risk. Healthcare providers should ask patients about sexual activity and offer advice and counselling.

Annual influenza vaccination is recommended - especially for patients aged 65 and over - to prevent further heart attacks and increase longevity.

"Women should receive equal access to care, a prompt diagnosis, and treatments at the same rate and intensity as men," said Professor Holger Thiele, Chairperson of the guidelines Task Force and medical director, Department of Internal Medicine/Cardiology, Heart Centre Leipzig, Germany.

The primary goal of this study by Amanda H. Anderson et al was to identify independent risk factors of CKD progression among participants with and without diabetes in a prospective CKD cohort study (N=3,379). Among those with diabetes, CKD progression rates approximately doubled with higher levels of the inflammatory chemokine CXCL12, the cardiac marker NTproBNP and the kidney injury marker urine NGAL. Among those without diabetes, rates increased over 1.5-fold with higher levels of high-sensitivity troponin T, NTproBNP, and urine NGAL. The strength of these associations exceeded that of systolic blood pressure ≥140 mmHg, a well-established risk factor for kidney disease progression. These findings provide insights into potential mechanisms of CKD progression and will guide future research in defining subgroups at highest risk for CKD progression.

New findings from a large European study of patients in 18 countries, including the UK, show that while many patients are able to reduce their risk through taking statins, those at the highest risk of cardiovascular events may benefit from combinations of lipid-lowering therapies.

According to the authors, the study highlights a gap between current clinical guidelines and clinical practice for cholesterol management across Europe. They explain that even among patients who are already receiving optimal doses of statins, greater use of other, non-statin cholesterol-lowering drugs could help to further reduce cholesterol levels and potentially improve health outcomes for those most at risk.

The findings, which will be presented at the virtual meeting of the European Society of Cardiology 2020, are published in the journal European Journal of Preventive Cardiology.

Professor Kausik Ray, from Imperial's School of Public Health, who led the DA VINCI study, said: "In order to tackle the burden of cardiovascular disease, a global approach is needed. After diet and lifestyle, cholesterol lowering with medications is a key approach to lowering risk of heart disease and strokes. Based on trial data we have compelling evidence that lower cholesterol levels benefit those at highest risk particularly.

"Though statins are first line treatment, it is clear from our contemporary study that statins alone even when optimally used will not help the majority of patients achieve European Society of Cardiology cholesterol goals. Only one in five very-high risk patients achieve 2019 recommended goals and to improve this will require use of combination therapy of more than one drug. Currently less than 10% of very-high risk patients in Europe receive some form of combination therapy, 9% with ezetimibe and 1% with PCSK9 inhibitors."

High levels of low-density lipoprotein (LDL) cholesterol, or so-called 'bad' cholesterol, in the blood are a known risk factor for cardiovascular disease. While diet and lifestyle are important factors in reducing LDL cholesterol, many patients are at increased risk - such as those with diabetes, inherited conditions or who have previously had heart attack or stroke - and are prescribed cholesterol-lowering drugs, like statins, to reduce their cholesterol.

But a number of other classes of cholesterol-lowering drugs are available, which act on different elements of the body's cholesterol-metabolism. These treatments, such as ezetimibe, bempedoic acid, or PCSK9 inhibitors, can be used in combination with statins to further reduce LDL-cholesterol levels.

In the DA VINCI study, a consortium of researchers led by the Imperial Clinical Trials Unit at Imperial College London looked at patients across Europe who were prescribed lipid-lowering therapies.

In total 5888 patients, enrolled across 18 countries, provided information at doctor's appointment or in hospital to manage cardiovascular conditions. Information included lifestyle factors, previous cardiovascular events (such as heart attack or stroke) as well as measures of their current LDL cholesterol levels and any current lipid-lowering medications.

Current guidelines from the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) recommend statins as first-line treatment for lowering LDL cholesterol. The guidance also recommends goals based on risk groupings, such as a target of 50% reduction in LDL-C levels in very-high risk patients and achieving LDL-C levels below 1.4mmol/L, in order to reduce the risk of additional cardiovascular events.

