Primary sclerosing cholangitis (PSC) is a rare, chronic, inflammatory disease of the bile ducts and is difficult to treat, since its causes have not yet been adequately researched. Using RNA sequencing, an international research consortium led by Michael Trauner, Head of MedUni Vienna’s Division of Gastroenterology and Hepatology (Department of Medicine III), has now succeeded in identifying a new prognostic factor for PSC from liver biopsies. This is so-called cellular ER stress. ER stress is the name given to a complex cellular response to stress caused by the build-up of misfolded proteins in the endoplasmic reticulum (ER).
PSC is a rare disease with a poor prognosis and can lead to cirrhosis of the liver or bile duct cancer. It affects 0.01% of the population but, even though it is rare, PSC is responsible for more than 10% of all liver transplants, making it the third most common indication on liver transplant waiting lists in Europe.
In the recent study, which has now been published in the leading journal Hepatology, the researchers were able to identify a molecular signature for ER stress both in the liver cells (hepatocytes) and also in the bile duct epithelium — and notably as a stand-alone factor that is independent of the disease stage or degree of liver fibrosis (laying down of scar tissue) as a precursor to possible liver cirrhosis. “Using transcriptional analysis, we were able to identify a personalised molecular signature of primary sclerosing cholangitis, which shows that patients with an impaired response to ER stress have a poorer prognosis with a higher incidence of complications,” explains Trauner. “This discovery also opens up new treatment options, since ER stress can be counteracted with drugs.”
Since the build-up of potentially toxic bile acids in cholestasis results in ER stress, it is now being attempted to restore this balance pharmacologically using the new bile acid therapeutics that are available. Beneficial effects can reportedly be expected from drugs already in clinically testing — however, more research has already been initiated to explore this further.
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Researchers have mapped the distribution of SARS-CoV-2, the virus that causes COVID-19, in deceased patients with the disease, and shed new light on how viral load relates to tissue damage.
Their study of 11 autopsy cases, published today in eLife, may contribute to our understanding of how COVID-19 develops in the body following infection.
More than 24 million SARS-CoV-2 infections have been reported to date, and the number of deaths attributed to COVID-19 has exceeded 828,000 worldwide. COVID-19 occurs with varying degrees of severity. While most patients have mild symptoms, some experience more severe symptoms and may need to be hospitalised. A minority of those in hospital may enter a critical condition, with respiratory failure, blood vessel complications, or multiple organ dysfunction.
“Clinical observations suggest that COVID-19 is a systemic disease, meaning that it affects the entire body rather than just a single organ such as the lungs,” explains co-first author Stefanie Deinhardt-Emmer, Resident in Medical Microbiology, Jena University Hospital, Jena, Germany. “But we don’t currently have a clear understanding of disease development in humans and other organisms, due to the lack of appropriate experimental models. Investigating the viral distribution of SARS-CoV-2 within the human body and how this relates to tissue damage would help us address this gap.”
To do this, Deinhardt-Emmer and colleagues studied 11 autopsy cases of patients with COVID-19. They performed the autopsies at the early postmortem stage to minimise bias due to the degradation of tissues and viral ribonucleic acid (RNA — a molecule similar to DNA).
Their analysis revealed high viral loads in most of the patients’ lungs, which had caused significant damage to those organs. Using an imaging technique called transmission electron microscopy, the team also visualised intact viral particles in the lung tissue.
“Interestingly, we also detected SARS-CoV-2 RNA throughout various other tissues and organs unrelated to the lungs that did not cause visible tissue damage,” says co-first author Daniel Wittschieber, Senior Forensic Pathologist at Jena University Hospital. The researchers say that this distribution of viral RNA throughout the body supports the idea that our immune system is unable to respond adequately to the virus’ presence in the blood.
“We show that COVID-19 is a systemic disease as determined by the presence of virus RNA, and yet unrelated to tissue damage outside the lungs,” says co-senior author Bettina Löffler, Director of the Institute for Medical Microbiology, Jena University Hospital. “To our knowledge, this study is the only one to date that has measured viral loads in a wide variety of organs and tissues, with more than 60 samples studied per patient.”
