Culture

Small bivalved crustacean ostracods are the most abundant fossil arthropods since the Ordovician and play an important role in paleoenvironmental reconstruction and evolutionary biology.

The vast majority of fossil ostracods are represented by calcified shells, and their soft parts, which can provide invaluable information about ancient ostracod autoecology, are extremely rare.

Recently, Dr. WANG He and Prof. WANG Bo, from the Nanjing Institute of Geology and Palaeontology of the Chinese Academy of Sciences (NIGPAS), and their collaborators presented exceptionally well-preserved ostracods with soft parts (appendages and reproductive organs) from mid-Cretaceous Myanmar amber (~100 million years old), which revealed sexual intercourse of ostracods.

The study was published in Proceedings of the Royal Society B on Sept. 15.

The ostracod assemblage in the amber is composed of 39 individuals in one amber piece and includes males, females and juveniles.

X-ray micro-computed tomography was used to obtain high-resolution three-dimensional images of their soft parts. The micro-CT reconstruction provided direct evidence of the male clasper, sperm pumps (Zenker organs), hemipenes, eggs and female seminal receptacles containing giant sperm.

This is the first time that giant ostracod sperm was found in Cretaceous ostracod fossils; its length was at least one-third of the body length of the ostracod. This discovery is also the earliest known animal sperm record, and approximately 50-million years older than the previous oldest fossil records of animal sperm.

Analyses of the fossil and extant ostracods show that during sexual reproduction, the male used its sexually dimorphic fifth limb, which has hook-like endopods, to grasp a female while introducing its hemipenes into the female's paired vaginas. The male's pair of Zenker organs then transferred the exceptionally long but immotile sperm via the male hemipenes into the female.

The Zenker organ is readily identified in extant cypridoidean ostracods as a large, spiny, sclerotized part of the deferent sperm duct. Muscle fibers alongside the organ connect the numerous spines, which are often arranged in a number of whorls that are taxonomically characteristic at the family level.

Once in the female, the sperm are pushed up the two long sperm canals, each ending in a sac-like seminal receptacle for sperm storage; there, they finally become motile, arrange themselves into a more organized assemblage and fertilize eggs during the process of oviposition.

Research reveals that the repertoire of reproduction behavior in ostracods, which is associated with considerable morphological adaptations, has remained unchanged over at least 100 million years - a paramount example of evolutionary stasis.

The appearance of a complex reproductive mechanism involving giant sperm improved mating success and may have been an important contributor to the late Mesozoic explosive radiation of the superfamily Cypridoidea, which today includes the vast majority of nonmarine ostracod species.

The ASF pathogen is a virus which infects domestic pigs and wild boar and which leads to a severe, often lethal, disease in these animals. It is transferred via direct contact or with excretions from infected animals, or through ticks. The ASF virus is endemic to infected wild animals in Africa, but there have also repeatedly been outbreaks in southern Europe. The pathogen has been spreading north-westwards since 2007 from Georgia through Armenia, Azerbaijan and Russia. Cases of ASF have been registered in wild boar along with outbreaks in domestic pigs in the Baltic states since 2014. The virus has also been detected in Romania, Hungary, Poland and the Czech Republic. In September 2018, the pathogen was also found in wild boars in Belgium and thus for the first time in Western Europe. On 10 September 2020, the ASF virus has been detected for the first time in Germany in a wild boar in Brandenburg.

The pathogen is very stable and can remain infectious in food over several months. If unheated food or food scraps from infected animals are fed to non-infected animals, the virus can therefore spread to previously ASF-free regions, thus infecting domestic pig herds too.

Although the ASF virus does not pose a hazard or a risk to humans, the meat of domestic pigs and wild boar should always be prepared under hygienic conditions, just like all other raw meats, as it can also contain other pathogens, advises the BfR. It should be kept refrigerated and prepared separately from other foods before cooking. When heating, a core temperature of 70 degrees Celsius or higher should be reached in the meat for at least two minutes, the BfR recommends.

The BfR has compiled some frequently asked questions about ASF for further information. They can be downloaded on the BfR website:

https://www.bfr.bund.de/en/frequently_asked_questions_about_african_swine_fever__asf_-205379.html

Cell therapy for cardiac regeneration, while promising, has been hampered by issues with long-term survival of the transplanted cells. Now, a technique that combines three different types of cells in a 3D cluster could improve its efficacy in reducing scar tissue and improving cardiac function after a heart attack.

Called CardioCluster, the bioengineering technique was developed by Megan Monsanto, a recent doctoral candidate who worked with Mark Sussman, distinguished professor of biology at the San Diego State University Heart Institute. They found there is strength in numbers, even in cell therapy.

Their research shows the cell clusters improve heart function because they have much better retention rates compared to single cell injections -- the clusters persisted inside the heart walls of mice models for as long as five months after transplantation, a significant advancement.

As a master's student in bioengineering at SDSU, Monsanto became very interested in tissue culture of cells for cardiac research. This led her to Sussman, a molecular biologist and longtime principal investigator at the institute.

When she learned about the challenges in getting injected cells to persist and survive inside the heart walls, she came up with the idea of a 3D cluster of cells that would interact with each other and stick together. But even she was surprised at how long they survived as a cluster.

"At 20 weeks we were still able to see the cells," Monsanto said. "Our design takes advantage of the inherent beneficial attributes of three distinct cardiac cell types, each known to possess beneficial properties that blunt heart disease in their own unique way."