In the DA VINCI study the team reviewed how lipid-lowering therapies were used in primary and secondary care and the attainment of cholesterol reduction goals set out by the guidelines.

Analysis revealed that 84% of patients1 received statins as their primary lipid-lowering therapy only, with high intensity statins used in approximately one-quarter (28%)2 of patients. Just 9% of patients were prescribed ezetimibe with moderate intensity statins and just 1% of patients used PCSK9 inhibitors in combination with statins and/or ezetimibe.

They found that overall, less than half of patients were achieving the most recent cholesterol-lowering goals set out by guidelines. Among patients receiving high-intensity statins, 2019 LDL-C goals were achieved in 22% of patients with established cardiovascular disease. However, among the patients receiving statins with a PCSK9 inhibitor about two thirds attained the new lower ESC recommended cholesterol goals.

According to the authors, the findings highlight the potential for combinations of lipid lowering drugs to help close the gap and reduce the risk for millions of patients across Europe. They explain that reducing LDL cholesterol levels in very-high risk patients (from the observed levels of above 2mmol/L to below 1.4 mmol/L) could offer an 11% relative reduction in cardiovascular events and 5% relative reduction in mortality.

The authors add that untreated lipid levels were not available and so they were unable to quantify to what extent the ?50% LDL-C reduction from baseline was achieved, but used high-intensity statin use as proxy. They add that physician choice of LLT, pre-treatment LDL cholesterol levels and local prescribing restrictions could have influenced our observations.

Professor Ray added: "Over the last 15 years we have seen improvements in guideline implementation and control of cardiovascular risk factors. These were based on better first line treatment such as statins. Now, with lowering of cholesterol goals, our data suggest this will not be enough and we need to think about cholesterol in the same way as we look at blood pressure where often combinations of treatments are needed to optimise targets."

A new study led by University of Hawai'i at Mānoa researchers, published in the journal Nature Communications this week, revealed that correctly simulating ocean current variations hundreds of feet below the ocean surface - the so-called Pacific Equatorial Undercurrent - during El Niño events is key in reducing the uncertainty of predictions of future warming in the eastern tropical Pacific.

Trade winds and the temperatures in the tropical Pacific Ocean experience large changes from year to year due to the El Niño-Southern Oscillation (ENSO), affecting weather patterns across the globe. For instance, if the tropical Pacific is warmer and trade winds are weaker than usual - an El Niño event -flooding in California typically occurs and monsoon failures in India and East Asia are detrimental to local rice production. In contrast, during a La Niña the global weather patterns reverse with cooler temperatures and stronger trade winds in the tropical Pacific. These natural climate swings affect ecosystems, fisheries, agriculture, and many other aspects of human society.

Computer models that are used for projecting future climate correctly predict global warming due to increasing greenhouse gas emissions as well as short-term year-to-year natural climate variations associated with El Niño and La Niña.

"There is, however, some model discrepancy on how much the tropical Pacific will warm," said Malte Stuecker, co-author and assistant professor in the Department of Oceanography and International Pacific Research Center at UH Mānoa. "The largest differences are seen in the eastern part of the tropical Pacific, a region that is home to sensitive ecosystems such as the Galapagos Islands. How much the eastern tropical Pacific warms in the future will not only affect fish and wildlife locally but also future weather patterns in other parts of the world."

Researchers have been working for decades to reduce the persistent model uncertainties in tropical Pacific warming projections.

Many climate models simulate El Niño and La Niña events of similar intensity. In nature, however, the warming associated with El Niño events tends to be stronger than the cooling associated with La Niña. In other words, while in most models El Niño and La Niña are symmetric, they are asymmetric in nature.

In this new study, the scientists analyzed observational data and numerous climate model simulations and found that when the models simulate the subsurface ocean current variations more accurately, the simulated asymmetry between El Niño and La Niña increases--becoming more like what is seen in nature.

"Identifying the models that simulate these processes associated with El Niño and La Niña correctly in the current climate can help us reduce the uncertainty of future climate projections," said corresponding lead author Michiya Hayashi, a research associate at the National Institute for Environmental Studies, Japan, and a former postdoctoral researcher at UH Mānoa supported by the Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowships. "Only one-third of all climate models can reproduce the strength of the subsurface current and associated ocean temperature variations realistically."