“The insights gathered from our work may add to our understanding of how COVID-19 develops in the body following infection,” concludes co-senior author Gita Mall, Head of the Institute of Forensic Medicine, Jena University Hospital.
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Recent studies indicate a link between children’s cardiorespiratory fitness and their school performance: the more athletic they are, the better their marks in the main subjects — French and mathematics. Similarly, cardiorespiratory fitness is known to benefit cognitive abilities, such as memory and attention. But what is the real influence of such fitness on school results? To answer this question, researchers at the University of Geneva (UNIGE), Switzerland tested pupils from eight Geneva schools. Their results, published in the journal Medicine & Science in Sport & Exercise, show that there is an indirect link with cardiorespiratory fitness influencing cognitive abilities, which in turn, influence school results.
Charles Hillman, a professor at Northeastern University in Boston and co-author of this study, has suggested in previous research that there is a link between children’s cardiorespiratory fitness and their academic performance, as well as a beneficial effect of cardiorespiratory fitness on executive functions. “There are three main executive functions,” explains Marc Yangüez, a researcher at the UNIGE’s Faculty of Psychology and Educational Sciences (FPSE) and first author of the study. “The first is inhibition, i.e., our ability to inhibit intrusive or irrelevant behaviour or thoughts. The second is cognitive flexibility, which often called multitasking, and refers to our ability to flexibility move between tasks or responses based on task demands. Finally, the third is working memory, which is our ability to maintain information in our minds and manipulate it.”
However, the link between fitness and academic skills does not seem obvious at first sight. This is why researchers at the UNIGE wanted to analyze it and observe how one influences the other and whether a specific cognitive process plays a predominant role.
Testing the physical and cognitive abilities of Geneva students
The Geneva investigators teamed up with eight schools in the canton of Geneva to conduct cognitive and physical tests on 193 pupils aged 8 to 12. First of all, children took a physical test known as the “shuttle run test”: the children had to run back and forth between two lines 20 meters apart at an increasingly fast pace. “Combined with height, weight, age and sex, this test allows us to assess the child’s cardiovascular fitness,” says Marc Yangüez. “Following this, we used nine tasks that allow us to assess children’s abilities in the three main executive functions — inhibition, cognitive flexibility and working memory — and we measured different indicators such as the precision and speed of their responses,” explains Julien Chanal, researcher at the FPSE of the UNIGE. For example, one of the tests of inhibition presents students with images of fish swimming. The central fish can either swim in the same direction as the others or in the opposite direction. The students have to indicate as quickly and accurately as possible the direction in which the central fish is swimming when they are only shown the picture for 200 milliseconds. To measure cognitive flexibility, the students took three tests as well, one of the tests asked the students to connect in ascending order numbers and letters (1-A-2-B-3-C, etc.). In one of the working memory tests, the students had to memorize a sequence of numbers, such as 2 6 4 9 7, and then repeat them in the reverse order. In addition, at the end of the year, the teachers, with the parents’ consent, transmitted the students’ marks for the three terms of the year in mathematics, French 1 (comprehension and expression of text) and French 2 (grammar, spelling and vocabulary).
An indirect link between cardiorespiratory fitness and school results
By combining the data obtained, the psychologists found that there was a link between better cardiorespiratory fitness and higher marks in mathematics and French 2. “French 1 is probably less directly concerned, because the evaluation of the text and the writing depend more on subjective factors, which is less the case for mathematics or grammar, for which there is little subjectivity in the right or wrong answers,” explains Marc Yangüez. In addition to the existence of a link between cardiorespiratory fitness and school results, the data obtained also confirm a link between cardiorespiratory fitness and executive functions. But does good cardiorespiratory fitness affect academic performance directly or indirectly through executive functions?
“By decomposing these effects via a statistical mediation model, we established that the link between cardiorespiratory fitness and academic performance was indirect. In fact, physical fitness is related to better executive functions, and it is indeed executive functions that influences school performance, more specifically cognitive flexibility,” emphasizes Julien Chanal.