The cluster combination she arrived at after extensive research comprises mesenchymal stem cells which help communicate and support other cells, endothelial progenitor cells which line the insides of blood vessels, and cardiac interstitial cells which are key to forming cardiac tissue. The study was published in Nature Communications in August.

Working in the Sussman lab with human heart cells surgically implanted into the hearts of immune-compromised mice, she genetically modified the transplanted cells to express a fluorescent tag to enable tracking. Each cell type has a different tag or color, so weeks later when she tracked them, all three color tags were consistently found by confocal microscopy imaging.

One reason for their high rates of retention and longevity is that they were cultured together before injection, and this familiarity maximizes cell-to-cell interaction.

"When you need to go into a bad neighborhood, it's better to go with some friends," Sussman explained. "Since these cells talk to each other, they support each other when they enter the hostile environment of the damaged heart."

CardioClusters closely mimic the natural environment within the human body much better than 2D cultured single cells that are easily pumped out of the heart. Their larger surface area as a cluster helps with retention.

"The tougher cells naturally go to the outside while protecting the slower growing cells in the center," Sussman said. "The cells seem to know what to do and they spontaneously figured out how to assemble within the cluster."

When Monsanto subjected the cluster cells to stress tests, the outer cells survived better. But when tested separately, about 50% of the cardiac interstitial cells died.

Each cell type within the cluster plays a specific role - the mesenchymal stem cells are the glue, the cardiac interstitial cells are the brain, and the endothelial progenitor cells are the highway on which nutrients travel which keeps the cluster alive, she explained.

The clusters can be modified and optimized for different needs, and cell ratios can be tweaked, which will form the next step in their research.

"While there are many who are skeptical of cardiac cell therapy, it's important to try innovative approaches like CardioClusters to build upon what we have learned and improve outcomes rather than becoming frustrated and giving up," Sussman said.

"For more than a decade, a major limitation of cell therapy has been that the cells don't stick around so the effectiveness of treatment is lost. With this approach, we get significantly better recovery and repair, and we are able to see the cells months later, which is groundbreaking."

The Wnt signalling pathway has been studied for decades, still it holds surprises in store. Bon-Kyoung Koo, group leader at IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Sciences and Tadasuke Tsukiyama at the Hokkaido University have now uncovered a new and unexpected role for a key component of the Wnt pathway, Casein Kinase-1, in regulating the pathway at the plasma membrane. This is the result of a study published today in Nature Communications, and broadens our understanding of the regulatory loops controlling the Wnt pathway, a pathway associated with stem cell maintenance, cell proliferation and cancer.

In the Wnt pathway, Casein Kinase-1 is well-known as a part of the destruction complex. In the steady-state, when no Wnt signal is present, this complex destines the downstream mediator ?-catenin for constant degradation. When a Wnt signal reaches the cell, the Wnt receptor Frizzled inhibits the destruction complex. This allows ??-catenin to enter the nucleus, where it sets downstream responses in motion.

Casein Kinase-1 responsible for phosphoswitch of RNF43

In the newly published study, Tadasuke Tsukiyama and Bon-Kyoung Koo find that Casein Kinase-1 also regulates Wnt signalling at the plasma membrane. At the plasma membrane, the ubiquitin ligase RNF43 marks the Wnt receptor Frizzled for degradation, effectively shutting off the Wnt signalling pathway. The researchers discovered that Casein Kinase-1 triggers the switch for RNF43: When Casein Kinase-1 phosphorylates RNF43, RNF43 is activated and marks Frizzled with ubiquitin for degradation. When Casein Kinase-1 does not phosphorylate RNF43, RNF43 is inactive and signalling via Frizzled can continue. "We find that Casein Kinase-1 has an essential function in activating RNF43. With our work, we are effectively reintroducing Casein Kinase-1 to the field, defining a new role for this well-known regulator", Bon-Kyoung Koo explains.

This new understanding could lead to a novel approach for reining the Wnt pathway in cancer cells. Tsukiyama and Koo found that a mutation in RNF43's extracellular domain interrupts its function in negative feedback regulation, the tumour suppressor function of RNF43. This mutation changes RNF43 into an oncogenic form that abnormally enhances Wnt signalling. The researchers found that mimicking the phosphorylation, by adding negatively charged residues to the mutant RNF43, can revert it back to a functional tumour suppressor. With this mimicked phosphoswitch, the mutant RNF43 was again able to inhibit Frizzled. "Some patients carry a mutation in RNF43's extracellular domain. We hope that, once we know how to mimic phosphorylation in cells, this phosphorylation would revive the RNF43 tumour suppressor, enabling it to again control the Wnt pathway", Bon-Kyoung Koo adds.

Rupert Seidl (Professor of Ecosystem Dynamics and Forest Management in Mountain Landscapes at TUM) and his colleague Cornelius Senf (lead author of the study) for the first time produced a high-resolution map of all openings in the canopy of European forests. They have analyzed more than 30,000 satellite images and identified more than 36 million areas where large trees have given way to open spaces of young trees. This corresponds to a loss of the canopy in 17 percent of the European forests in 30 years.

The reasons for the canopy openings range from regulated wood use to wind storms and forest fires. The team also found that the size of the canopy openings varied widely from area to area.