"Remarkably, in these models we see a very close relationship between the change of future El Niño and La Niña intensity and the projected tropical warming pattern due to greenhouse warming," noted Stuecker.

That is, the models within the group that simulate a future increase of El Niño and La Niña intensity show also an enhanced warming trend in the eastern tropical Pacific due to greenhouse warming. In contrast, the models that simulate a future decrease of El Niño and La Niña intensity show less greenhouse gas-induced warming in the eastern part of the basin. The presence of that relationship indicates that those models are capturing a mechanism known to impact climate--signifying that those models are more reliable. This relationship totally disappears in the two-thirds of climate models that cannot simulate the subsurface ocean current variations correctly.

"Correctly simulating El Niño and La Niña is crucial for projecting climate change in the tropics and beyond. More research needs to be conducted to reduce the biases in the interactions between wind and ocean so that climate models can generate El Niño - La Niña asymmetry realistically," added Fei-Fei Jin, co-author and professor in the Department of Atmospheric Sciences at UH Mānoa.

"The high uncertainty in the intensity change of El Niño and La Niña in response to greenhouse warming is another remaining issue," said Stuecker. "A better understanding of Earth's natural climate swings such as El Niño and La Niña will result in reducing uncertainty in future climate change in the tropics and beyond."

Sophia Antipolis, France - 28 Aug 2020: Men with untreated high blood pressure have poorer penile blood flow than those with normal blood pressure, according to research presented today at ESC Congress 2020.1 The differences disappeared with blood pressure medication. The results provide reassurance to men concerned about the effects of blood pressure-lowering medications.

Hypertension (high blood pressure) affects more than one billion people worldwide and is the leading cause of premature death.2 A healthy lifestyle is advised, including salt restriction, alcohol moderation, exercise, weight control, and smoking cessation. Most patients also require drug treatment, which is linked to reduced risks of death, stroke, and heart disease - but around half of patients do not take their pills. Sexual dysfunction is one reason why patients stop medication.

Men with hypertension are almost twice as likely to have impaired penile blood flow and erectile dysfunction compared to men with normal blood pressure, increasing their risk of heart disease and death. High blood pressure damages artery walls, causing them to harden and narrow, and reducing blood flow to the penis. Erectile dysfunction is an early warning sign of damaged blood vessels.

However, previous studies have shown that erectile dysfunction is more common in treated, than untreated, men with high blood pressure. And certain antihypertensive drugs - notably diuretics and beta blockers - have been linked with deterioration in sexual function. This study examined the association between blood pressure level and penile blood flow, and whether blood pressure-lowering medication had an effect on the relationship.

The study included 356 men with erectile dysfunction and no history of diabetes or cardiovascular disease who attended a clinic between 2006 and 2019. The cohort was divided into three categories according to blood pressure: normal, high-normal, and hypertension. A total of 164 (46%) patients were being treated with antihypertensive medications.

All patients underwent a penile colour Doppler ultrasound which is the standard method for evaluating penile blood vessels and erectile dysfunction. The method involves injecting a drug into the base of the penis to open the blood vessels then measuring blood flow. Penile blood flow is considered impaired when the velocity is lower than 25 cm/s.

Among men not receiving antihypertensive medication, penile blood flow velocity progressively decreased with rising blood pressure - i.e. blood flow was fastest in those with normal blood pressure, slower in those with high-normal blood pressure, and slowest in those with hypertension (see Figure). In contrast, among men taking antihypertension therapy, there was no difference in penile blood flow velocity between the three blood pressure categories.

"The progressive decrease in penile blood flow velocity across the three blood pressure categories in men not taking antihypertensive medication indicates significant structural changes in the penile blood vessels from longstanding hypertension," said study author Professor Charalambos Vlachopoulos of the National and Kapodistrian University of Athens, Greece. "The blood flow differences across the three blood pressure categories disappeared with treatment, suggesting a medication effect."