Important results for the planning of physical education in schools
The results of this study are important for the organization of school planning. “By demonstrating the link between physical capacities, such as cardiorespiratory capacity, cognitive abilities and grades, it underlines the importance of not reducing physical activity (and in particular physical education hours) in favour of other subjects, as this could ultimately have a negative impact on the development of the child as a whole,” says Marc Yangüez. This study also challenges the idea of forcing children to study more and spend more time at their desks in order to succeed at school, depriving them of physical exercise. Finally, and all the more so in times of a pandemic, the Geneva psychologists stress the importance of not depriving children of movement, which would be detrimental to both their physical health and their cognitive health. “We would now like to carry out an intervention study into schools in different regions of Switzerland, in order to demonstrate on a large scale that when children’s weekly physical activity increases, it has a positive impact on the development of executive functions, leading to a significant improvement in school results,” concludes Julien Chanal.

Humans are creating or exacerbating the environmental conditions that could lead to further pandemics, new University of Sydney research finds.
Modelling from the Sydney School of Veterinary Science suggests pressure on ecosystems, climate change and economic development are key factors associated with the diversification of pathogens (disease-causing agents, like viruses and bacteria). This has potential to lead to disease outbreaks.
The research, by Dr Balbir B Singh, Professor Michael Ward, and Associate Professor Navneet Dhand, is published in the international journal, Transboundary and Emerging Diseases.
They found a greater diversity of zoonotic diseases (diseases transmitted between animals and humans) in higher income countries with larger land areas, more dense human populations, and greater forest coverage.
The study also confirms increasing population growth and density are major drivers in the emergence of zoonotic diseases. The global human population has increased from about 1.6 billion in 1900 to about 7.8 billion today, putting pressure on ecosystems.
Associate Professor Dhand said: “As the human population increases, so does the demand for housing. To meet this demand, humans are encroaching on wild habitats. This increases interactions between wildlife, domestic animals and human beings which increases the potential for bugs to jump from animals to humans.”
“To date, such disease models have been limited, and we continue to be frustrated in understanding why diseases continue to emerge,” said Professor Ward, an infectious diseases expert.

Working with fruit flies, scientists at Johns Hopkins Medicine say they have identified a new molecular pathway that helps steer moving cells in specific directions. The set of interconnected proteins and enzymes in the pathway act as steering and rudder components that drive cells toward an “intended” rather than random destination, they say.
In a report on the work, published March 2 in Cell Reports, these same molecular pathways, say the scientists, may drive cancer cells to metastasize or travel to distant areas of the body and may also be important for understanding how cells assemble and migrate in an embryo to form organs and other structures.
The team of scientists was led by Deborah Andrew, Ph.D., professor of cell biology and associate director for faculty development for the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.
Andrew and her colleagues began this research while studying a gene called Tre1 and its role in the development of salivary glands in fruit flies. The tools to study the effects of turning the gene on and off weren’t ideal, she says. So, two of the team members, Caitlin Hanlon, Ph.D., of Quinnipiac University and JiHoon Kim, Ph.D., of Johns Hopkins, generated fruit flies that lack the protein-coding portion of the Tre1 gene. The pair also put a fluorescent tag on the Tre1 protein to learn where it localized during key steps in development.
In experiments with fruit fly embryos carrying an intact Tre1 gene, cells that produce future generations of the organism, called germ cells, migrate correctly to the sex organ, known as the gonad.
“Without the Tre1 gene, however, most of the germ cells failed to meet up with other nongerm cells, or somatic cells, of the gonad,” says Andrew. “Correct navigation of germ cells is important to ensure that future generations of the organism will happen.”
This is not the first time that scientists noted Tre1’s importance in germ cell navigation. Two research teams from Indiana University and the Massachusetts Institute of Technology had previously made the link. However, says Andrew, questions remained about what happens inside germ cells to get cells to the right place once Tre1 activates.

One in four Germans suffers from metabolic syndrome. Several of four diseases of affluence occur at the same time in this ‘deadly quartet’: obesity, high blood pressure, lipid metabolism disorder and diabetes mellitus. Each of these is a risk factor for severe cardiovascular conditions, such as heart attack and stroke. Treatment aims to help patients lose weight and normalise their lipid and carbohydrate metabolism and blood pressure. In addition to exercise, doctors prescribe a low-calorie and healthy diet. Medication is often also required. However, it is not fully clear what effects nutrition has on the microbiome, immune system and health.