For example, Sweden has the largest canopy openings (averaging almost two hectares) while Portugal has the highest number of canopy openings. Switzerland has the smallest openings with just 0.6 hectares on average (which is smaller than a soccer field) while the average size opening in Germany is 0.7 hectares and in Italy 0.75 hectares. The largest opening documented by the researchers is in Spain, where a single fire in 2012 burned 17,000 hectares.

Chance for tree generation adapted to climate change

The novel map the team has created also makes it possible to describe changes in forest conditions. The researchers have found, for example, that throughout Europe forests have become more open and the frequency of forests being interrupted by open spaces has increased. In addition, the openings themselves on average have increased in size primarily due to wind storms and forest fires in recent years.

In such areas, however, the tendency is that more trees are surviving due to the availability of seed material. This, in turn, promotes the recovery of forests after a disturbance and can be seen as an indication of the increase in low-intensity forestry in Europe, where only single trees or crops of trees are taken rather than clear cutting large areas.

Therefore, despite the major changes in Europe's forests, the researchers see positive developments. As Cornelius Senf has said, "In most cases, new, young trees grow up after a loss of the old stand." However, he goes on to say: "To understand where forests may be at risk of irreversible damage, we need a baseline as a reference. This is provided by the newly created map."

Professor Rupert Seidl adds: "The new maps help us to understand how Europe's forests are changing. After all, increasing opening in the canopy pose a risk to the forest, but also other opportunities for new generations of trees that are better adapted to climate change to establish themselves. Among other things, the maps can help to identify areas where regeneration needs to be promoted through targeted planting or where the forests can rejuvenate themselves. In this way, the forest can be made fit for climate change - a task that, especially in the last two years, has gained in urgency."

A new study has shown HGV drivers drive much more safely when there are cameras in their cabs monitoring their behaviour.

Computer scientists and driving psychologists from the University of Nottingham analysed data collected before and after the installation of unobtrusive cameras in the cabs of Heavy Good Vehicles (HGV) and found there is a significant reduction of risky driving behaviours with camera monitoring, and that this is even more effective when coupled with coaching. Their findings have been published in Accident Analysis and Prevention Journal.

Driving errors and violations are the leading determinants of road safety and this research highlights the importance of understanding the safety implications of risky driving styles and the extent of the influence of driver-monitoring technologies in improving driving behaviour.

The researchers analysed the largest dataset ever undertaken for this type of research looking at 669 HGVs for the longest period of time ever investigated - June 2017 to August 2019. They analysed three safety critical telematics incidents - harsh braking, harsh cornering and over speeding incidents. The research was split into cameras with and without the addition of coaching.

The data showed that monitoring and educating drivers with coaching about the risk and consequence of their driving styles has a significantly greater effect in reducing driving errors, with this intervention reducing harsh-braking by 16%, over-speeding by 34% and harsh-cornering by 31%. Without the coaching these percentages dropped to 4%, 28% and -13%.

The research also showed that weather or seasonal changes can influence HGV risky driving behaviours with highest rates of driving incidents observed during spring and summer seasons. This is likely due to the vast majority of families taking their summer holidays at this time, thereby creating busier roads and tailgating.

Jimiama Mosima Mafeni Mase, PhD researcher with the Horizon Centre for Doctoral Training at the University of Nottingham who conducted the research under the supervision of Dr Grazziela Figueredo, Dr Peter Chapman and Dr Mercedes Torres Torres, said: "As drivers are made aware of their monitoring especially with the use of cameras, they become conscious and improve their driving behaviours. With the affordability of in-vehicle cameras, the government can enforce policies that enables all HGV companies to install cameras in their vehicles for safety purposes. We are aware of the privacy concerns with collecting and storing videos of drivers, however, experts in data privacy can guide decision makers on how to efficiently implement such policies. In addition, decision makers can provide incentives to encourage frequent coaching of HGV drivers using the videos collected during monitoring as educating drivers has shown to significantly improve their driving styles".

We observed that driving violations such as over speeding are harder to monitor with cameras and may require other factors or methods to detect their causes. Therefore, more multidisciplinary research and collaboration is required between computer scientists, psychologists and human factor specialists to develop more advanced driver assistance systems that can incorporate more information such as external factors and drivers' affective states to accurately detect the cause of incidents or risky driving behaviours."

Grazziela Figueredo, lead supervisor added: "This large-scale study is really significant in showing how important monitoring and coaching is in changing driving behaviour. With further support from policy makers and HGV companies the findings from this research could be an important step in improving the safety of our roads."

Increasingly, everyday activities and services are shifting online, making the ability to use the internet an essential skill. The current COVID-19 pandemic has further highlighted the importance of digital connectivity, especially for older and vulnerable adults, for their continued contact with family and friends. Digital Ambassadors, a Singapore Government initiative to ensure all Singaporeans have access to the fundamental digital tools, helps older adults learn how to use technological tools.

Analysing data from almost 4,000 older Singaporeans who took part in a national survey conducted by Duke-NUS' Centre for Ageing Research & Education (CARE) in 2016-2017, the team found that one in 15 respondents had difficulties using the internet because of poor health. And 57 per cent did not use the internet because of other reasons.

"Our findings suggest that health-related difficulties are relevant in understanding the digital divide between the young and the old. Concurrent with optimising the health of older persons, policymakers should consider supporting research and development into assistive technology and design aimed at helping older internet users overcome health-related difficulty in internet use," said Assistant Professor Rahul Malhotra, Head of Research of Duke-NUS' CARE. Asst Prof Malhotra is also a faculty at the Duke-NUS' Health Services and Systems Research Programme.