An additional analysis compared treated and untreated men within each blood pressure group. In the hypertension category, treated and untreated patients had similar penile blood flow velocities. However, in the high-normal category, treated men had worse penile blood flow than untreated men. Similarly, in the normal blood pressure category, treated men had worse penile blood flow than untreated men.

Professor Vlachopoulos said: "These results imply that hypertensive patients already have significant structural damage in the penile arteries and adding antihypertensive drugs does not further reduce penile blood flow. But in men with normal or high-normal blood pressure, the penile arteries have minimal structural damage and medications could have a negative impact on penile blood flow."

He urged men with concerns about sexual dysfunction to discuss it with their doctor. "For men with as yet untreated hypertension, older medications (beta blockers and diuretics) are not ideal and should be used only if absolutely indicated," he said.

Professor Vlachopoulos noted that changing hypertensive medications in men with erectile dysfunction must be handled with caution. He said: "First, if a co-existing disease dictates using a specific drug category (for example, beta blockers for coronary artery disease and heart failure, diuretics for heart failure), then switching is not advocated. Alternatives might be considered if patients are at risk of stopping lifesaving therapy because of the detrimental impact of erectile dysfunction on their life."

"Second, switching to another drug class does not guarantee either the restoration or improvement of erectile function. This has to be carefully explained to patients in advance to avoid unreasonable expectations," he said.

Professor Vlachopoulos concluded: "Our study shows that high blood pressure can be treated without causing erectile dysfunction. Patients and doctors need to have open discussions to find the best treatment option."

Figure: Penile blood flow velocity across blood pressure categories in treated and untreated men

BP = blood pressure; PSV = peak systolic velocity.

A protein that's common throughout the body plays a key role in regulating glucose levels, says new research conducted in the Cell Signal Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) and Riken Center of Integrative Medical Sciences. Called CNOT3, this protein was found to silence a set of genes that would otherwise cause insulin-producing cells to malfunction, which is related to the development of diabetes.

Diabetes is a common disorder that causes very high blood glucose levels. Left untreated, it can lead to serious health problems like kidney failure, heart disease, and vision loss. This disorder occurs when there isn't enough insulin in the body or when insulin-induced responses are weakened. Insulin normally lets glucose into cells for energy-use and so, without it, glucose builds up in the blood instead. A lack of insulin is often because the pancreatic beta cells, which normally synthesize and secrete insulin, have stopped functioning correctly.

"We know that defects in beta cells can lead to high levels of glucose in the blood and, eventually, diabetes." said Dr. Dina Mostafa, former PhD student in the Unit and first author of the paper published in Communications Biology. "Our results suggest that CNOT3 has a hand in this and plays a key role in maintaining normal beta cell function."

Knocking out CNOT3 found to lead to diabetes in mice:

CNOT3 is a jack-of-all-trades. Many organs throughout the body express it, and it regulates different genes in different tissues. But its activity has a common basis - it helps to keep cells alive, healthy, and functioning correctly. It does this through several different mechanisms, such as producing the right proteins or suppressing certain genes.

Here, researchers studied its function in islet cells from pancreatic tissue in mice. These islets are notoriously difficult to work with, taking up just only one to two percent of the pancreas, but they're where the beta cells are located.

The researchers first looked at whether CNOT3 expression differed in diabetic mice compared with non-diabetic mice. By looking at these islets, they found that there was a significant decrease in the CNOT3 in the diabetic islets as opposed to the non-diabetic ones.

To further investigate the protein's function, the researchers blocked its production in the beta cells of otherwise normal mice. For four weeks, the animals' metabolism functioned normally, but by the eighth week, they had developed an intolerance to glucose, and by 12 weeks they had full-blown diabetes.

Without CNOT3, the researchers found that some genes, which are normally switched off in beta cells, switch on and start to produce proteins. Under normal circumstances, these genes are silenced because once they switch on, they cause all kinds of problems for the beta cells, such as stopping them from secreting insulin in response to glucose.

"We still don't know that much about these kinds of genes, such as what their normal function is and the mechanism that's involved in their silencing," Dr. Mostafa said. "So, it was very rewarding to find that CNOT3 in an important factor in keeping them switched off."