A research group led by Dr Sofia Forslund and Professor Dominik N. Müller from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Experimental and Clinical Research Center (ECRC) has now examined the effect a change of diet has on people with metabolic syndrome. The ECRC is jointly run by the MDC and Charité Universitätsmedizin Berlin. “Switching to a healthy diet has a positive effect on blood pressure,” says Andras Maifeld, summarising the results. “If the diet is preceded by a fast, this effect is intensified.” Maifeld is the first author of the paper, which was recently published in the journal Nature Communications.
Broccoli over roast beef
Dr Andreas Michalsen, Senior Consultant of the Naturopathy Department at Immanuel Hospital Berlin and Endowed Chair of Clinical Naturopathy at the Institute for Social Medicine, Epidemiology and Health Economics at Charité — Universitätsmedizin Berlin, and Professor Gustav J. Dobos, Chair of Naturopathy and Integrative Medicine at the University of Duisburg-Essen, recruited 71 volunteers with metabolic syndrome and raised systolic blood pressure. The researchers divided them into two groups at random.
Both groups followed the DASH (Dietary Approach to Stop Hypertension) diet for three months, which is designed to combat high blood pressure. This Mediterranean-style diet includes lots of fruit and vegetables, wholemeal products, nuts and pulses, fish and lean white meat. One of the two groups did not consume any solid food at all for five days before starting the DASH diet.
On the basis of immunophenotyping, the scientists observed how the immune cells of the volunteers changed when they altered their diet. “The innate immune system remains stable during the fast, whereas the adaptive immune system shuts down,” explains Maifeld. During this process, the number of proinflammatory T cells drops, while regulatory T cells multiply.
A Mediterranean diet is good, but to also fast is better
The researchers used stool samples to examine the effects of the fast on the gut microbiome. Gut bacteria work in close contact with the immune system. Some strains of bacteria metabolise dietary fibre into anti-inflammatory short-chain fatty acids that benefit the immune system. The composition of the gut bacteria ecosystem changes drastically during fasting. Health-promoting bacteria that help to reduce blood pressure multiply. Some of these changes remain even after resumption of food intake. The following is particularly noteworthy: “Body mass index, blood pressure and the need for antihypertensive medication remained lower in the long term among volunteers who started the healthy diet with a five-day fast,” explains Dominik Müller. Blood pressure normally shoots back up again when even one antihypertensive tablet is forgotten.
Blood pressure remains lower in the long term — even three months after fasting
Together with scientists from the Helmholtz Centre for Infection Research and McGill University, Montreal, Canada, Forslund’s working group conducted a statistical evaluation of these results using artificial intelligence to ensure that this positive effect was actually attributable to the fast and not to the medication that the volunteers were taking. They used methods from a previous study in which they had examined the influence of antihypertensive medication on the microbiome. “We were able to isolate the influence of the medication and observe that whether someone responds well to a change of diet or not depends on the individual immune response and the gut microbiome,” says Forslund.
If a high-fibre, low-fat diet fails to deliver results, it is possible that there are insufficient gut bacteria in the gut microbiome that metabolise fibre into protective fatty acids. “Those who have this problem often feel that it is not worth the effort and go back to their old habits,” explains the scientist. It is therefore a good idea to combine a diet with a fast. “Fasting acts as a catalyst for protective microorganisms in the gut. Health clearly improves very quickly and patients can cut back on their medication or even often stop taking tablets altogether.” This could motivate them to stick to a healthy lifestyle in the long term.

The latest gene editing technology, prime editing, expands the “genetic toolbox” for more precisely creating disease models and correcting genetic problems, scientists say.
In only the second published study of prime editing’s use in a mouse model, Medical College of Georgia scientists report prime editing and traditional CRISPR both successfully shut down a gene involved in the differentiation of smooth muscle cells, which help give strength and movement to organs and blood vessels.