The study, which was published in The Gerontologist, found that those who were male, were less educated, and those who had limitations in instrumental activities of daily living such as using the phone and doing housework, were more likely to face challenges in using internet due to poor health. The team also found that those of higher age, females, with less education, and residing in low-income housing were more likely to not use the internet for non-health-related reasons.

"In this study, we were not able to identify the specific obstacles faced by those not using the internet for non-health-related reasons. But hurdles such as the lack of digital literacy and the cost of devices and internet service provision likely play a role," said Asst Prof Malhotra.

A particularly concerning finding of the study, relevant in the current time when safe distancing is a new norm for preventing the spread of COVID-19 infections, was that health-related difficulties in internet use created additional barriers to online communication between older adults and their family and friends, and poor social connections and support. Cumulatively, this resulted in a lower quality of life for older adults.

"Health-related difficulties in using the internet matter, because it means that teaching digital skills and offering cheap internet access to seniors may not fully address the digital divide. Online communication tools are thought to benefit seniors with physical limitations, since it does not require travel. Unfortunately for some seniors, health issues stand in the way of even their internet use. Providing social support to these older adults through non-digital means thus remains key, even as we work towards identifying and minimising health-related difficulties in internet use," said Assistant Professor Shannon Ang, from Sociology, NTU Singapore.

"Singapore is addressing ageing as a prioritised national agenda by studying trends and implications, and recommending solutions. This collaborative study on the ability of the elderly to use the internet shows that it is imperative to help older adults who rely on the internet to stay socially connected, which will aid in their ability to maintain a high overall quality of life as they age," said Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS.

In future work, the research team plans to gain a deeper understanding of the specific health problems that directly lead to difficulty in internet use among older adults. These may include poor vision and loss of fine motor skills.

The data is from the Transitions in Health, Employment, Social engagement and Inter-Generational transfers in Singapore Study, Wave 1 (THE SIGNS Study-I), a large population-based survey of older Singaporeans conducted in 2016-2017, by Duke-NUS' CARE with support from the Ministry of Health, Singapore.

In a recently published study, researchers from the Turku Bioscience Centre at the University of Turku and Åbo Akademi University in Finland monitored the production of new proteins as they were produced by the cells' protein building machinery, the ribosome.

They found that in the skin cells obtained from the forearm of Parkinson's patients, translation of RNA into protein was reduced compared to cells from healthy donors of a similar age. The reason for this was an enzyme called LRRK2 which was more active in patient cells compared to cells from healthy donors.

"These results are interesting because LRRK2 is thought to contribute to Parkinson's disease, but precisely how, it is not yet known," says lead author Eleanor Coffey, the lead author of the article.

"Although drug programmes developing LRRK2 inhibitors for treating Parkinson's are already underway, it is still important to understand what LRRK2 is doing in cells that may contribute to the disease," adds first author of the study Prasannakumar Deshpande.

Once common pesticide helped unravel the mechanism

When the researchers added LRRK2 inhibitor drugs to the patient samples, they found that the synthesis of new proteins returned to control levels. They next used the pesticide rotenone, exposure to which induces Parkinson's-like symptoms in humans, to model Parkinson's disease in rodent brain cells. They found that rotenone repressed protein synthesis and caused the axons of dopamine-producing nerve cells, which also die in Parkinson's, to waste away.

Both effects were reversed when treated with LRRK2 inhibitor drugs. Moreover, in mice lacking the gene for LRRK2, protein synthesis was increased in nerve cells.

"These data identify a critical role for LRRK2 in the control of the process that converts genetic code into protein," tells Coffey.

To understand how LRRK2 reduced protein synthesis, researchers examined a brain region called the substantia nigra, which is affected in Parkinson's disease. In rats exposed to rotenone, they found that controllers of protein synthesis acquired "phosphate marks" which signal protein synthesis to stop. One such mark was particularly prominent in patient skin cells. The authors were able to show that LRRK2 inhibitor drug reversed these marks and allowed the cell to resume making new proteins.

Reduced protein synthesis might be an indicator for Parkinson's disease

"It is significant in this study that we found no evidence of decreased protein synthesis in individuals with multiple system atrophy, a movement disorder that is symptomatically difficult to distinguish from Parkinson's disease, but with distinct etiology and prognosis," Coffey explains.

This suggests that a reduction in the synthesis of certain proteins are specific to Parkinson's disease and could be used as a biomarker readout. Also, as patients aged and the disease progressed, the repression of protein synthesis was more notable, adds Deshpande. This did not happen in healthy individuals. Analysing the repression of the synthesis of certain proteins will provide a means to monitor disease progression.

Early detection may help treatment

The research group is now examining hundreds of patient samples to determine which group of downregulated proteins shows the best discriminating power to identify Parkinson's disease and if it can be used to detect Parkinson's before motor symptoms appear.

"If such a signature can be found, it could help improve clinical trial outcome by providing a tool for patient stratification. If successful, this would help accelerate the development of better treatments for Parkinson's disease patients," summarises Coffey.

The study was carried out on samples from individuals from Finland and the United States. The work was done in collaboration with Drs Valtteri Kaasinen and Sirkku Peltonen at Turku University Hospital and Prof. Peter James at Åbo Akademi University.