The messenger RNA connection:

Further research into the cellular mechanisms behind this found a surprising link between CNOT3 and the messenger RNA of these normally switched-off genes. A messenger RNA (mRNA) is a single strand molecule that corresponds to the genetic sequence of a gene and is essential for synthesizing proteins.

Under normal circumstances, the mRNA of these genes hardly expresses. But once CNOT3 was removed, the researchers found that the mRNA was much more stable. In fact, protein was produced from the stabilized mRNA, which have unfavorable effects on normal tissue function. This suggests that at least one way that these genes are kept switch off is through the destabilization of their mRNA, driven by CNOT3.

"This study is a step towards understanding the molecular mechanisms that govern normal beta cell function," Dr. Mostafa said. "Ultimately, it could contribute to new ways of preventing and treating diabetes."

Cells that are infected by a virus or carry a carcinogenic mutation, for example, produce proteins foreign to the body. Antigenic peptides resulting from the degradation of these exogenous proteins inside the cell are loaded by the peptide-loading complex onto so-called major histocompatibility complex molecules (MHC for short) and presented on the cell surface. There, they are specifically identified by T-killer cells, which ultimately leads to the elimination of the infected cells. This is how our immune system defends us against pathogens.

Machine operates with atomic precision

The peptide-loading complex ensures that the MHC molecules are correctly loaded with antigens. "The peptide-loading complex is a biological nanomachine that has to work with atomic precision in order to efficiently protect us against pathogens that cause disease," says Professor Lars Schäfer, Head of the Molecular Simulation research group at the Centre for Theoretical Chemistry at RUB.

In previous studies, other teams successfully determined the structure of the peptide-loading complex using cryo-electron microscopy, but only with a resolution of about 0.6 to 1.0 nanometres, i.e. not in atomic detail. Based on these experimental data, Schäfer's research team in collaboration with Professor Gunnar Schröder from Forschungszentrum Jülich has now succeeded in creating an atomic structure of the peptide-loading complex.

Exploring structure and dynamics

"The experimental structure is impressive. But only with our computer-based methods were we able to extract the maximum information content contained in the experimental data," explains Schröder. The atomic model enabled the researchers to perform detailed molecular dynamics computer simulations of the peptide-loading complex and thus to study not only the structure but also the dynamics of the biological nanomachine.

Since the simulated system is extremely large with its 1.6 million atoms, the computing time at the Leibnitz Supercomputing Centre in Munich aided this task considerably. "Using the high-performance computer, we were able to push into the microsecond time scale in our simulations. This revealed the role of sugar groups bound to the protein for the mechanism of peptide loading, which had previously only been incompletely understood," outlines Dr. Olivier Fisette, postdoc researcher at the Molecular Simulation research group.

Direct intervention in immune processes

The atomic model of the peptide-loading complex now facilitates further studies. For example, some viruses try to cheat our immune system by selectively switching off certain elements of the peptide-loading complex. "One feasible objective we'd like to pursue is the targeted intervention in these processes," concludes Schäfer.

The COVID-19 crisis has increasingly highlighted shortcomings in Australia's National Broadband Network, Flinders University experts say.

With access to high-speed broadband (HSB) and the internet via the NBN now central to people's livelihoods, education, healthcare delivery and even social connections, the Flinders University researchers say the "short-term politics of the 2013 federal election" led to decisions which caused an expensive rollout and current problems with the network.

"Our research shows that the way Australia's NBN was implemented has meant that access to HSB is expensive compared to other countries," Flinders University Southgate Institute for Health, Society and Equity researcher Dr Matt Fisher says in a new paper.

"This contributes to more than one million Australian households not having an internet connection at home."

The paper, 'Implementing Policy On Next-generation Broadband Networks and Implications for Equity of Access To High Speed Broadband: a Case Study of Australia's NBN' published in Telecommunications Policy, examines NBN policy and implementation from 2008 to 2018 through Australian Government policy documents and interviews with experts.

"We found that equity considerations competed with political and commercial imperatives during the rollout of the NBN," the Flinders Southgate researchers conclude.

"This resulted in positive and negative consequences for equity of access to HSB, with a change in policy and implementation in 2013 bringing greater risks to equity of access."