However, prime editing snips only a single strand of the double-stranded DNA. CRISPR makes double-strand cuts, which can be lethal to cells, and produces unintended edits at both the work site as well as randomly across the genome, says Dr. Joseph Miano, genome editor, molecular biologist and J. Harold Harrison, MD, Distinguished University Chair in Vascular Biology at the MCG Vascular Biology Center.
“It’s actually less complicated and more precise than traditional CRISPR,” Miano says of prime editing, which literally has fewer components than the game-changing gene-editing tool CRISPR.
Miano was among the first wave of scientists to use CRISPR to alter the mouse genome in 2013. Two scientists were awarded the 2020 Nobel Prize in Chemistry for the now 9-year-old CRISPR, which enabled rapid development of animal models, as well as the potential to cure genetic diseases like sickle cell, and potentially reduce the destruction caused by diseases like cancer, in which environmental and genetic factors are both at play.
Prime editing is the latest gene-editing technology, and the MCG scientists report in the journal Genome Biology that they were able to use it to remove expression of a gene in smooth muscle tissue, illustrating prime editing’s ability to create cell-specific knockout mice without extensive breeding efforts that may not result in an exact model, says Dr. Xiaochun Long, molecular biologist in the Vascular Biology Center. Miano and Long are corresponding authors of the new study.

Artificial Intelligence is now capable of generating novel, functionally active proteins, thanks to recently published work by researchers from Chalmers University of Technology, Sweden.
“What we are now able to demonstrate offers fantastic potential for a number of future applications, such as faster and more cost-efficient development of protein-based drugs,” says Aleksej Zelezniak, Associate Professor at the Department of Biology and Biological Engineering at Chalmers.
Proteins are large, complex molecules that play a crucial role in all living cells, building, modifying, and breaking down other molecules naturally inside our cells. They are also widely used in industrial processes and products, and in our daily lives.
Protein-based drugs are very common — the diabetes drug insulin is one of the most prescribed. Some of the most expensive and effective cancer medicines are also protein-based, as well as the antibody formulas currently being used to treat COVID-19.
From computer design to working proteins in just a few weeks
Current methods used for protein engineering rely on introducing random mutations to protein sequences. However, with each additional random mutation introduced, the protein activity declines.

SharecloseShare pageCopy linkAbout sharingimage copyrightGetty ImagesRoughly half of people in the UK now have antibodies against Covid, either through infection or vaccination, tests conducted by the Office for National Statistics (ONS) show. Most of this will be through vaccination – with 30 million people having received at least one dose.Antibodies are proteins in the blood which recognise specific infections and fight them off.Among the oldest who are most at risk, levels are even higher.But there has been a small decline in detectable antibodies in that group since the peak of infections in January.The ONS speculates this might be people who received the vaccine earliest having had their first dose but not their second – but they stress this is not evidence that these people have less immunity.Yes/no resultOnce someone has had an infection, antibodies help your body to be ready if it encounters it again. Vaccines provide a safe way to develop antibodies without risking getting ill. The tests used in the ONS study give a yes/no result based on whether the amount of antibodies in your blood cross a certain threshold.But people can be protected by lower levels of antibodies. And there are other element of your immune system like T-cells which are not being measured here. There is some evidence to suggest protective T-cells might be detectable for longer than antibodies.It’s possible some of the decline is from infections in the first wave, as we know antibodies from infection drop off over time. The study is conducted by taking blood from a representative sample of people around the UK to estimate what proportion of the whole population has antibodies. By 14 March, an estimated 55% of people in England had antibodies, 51% in Wales, 49% in Northern Ireland and 43% in Scotland. Vast majority retain Covid antibodies six months onCan you catch Covid twice?But among the over-65s, who are most likely to have been vaccinated, roughly 90% had antibodies. The figures mark a rapid rise in people in the population having protection against Covid – up from roughly a third of people testing positive when levels were measured at the start of March.Other data published today shows the number of deaths seen across the UK has remained below what is expected at this time of year, having dipped under average last week. There were 11,666 deaths registered in the week ending 19 March – 8% below the five-year average for this week.