A healthy heart beats 50 to 100 times a minute and pumps 8,000 litres of blood around our body every day. A precondition for this function is the elasticity of the cardiac walls, which dilate as blood flows in (diastole) and contract again as the blood flows out (systole). Millions of tiny cavities in the heart muscle fibres, the sarcomeres, are responsible for this movement. These contractile units contain the largest protein found in the human body called titin. It has the function of a mechanical spring, which develops a restoring force during the extension of the sarcomeres - just like a rubber band.

Working with researchers from the Universities of Bochum, Würzburg, Cologne, Regensburg, Göttingen and Düsseldorf, a team of researchers at the University of Münster headed by Prof. Wolfgang Linke, Director of the Institute of Physiology II, has now discovered that oxidative stress, in combination with the stretching of the heart walls, triggers a change in cardiac stiffness. The elastic titin in the sarcomeres is more strongly oxidised and, as a result, is modulated in its extensibility. The researchers call this newly discovered mechanism UnDOx ("Unfolded Domain Oxidation"). The study has been published in the journal "PNAS".

Background and method

In the human organism, titin forms the backbone of the sarcomeres, the smallest functional units of the skeletal muscles and the heart. Titin provides both stability and elasticity to muscle cells, due its unique structure. For the first time, the research team has now shown in heart tissue of mice that oxidative stress together with the extension of the heart modulates the spring function of titin. Oxidative stress occurs when too many reactive oxygen species are present in the cell of an organism. These oxygen species, which include so-called free radicals, can cause cell damage. In small quantities, however, they regulate important physiological functions.

The researchers used a mass spectrometer to determine the oxidation status of the proteins in the heart, including titin. Additionally, they isolated heart muscle cells from deep-frozen tissue of a human heart and attached them to a force sensor and a micromotor, in order to stretch the specimens. This enabled them to measure the forces generated upon stretch and observe their increase or decrease during different forms of oxidative stress. In addition, the team produced recombinant titin molecules and also mutated them in a test tube, such that oxidation could no longer occur. "We then used a so-called atomic force microscope to directly measure the effects of stretch and oxidation on the titin spring," Wolfgang Linke explains. "Using this device, we were able to stretch individual titin molecules like a rubber band and record the force upon extension , as well as the changes in force in the presence of an oxidant."

The researchers demonstrated in their experiments that the UnDOx mechanism occurs in hearts under oxidative stress. This is the case, for example, after an acute heart attack or in chronic heart disease associated with altered cardiac filling. "The mechanism regulates the distensibility of the heart," Linke adds. "Extensive wall stiffness is not good for the heart, because less blood flows in. In the case of diastolic heart failure, which is often found in elderly people, the stiffening of the heart is a major problem. We hope that such hearts can be made more distensible through the pharmacological regulation of titin oxidation, i.e. by using medication."

A genetic predisposition to late-onset Alzheimer's disease affects how the brains of young adults cope with certain memory tasks. Researchers from the German Center for Neurodegenerative Diseases (DZNE) and the Ruhr-Universität Bochum report on this in the scientific journal "Current Biology". Their findings are based on studies with magnetic resonance imaging in individuals at the age of about 20 years. The scientists suspect that the observed effects could be related to very early disease processes.

The causes for Alzheimer's in old age are only poorly understood. It is believed that the disease is caused by an unfavorable interaction of lifestyle, external factors and genetic risks. The greatest genetic risk factor for late-onset Alzheimer's disease stems from inherited mutations affecting "Apolipoprotein E" (ApoE), a protein relevant for fat metabolism and neurons. Three variants of the ApoE gene are known. The most common form is associated with an average risk for Alzheimer's. One of the two rarer variants stands for an increased risk, and the other for a reduced risk.

"We were interested in finding out whether and how the different gene variants affect brain function. That is why we examined the brains of young adults in the scanner while they had to solve a task that challenged their memory," explained Dr. Hweeling Lee, who led the current study at the DZNE in Bonn.

Distinguishing similar events

The group of study participants comprised of 82 young men and women. They were on average 20 years old, and all of them were university students considered to be cognitively healthy. According to their genotype for ApoE, 33 of them had an average, 34 an increased and 15 a reduced risk of developing Alzheimer's disease at a late age. During the study in the brain scanner, all individuals were presented with more than 150 successive images displayed on a monitor. These were everyday objects such as a hammer, a pineapple or a cat. Some pictures were repeated after a while, but sometimes the position of the displayed objects on the screen had changed. The study participants had to identify whether an object was "new" or had been shown before - and if so, whether its position had shifted.

"We tested the ability to distinguish similar events from one another. This is called pattern separation," said Hweeling Lee. "In everyday life, for example, it's a matter of remembering whether a key has been placed in the left or right drawer of a dresser, or where the car was parked in a parking garage. We simulated such situations in a simplified way by changing the position of the depicted objects."

High-resolution through modern technology

Simultaneously to this experiment, the brain activity of the volunteers was recorded using a technique called "functional magnetic resonance imaging". Focus was on the hippocampus, an area only a few cubic centimeters in size, which can be found once in each brain hemisphere. The hippocampus is considered the switchboard of memory. It also belongs to those sections of the brain in which first damages occur in Alzheimer's disease.