Dr Fisher says the NBN rollout also created differences in the quality of HSB services in different areas. "This is likely to mean that people already well-off will gain more health and social benefits from the NBN than those less well-off.

"As work, education, employment, healthcare and other social services increasingly go online, the inequalities built into the NBN could add to health inequalities in Australia."

Portland State University researchers used advanced electron microscopy to create a 3-D reconstruction of a membrane protein at an unprecedented level of resolution, setting the stage for the development of drugs that could target the protein more effectively to treat a variety of diseases.

The Reichow Lab, led by chemistry professor Steve Reichow and made up of undergraduate and graduate students, uses cryo-electron microscopy (cryo-EM) and computer modeling to visualize how individual proteins in cells interact and function at the molecular level.

The Reichow Lab is particularly interested in a class of proteins known as membrane proteins. Membrane proteins are key for cells to communicate with one another and are the target of 50% of pharmaceutical drugs, Reichow said.

The focus of this research was connexin-46/50, two proteins from the eye lens that form pathways for cell-to-cell communication. The group used lipid nanodisc technology to coax the proteins back into their native-like membrane environment, which allowed them to image the protein at a remarkably high resolution of 1.9-Angstrom (an angstrom is one 100 millionth of a centimeter). The group was the first to image a membrane protein below 2.0-Angstrom using cryo-EM, which momentarily set a world record for this technology.

Reichow said a resolution below 2.0-Angstrom is the precision desired for structure-based drug design, which uses the atomic-level detail of a 3D structure to computationally design novel therapeutic agents. The high resolution provided new insight into how this group of membrane proteins interact with their native lipid environment as well as allowed them to see nearly 400 water molecules, which play an important role in protein structure and function.

"Drugs use water to extend their interaction with proteins," Reichow said. "Drug manufacturers are missing a big piece of the puzzle if they don't know where the water molecules are."

Personality traits help to understand why some people are physically active and others are not. A new study from the Gerontology Research Center and the Faculty of Sport and Health Sciences at the University of Jyväskylä, Finland, shows that the role of personality may vary depending on how physical activity is measured.

Personality traits reflect people's characteristic patterns of thinking, feeling and behaving. A study at the University of Jyväskylä focused on two traits: extraversion and neuroticism. Individuals who score high in extraversion are typically social, active and talkative. High scores in neuroticism indicate a tendency to have negative feelings, such as anxiety and self-pity.

The results showed that high extraversion and low neuroticism were linked to higher leisure time physical activity in middle-aged women. Women who scored high in extraversion reported more physical activity, but this was not seen in the physical activity measured by an activity monitor. Women who scored high in neuroticism reported less physical activity and had less physical activity captured by activity monitors.

"Even though both methods assess the frequency, duration and intensity of physical activity, they measure partly different aspects of physical activity," explains postdoctoral researcher Tiia Kekäläinen from the Gerontology Research Center. "Activity monitors are better at capturing all daily stepping activities whereas self-reporting better accounts for all types of physical activities. Therefore, it is natural that results are partly different between different physical activity measures. It is important to use both ways to assess physical activity behavior."

Personality traits may explain individual tendencies to estimate one's own physical activity level

Personality may explain the way individuals assess their own level of physical activity. The results showed that older adults scoring high in neuroticism reported less physical activity than what was measured by accelerometers.

"Neuroticism describes a predisposition to experience negative feelings," Kekäläinen says. "In addition to lower willingness to participate in physical activities, this kind of tendency seems to be related to underreporting physical activity behavior. The information about the role of personality could be used to help identify risk groups for inactivity and in physical activity promotion work."

Two larger research projects conducted at the Gerontology Research Center and Faculty of Sport and Health Sciences provided data for the study: from a total of 314 older men and women aged 70 to 85 years who participated in the PASSWORD study, and from 1,098 middle-aged women aged 47 to 55 years who participated in the ERMA study.

The pathogenic fungus Candida auris, which first surfaced in 2009, is proving challenging to control. It is resistant to many fungicides and not easy to diagnose. Researchers from Radboud university medical center, Canisius-Wilhelmina Hospital (CWZ) and international colleagues have discovered that the human immune system recognizes the fungus well. The study has been able to pin-point the fungus' Achilles heel for new, effective drugs. Meanwhile, the threat posed by this emerging public health pathogen should not be underestimated.

In 2009, an unknown fungus was discovered in the infected ear of a seventy-year-old Japanese woman; this was called Candida auris. Where C. auris suddenly came from was not clear, but soon after that, different strains appeared all over the world. It turned out to be a persistent, difficult to control fungus, which was also usually resistant to fungicides.

Last year, the New York Times published an alarming article about the growing problem. The authors cited the example of a man infected with C. auris who died after 90 days at Mount Sinai Hospital. The fungus, which in the meantime had settled in the mattress, curtains, walls, telephone, basically everywhere in the hospital room, could only be removed with a lot of effort. Only after special cleaning and removal of part of the ceiling and the tile floor did the hospital control the fungus.

Reduced immunity

"We started to investigate C. auris with international colleagues because there was virtually nothing known about this fungus," says Mariolina Bruno of Radboud university medical center's Department of Internal Medicine. The research results have now been published in Nature Microbiology. The study shows that the fungus is especially dangerous for people with compromised immunity. Bruno: "A well-functioning immune system recognizes the fungus clearly and can control it well."

A careful study of the human immune response to the C auris infection demonstrated that specific components of the cell wall of the fungus play an essential role in this recognition. David Williams, East Tennessee State University: "These are unique structures that you do not encounter with other fungi. Those specific chemical structures stimulate the immune system enough to take action and clear the fungus."

Resistant to fungicides

The fact that C. auris is considered a serious and emerging infectious disease is mainly due to its resistance to many disinfectants and fungicides. People with an invasive C. auris fungal infection have thirty to sixty percent chance of dying, precisely because of the immunity of the fungus to many fungicides. Alistair Brown, University of Exeter: "Our research not only shows that these cell wall components are important for the detection by the immune system, but also that they are indispensable to the fungus. Drugs that selectively block the production and operation of these components are currently being investigated for safety and effectiveness. Perhaps one of these is the ideal candidate to tackle the fungus."

Since these cell wall components are indispensable to C. auris, the risk of resistance to such a new drug is small. In order to develop resistance, the fungus must at least remain alive so that it can gradually adapt to the new drug.

Diagnosis and monitoring

Candida auris is related to the much better-known Candida albicans, which can cause vaginal fungal infections. In the study, C. albicans has therefore served as comparison material. Bruno: "On the one hand, we see that C auris evokes a better immunity reaction than C. albicans. On the other hand, C. auris appears less pathogenic, but once in the bloodstream, both fungi are usually life-threatening."

What makes the problem even worse is that C auris is not so easy to identify. This makes it easy to confuse with other fungi, which can lead to a delay in treatment. Jacques Meis, a physician-microbiologist at the CWZ: "You should determine the fungi type on a molecular level, enabling you to immediately see which fungus you are dealing with, but not every laboratory has the facilities for that." Earlier this year, he and Paul Verweij (Radboud university medical center) called for the nation-wide monitoring of serious fungal infections to gain a better understanding of the burden of disease and mortality rates.

Global warming?

The question why C auris suddenly appeared in 2009 has still not been answered. The fungus was not found in stored patient material from previous years, so it seems to be a new or mutated fungus. Perhaps global warming plays a role, suggests American microbiologist Arturo Casadevall in TIME. Most fungi thrive at relatively low temperatures, but due to an increase in the average temperature, it is conceivable that a fungus breaks through its thermal restriction and can suddenly colonize the human body.

"An interesting point of view," says Bruno, "but without further evidence, it is as yet highly speculative. Apart from the actual origin history or 'birth' of C. auris, the article in Nature Microbiology provides information on how the interaction between humans and the fungus C. auris occurs: how the fungus stimulates the immune system, what C. auris' pharmacological Achilles heel is and what the opportunities for immunotherapy are."

The human genome contains over 4.5 million sequences of DNA called "transposable elements", these virus-like entities that "jump" around and help regulate gene expression. They do this by binding transcription factors, which are proteins that regulate the rate of transcription of DNA to RNA, influencing gene expression in a broad range of biological events.