When measuring brain activity, the scanner was able to show its full potential: It was an "ultra-high field tomograph" with a magnetic field strength of seven Tesla. Such devices can achieve a better resolution than brain scanners usually used in medical examinations. This enabled the researchers to record brain activity in various sub-fields of the hippocampus with high precision. "Up to now, there were no comparable studies with such level of detail in ApoE genotyped participants. This is a unique feature of our research," said Hweeling Lee.

No differences in memory performance

There were no differences between the three groups of subjects with regard to their ability for pattern separation. "All study participants performed similarly well in the memory test. It did not matter whether they had an increased, reduced or average risk for Alzheimer's disease. Such results are certainly to be expected in young healthy people," said Nikolai Axmacher, Professor of Neuropsychology at the Ruhr-Universität Bochum, who was also involved in the current study. "However, there were differences in brain activity. The different groups of study participants activated the various subfields of the hippocampus in different ways and to varying degrees. Their brains thus reacted differently to the memory task. In fact, we saw differences in brain activation not only between people with average and increased risk, but also between individuals with average and reduced risk."

At present, it is uncertain whether these effects are significant for developing Alzheimer's in old age. "Our findings might be related to very early disease processes. Determining this is a task for future studies and could help to devise biomarkers for the early diagnosis of dementia," said Hweeling Lee. "In any case, it is remarkable that a genetic predisposition for Alzheimer's disease is already reflected in the brain at young adulthood."

There are billions of bacteria around us and in our bodies, most of which are harmless or even helpful. But some bacteria such as E. coli and salmonella can cause infections. The ability to swim can help bacteria to seek out nutrients or to colonize parts of the body and cause infection.

Researchers from the Faculty of Health and Medical Sciences, University of Copenhagen, have now provided fundamental insight into how this bacterial movement is powered, solving a yearlong mystery within the field.

'A lot of bacteria can move, or swim, because they have long threads, also known as flagella, which they can use to propel themselves forward. They do this by rotating these threads. The rotation is powered by a rotary motor, which again is powered by a protein complex known as the stator unit. This is all well known within our field. What we now show is how this stator unit powers the motor, which has been a mystery so far', says Associate Professor and Group Leader Nicholas Taylor, Novo Nordisk Foundation Center for Protein Research.

Quite surprisingly, the team shows that the stator unit itself is in fact also a tiny rotary motor. This tiny motor powers the large motor, which makes the threads rotate, causing the bacteria to move. The results contradict existing theories on the mechanism of the stator unit, and this new knowledge might be useful in the fight against bacteria-based diseases.

'Most researchers, including ourselves, actually thought that the technical mechanism and the architecture of the stator unit was quite different to what our study shows. Knowing the actual composition and function of this unit paves the way for therapeutic purposes. When we know what makes bacteria move, we might also be able to inhibit this movement and thereby stop it from spreading', says Nicholas Taylor.

Cryo-electron microscopy reveals the architecture of the motor

The researchers determined the structure of the stator unit complex by using cryo-electron microscopy. Working with this technique, they were able to elucidate its architecture, see how it is activated and provide a detailed model for how it powers rotation of the flagellar motor.

"The motor consists of two proteins: MotA and MotB. The MotB protein is anchored to the cell wall, and is surrounded by MotA proteins, which, upon dispersion of the ion motive force, rotates around MotB. The rotation of MotA in turn powers rotation of the large bacteria motor," says Nicholas Taylor.

"Furthermore, our model shows how the stator unit can power rotation of the bacterial flagellar motor in both directions, which is crucial for the bacteria to change their swimming direction. Without direction change, bacteria would only be able to swim straight in one direction."

Next step for the group is to find out if it is possible to inhibit the stator units using chemical compounds, which could have antibiotic effects.

The cancer called biliary tract cancer (BTC) is not the most widespread form of cancer. In western countries, about 1.6 in 100.000 gets the diagnose every year. It is, however, a very aggressive form of cancer.

The majority of patients with BTC are diagnosed with advanced disease and has an average survival of only 1 year from initiation of chemotherapy. With such narrow survival windows, it is crucial to improve our understanding of the disease.

Now, researchers from Biotech Research & Innovation Centre at the University of Copenhagen and Herlev and Gentofte Hospital along with collaborators from Rigshospitalet and Sygehus Lillebaelt have identified a biomarker that can tell doctors how aggressive a patient's disease may be.

"We have found a biomarker that reliably predicts how aggressive a patients disease will evolve, which in the future could help doctors in the hospitals make the right decisions about chemotherapy for the benefit of each BTC patient," says Jesper Andersen, Associate Professor at BRIC.

Biomarkers can used for more than the diagnose

The researchers measured the levels of two inflammatory proteins and a biomarker commonly used in pancreatic cancer before and during chemotherapy in patients with advanced BTC and found that patients with higher levels of these markers before chemotherapy had a lower survival rate. Especially one protein called IL6 (interleukin-6) proved to be superior to the other markers in predicting those patients at greatest risk of death.

"A common misperception may be that biomarkers are mainly needed to diagnose a specific cancer type, but diverse biomarkers are also needed to guide clinical decision-making throughout each patients' individual journey. These types of prognostic and predictive biomarkers deserve increased attention, in particular as they are playing important roles in the increasingly individualized management of more common cancer types", says Jesper Andersen.

There are several markers to predict patients at greatest risk of death, however it was confirmed that the prognostic information provided by measuring IL-6 is not captured by other inflammatory markers already in routine clinical use. For instance, about 10 percent of the population does not express the marker that is normally measured (CA19-9) to predict the patient clinical outcome. Therefore, the course of disease cannot be predicted for these patients using CA19-9, for which IL-6 may be used instead.