Now, an international team of scientists led by Didier Trono at EPFL has discovered that transposable elements play a significant role in influencing the development of the human brain. The study is published in Science Advances.

The scientists found that transposable elements regulate the brain's development by partnering up with two specialized proteins from the family of proteins known as "Krüppel-associated box-containing zinc finger proteins, or KZFPs. In 2019, another study led by Trono showed that KZFPs tamed the regulatory activity of transposable elements in the first few days of the fetus's life. However, they suspected that these regulatory sequences were subsequently re-ignited to orchestrate the development and function of adult organs.

The researchers identified two KZFPs as specific only to primates, and found that they are expressed in specific regions of the human developing and adult brain. They further observed that these proteins kept controlling the activity of transposable elements - at least in neurons and brain organoids cultured in the lab. As a result, these two KZFPs influenced the differentiation and neurotransmission profile of neurons, as well as guarded these cells against inflammatory responses that were otherwise triggered if their target transposable elements were left to be expressed.

"These results reveal how two proteins that appeared only recently in evolution have contributed to shape the human brain by facilitating the co-option of transposable elements, these virus-like entities that have been remodeling our ancestral genome since the dawn of times," says Didier Trono. "Our findings also suggest possible pathogenic mechanisms for diseases such as amyotrophic lateral sclerosis or other neurodegenerative or neurodevelopmental disorders, providing leads for the prevention or treatment of these problems."

Researchers have revealed a new molecular mechanism by which bacteria adhere to cellulose fibers in the human gut. Thanks to two different binding modes, they can withstand the shear forces in the body. Scientists of the University of Basel and ETH Zurich published their results in the journal "Nature Communications".

Cellulose is a major building block of plant cell walls, consisting of molecules linked together into solid fibers. For humans, cellulose is indigestible, and the majority of gut bacteria lack the enzymes required to break down cellulose.

However, recently genetic material from the cellulose-degrading bacterium R. champanellensis was detected in human gut samples. Bacterial colonization of the intestine is essential for human physiology, and understanding how gut bacteria adhere to cellulose broadens our knowledge of the microbiome and its relationship to human health.

The bacterium under investigation uses an intricate network of scaffold proteins and enzymes on the outer cell wall, referred to as a cellulosome network, to attach to and degrade cellulose fibers. These cellulosome networks are held together by families of interacting proteins.

Of particular interest is the cohesin-dockerin interaction responsible for anchoring the cellulosome network to the cell wall. This interaction needs to withstand shear forces in the body to adhere to fiber. This vital feature motivated the researchers to investigate in more detail how the anchoring complex responds to mechanical forces.

By using a combination of single-molecule atomic force microscopy, single-molecule fluorescence and molecular dynamics simulations, Professor Michael Nash from the University of Basel and ETH Zurich along with collaborators from LMU Munich and Auburn University studied how the complex resists external force.

Two binding modes allow bacteria to stick to surfaces under flow

They were able to show that the complex exhibits a rare behavior called dual binding mode, where the proteins form a complex in two distinct ways. The researchers found that the two binding modes have very different mechanical properties, with one breaking at low forces of around 200 piconewtons and the other exhibiting a much higher stability breaking only at 600 piconewtons of force.

Further analysis showed that the protein complex displays a behavior called a "catch bond," meaning that the protein interaction becomes stronger as force is ramped up. The dynamics of this interaction are believed to allow the bacteria to adhere to cellulose under shear stress and release the complex in response to new substrates or to explore new environments.

"We clearly observe the dual binding modes, but can only speculate on their biological significance. We think the bacteria might control the binding mode preference by modifying the proteins. This would allow switching from a low to high adhesion state depending on the environment," Professor Nash explains.

By shedding light on this natural adhesion mechanism, these findings set the stage for the development of artificial molecular mechanisms that exhibit similar behavior but bind to disease targets. Such materials could have applications in bio-based medical superglues or shear-enhanced binding of therapeutic nanoparticles inside the body. "For now, we are excited to return to the laboratory and see what sticks," says Nash.