Inhibiting IL-6 may improve response to chemotherapy

By inhibiting signalling of the protein IL-6 in a mouse model of human BTC, researchers discovered that the response of mouse tumours to chemotherapy significantly increased.

"Our data suggests that inhibiting IL-6 signalling may extend therapeutic benefit compared to chemotherapy alone. However, this will require careful evaluation in randomized clinical trial settings. Such a trial is currently ongoing at Herlev and Gentofte Hospital and results from this and potential future trials will contribute to our knowledge in regards to the potential of targeting the IL-6 pathway in patients with BTC", says Jesper Andersen

Large sample size made possible through collaboration

Researchers studying BTC face a data-challenge since only 1.6 per 100,000 of Western populations are diagnosed with BTC annually. This makes it difficult to collect comprehensive amounts of patient data. Therefore, one of the key strengths of this study lies in the patient numbers attained and analysed in this rare cancer demographic, amounting to 1590 serum samples from 452 patients with advanced BTC.

Furthermore, the study explores advanced BTC patients who represent the majority of patients at diagnosis, while the majority of previous BTC studies published to date have focused on early stage disease.

"It is imperative to increase representation of these patients with the worst prognosis in subsequent studies. These studies should also include longitudinal sampling throughout the patient's clinical history, as we have done here", says Jesper Andersen, group leader at BRIC.

The sample size achieved in this study was only made possible through the comprehensive collaboration between Herlev and Gentofte Hospital, Rigshospitalet and Sygehus Lillebaelt in Denmark.

"The number of patients and consecutively collected blood samples is among the largest cohorts presented in BTC and has, despite the small Danish population, been possible to analyze due to a decade of biobank work at the participating hospitals. Our results emphasize further biological and clinical investigation of the complex role of inflammation in BTC. For this, we have a uniquely established foundation due only to the contribution by all the patients" says Dan Høgdall, first-author on the current study and MD at Department of Oncology, Herlev and Gentofte Hospital.

Researchers of the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have discovered a cell-cleaning system that is key to keeping a healthy heart. This mechanism allows the heart's contractile cells (the cardiomyocytes) to release damaged components outside the cell into particles called exophers. These exophers are then taken up by a network of immune cells living inside the heart-the macrophages, which are in charge of removing them before they cause inflammation in the heart.

The study is published in Cell, through collaboration of two groups at CNIC-led by Dr. Andrés Hidalgo and Dr. José Antonio Enríquez- compiles the results of over five years of research, with collaborations with laboratories in Europe, Asia and the US. The insights that this study provides suggests that cardiac dysfunction can emerge in some instances from defects in resident immune cells, rather than from cardiomyocytes. This finding has important implications for the diagnosis and treatment of heart disease.

The assumption so far was that most cells could dispose of, or recycle, their waste products on their own. However, the CNIC teams discovered that in the heart this process requires the close collaboration of two types of cells, such that the material is transferred from cardiomyocytes to neighboring macrophages, which are ultimately responsible for disposing of the waste.

"Macrophages are cells with high phagocytic [gobbling] capacity and their functions have been mostly studied in inflammation and disease. However, we now know that they are also part of most healthy tissues and that they play pivotal tasks in their daily functions," explained Dr. José Ángel Nicolás-Ávila, first author of the article and researcher at CNIC.

These cells were first described in the heart only a decade ago, and we are just beginning to understand what it is that they do. The finding that cardiomyocytes surrogate the removal of their waste to macrophages has many implications. "The fact that the heart requires a population of macrophages to do their cleaning work, among other tasks, suggests that many heart diseases of unknown origin can be explained by failure of these macrophages." Dr. Enriquez says.

Another potential implication pointed out by Dr. Nicolás-Ávila, is that there may be similar processes supporting the fitness of specialized cells in other tissues, including the brain, whose cells share features with cardiomyocytes. "We are currently exploring if phenomena like the ones found in hearts can take place in other organs, and whether they degenerate with age", he says.

Dr. Ana Victoria Lechuga Vieco, co-first author of the article, adds, "cardiomyocytes are cells with extremely high energy demands. The heart needs to beat uninterruptedly to keep the body alive, which explains why cardiomyocytes are full of mitochondria, the organelles that produce energy. Similar to a boiler, the mitochondria suffer wear-and-tear with use and need to be replaced to prevent cell damage. The most striking finding from our study -she notes- is that cardiomyocytes pass this task on to macrophages, possibly because cardiomyocytes are too busy beating and cannot process all this waste material on their own."

Each cardiomyocyte is invaluable, because they cannot proliferate or be replaced once they die. "This is why we believe that this 'surrogation' phenomenon has evolved to allow cardiomyocytes to beat in optimal conditions for many years, with macrophages helping with their maintenance," says Dr. Hidalgo. "In a way, this is like the cleaning system of a city. It lacks glamour, but is essential for the whole city to function." he sums up.

The combined effects of the body's microbiota working together with COVID-19 in the lungs could explain the severity of the disease in people with obesity and diabetes, according to a new article published today in eLife.

The review offers important mechanistic insights into why people with obesity and diabetes seem to be at increased risk of developing severe acute respiratory syndrome (SARS) after infection with the COVID-19 virus, and more often require hospitalisation and ventilation.

"There is rapidly emerging evidence highlighting obesity and type 2 diabetes as key risk factors linked to severity of COVID-19 infections in all ethnic groups, but the detailed underlying connections with these risk factors remain largely unknown," says author Philipp Scherer, Professor at the Department of Internal Medicine, and Director of the Touchstone Diabetes Center, at the University of Texas Southwestern Medical Center, Dallas, US. "There is a paradox that people with obesity and diabetes are generally known to recover better from lung conditions than others. So, what is it about COVID-19 that makes this group of people more susceptible?"

In their article, Scherer and his coauthors revisit the factors and disease pathways that connect obesity and diabetes to the severity of COVID-19 infection. The mechanisms can be roughly divided into two groups: those connected with the ACE2 receptor, and those providing an interaction between COVID-19 and pre-existing bacterial conditions.

ACE2 resides on the surface of many cells in the human body and is involved in regulating fluid volumes, blood pressure and the function of blood vessels. It is also used by COVID-19 to enter human cells. One theory is that increased amounts of ACE2 in people with obesity or diabetes makes it easier for the virus to enter cells and increases the viral load - an important factor in determining disease severity. Alternatively, increased shedding of ACE2 in people with obesity causes it to move to the lungs, where the virus can use it.

Another factor known to be influential in the progression of lung diseases is our body's microbiota. We carry more than 100 trillion bacteria in our body - outnumbering the number of our own cells. People with obesity and diabetes are thought to suffer from a body-wide dissemination of bacteria and the substances they produce, which in turn causes low-level continuous inflammation in different tissues.

The team considered how host bacteria might influence COVID-19 severity. One potential culprit is the lipopolysaccharides (LPS) that bacteria produce, which have been shown to cooperate with other coronaviruses to induce SARS in pigs. It is possible that these LPS molecules join forces with COVID-19 in humans and trigger a chain of events that causes healthy tissue to transform into scarred tissue - as COVID-19 does in the lungs.

"While all of these potential mechanisms can contribute to the severity of COVID-19, we believe that one of them plays the predominant role, and that this must be present not only in obese and diabetic patients, but also in other groups of increased risk in COVID-19," Scherer explains.

The authors propose that a combined deficiency in ACE2 caused by COVID-19, together with obesity or diabetes, leads to impaired gut barrier function, allowing bacteria and their toxins to leak into the circulation. In the lungs, these bacteria and toxins work with the virus to cause more severe lung injury than either would do alone.

"Our theory is supported by experiments showing that the combination of bacterial and viral infection can lead to a 'cytokine storm' - an extreme inflammatory reaction - which is a hallmark of COVID-19", Scherer concludes. "Moreover, the involvement of viral-bacterial interactions can also explain the increased risk of severe COVID-19 seen in older people, those with heart disease and in some ethnic groups."

As the COVID-19 pandemic has swept the world, researchers have published hundreds of papers each week reporting their findings - many of which have not undergone a thorough peer review process to gauge their reliability.

In some cases, poorly validated research has massively influenced public policy, as when a French team reported COVID patients were cured by a combination of hydroxychloroquine and azithromycin. The claim was widely publicized, and soon U.S. patients were prescribed these drugs under an emergency use authorization. Further research involving larger numbers of patients has cast serious doubts on these claims, however.

With so much COVID-related information being released each week, how can researchers, clinicians and policymakers keep up?

In a commentary published this week in Nature Biotechnology, University of New Mexico scientist Tudor Oprea, MD, PhD, and his colleagues, many of whom work at artificial intelligence (AI) companies, make the case that AI and machine learning have the potential to help researchers separate the wheat from the chaff.

Oprea, professor of Medicine and Pharmaceutical Sciences and chief of the UNM Division of Translational Informatics, notes that the sense of urgency to develop a vaccine and devise effective treatments for the coronavirus has led many scientists to bypass the traditional peer review process by publishing "preprints" - preliminary versions of their work - online.

While that enables rapid dissemination of new findings, "The problem comes when claims about certain drugs that have not been experimentally validated appear in the preprint world," Oprea says. Among other things, bad information may lead scientists and clinicians to waste time and money chasing blind leads.

AI and machine learning can harness massive computing power to check many of the claims that are being made in a research paper, the suggest the authors, a group of public and private-sector researchers from the U.S., Sweden, Denmark, Israel, France, the United Kingdom, Hong Kong, Italy and China led by Jeremy Levin, chair of the Biotechnology Innovation Organization, and Alex Zhavoronkov, CEO of InSilico Medicine.

"I think there is tremendous potential there," Oprea says. "I think we are on the cusp of developing tools that will assist with the peer review process."

Although the tools are not fully developed, "We're getting really, really close to enabling automated systems to digest tons of publications and look for discrepancies," he says. "I am not aware of any such system that is currently in place, but we're suggesting with adequate funding this can become available."

Text mining, in which a computer combs through millions of pages of text looking for specified patterns, has already been "tremendously helpful," Oprea says. "We're making progress in that."

Since the COVID epidemic took hold, Oprea himself has used advanced computational methods to help identify existing drugs with potential antiviral activity, culled from a library of thousands of candidates.

"We're not saying we have a cure for peer review deficiency, but we are saying that that a cure is within reach, and we can improve the way the system is currently implemented," he says. "As soon as next year we may be able to process a lot of these data and serve as additional resources to support the peer review process."