Culture

Although the DNA and its double-helix are one of the most familiar molecules of our time, our knowledge of how cells control what genes they want to express still is rather limited. In order to create, for example, an enzyme, the information that's inscribed in our DNA about this enzyme needs to be transcribed and translated. To start this highly complex process special regulatory proteins called transcription factors (TFs) bind to specific DNA regions. That way, they can turn the expression of a gene on and off. The big question is: How can transcription factors find the right place on the DNA to properly regulate gene expression?

Simple model - big effect

For prokaryotes - simple cellular organisms without a nucleus, like bacteria - biophysical models already manage to predict gene expression based on the interaction between TFs and DNA regulatory regions. In prokaryotes, the TF binding sites on DNA are rather long and specific, making it easier for the TFs to find their target. In higher organisms called eukaryotes whose cells have a nucleus, mathematically describing the process of gene regulation proved to be much more difficult. Now, a team of researchers at the Institute of Science and Technology Austria (IST Austria) found a way to describe how the interaction between the different regulatory molecules in eukaryotes could look like.

In a new study published in PNAS, Rok Grah, a former graduate student at IST and now a data scientist, working with IST professor Gašper Tkačik and Benjamin Zoller from Princeton University proposed a minimal extension to a classic equilibrium model that can be applied to the switching between the active and inactive states of a gene. To this end, they selected a number of characteristics or "regulatory phenotypes" the desired model should satisfy. "We wanted a gene with a high specificity, meaning that the gene is activated only by the right TFs," says Rok Grah. Another regulatory phenotype included in the model was the TF residence time on a specific region and a random region of the DNA. "We were able to show that there is a class of simple models that perform well on all of these phenotypes, which wasn't done so far," explains Benjamin Zoller. Even though the proposed extension to classical model was minimal, it revealed a wealth of qualitatively new, non-equilibrium behaviors that are consistent with current experimental constraints.

Noisy genes

Based on existing data, the researchers argued that individual TFs are limited in their ability to differentiate between specific and random sites on the DNA. Therefore, although each type of TF preferentially binds certain regulatory DNA sequences, TFs bind other non-cognate targets, too. "The main motivation was to find a model to describe how the regulatory elements on the DNA don't get activated by non-cognate transcription factors," says Benjamin Zoller. Their findings suggest that high specificity of gene expression must be a collective effect of the regulatory molecules operating in the "proofreading regime".

Furthermore, if a gene is active, the number of proteins it produces fluctuates, creating what scientists call gene expression noise. "What surprised me was the tradeoff between noise and specificity. It seems like if you want to have high specificity, it tends to lead to more noise, which is intriguing," says Benjamin Zoller. High noise is often thought to be detrimental for cells, yet genes in eukaryotes are quite noisy. "So far, we don't really know why this whole transcription machinery has evolved that way. Perhaps an explanation is that high noise is unavoidable if you want high specificity. Within our model, there seems to be no way around it. High specificity will always mean high noise, and it is possible cells have evolved mechanisms to lower the noise later on in the gene expression process," adds Rok Grah. The next step in the collaboration is the experimental test of the new model. Its simplicity makes it perfectly suited for confrontation with precise real-time gene expression measurements, for example, on perturbed DNA regulatory sequences.

Announcing a new publication for BIO Integration journal. In this article the authors Meng Zhang, Wu Zhang, Zihuang Wang and Weiqian Chen from Sun Yat-Sen University, Guangzhou, China, Harvard University, Cambridge, MA, USA and Guangzhou University, Guangzhou, China review viscoelastic flow mixing in microfluidics.
The study of blood flow in vessels is crucial to understand cardiovascular diseases such as arrhythmias, coronary artery disease and deep vein thrombosis. In this paper a viscoelastic fluid in a microchannel is modelled to study blood flow. The authors found that viscoelastic fluid has a transiently unstable flow pattern compared to the normal Newtonian fluid, and mixing is increased due to its elastic property. The integration of microfluidic technology with blood flow research could provide a new approach to understanding related disease mechanisms, and to analyse drug mixing and delivery in blood flow.

Article reference: Meng Zhang, Wu Zhang, Zihuang Wang and Weiqian Chen, Experimental Study on the Viscoelastic Flow Mixing in Microfluidics, BIO Integration, 2020, https://doi.org/10.15212/bioi-2020-0029

Company reporting frequency should be relaxed to allow for greater innovation and longer-term thinking, according to new research from the Business School (formerly Cass).

The study, co-authored by Dr Arthur Kraft, Reader in Accounting, found that managers are forced to focus on maximising cursory gains at the expense of implementing long-term strategy if their organisations are imposed with - or self-impose - more regular filing of financial accounts. The reduced focus on long-term goals hinders forward-thinking, which prevents investment in innovation for fear of short-term expenditure.

On the other hand, a more relaxed approach to reporting requirements gives managers the space they require to focus less on short-term increments to appease shareholders, and more scope to increase expenditure on more valuable projects.

The research examined the number, value and citations of patent applications of US firms throughout changes to the Securities and Exchange Commission's (SEC) financial regulatory requirements in the twentieth century. During the time frame covered by the research, the statutory requirements ranged from annual reporting in 1934, to semi-annual reporting in 1955 and eventually quarterly reporting in 1970.

By analysing changes in companies that underwent the evolving financial requirements alongside those that were not bounded by the enforced regulations, the report found that firms that increased reporting frequency during this time experienced:

A decrease of 1.87 patents per annum

A decrease of 19.58 non-self-citations of their patents

A loss of $1.76 million worth of patent value

The results suggest that both quantity and quality of innovative output decreases as managers are more regularly placed under the microscope. In turn, this can lead to inertia and a culture of 'standing still' if organisations are unwilling to invest.

Dr Kraft said although managers have legal and ethical obligations to be accountable to their shareholders, over-scrutiny in the form of regular reporting could encourage an over-cautious approach.

"Increasing the frequency of reporting can increase transparency and generate external investment opportunities.

"However, shareholders and financial regulators should consider the inhibiting factors this can have on managers and their performance motivations.

"Corporate innovation has significant benefits for the global economy and managers should be encouraged to take a more holistic approach to long-term planning to help improve business sustainability," he said.

Dr Kraft pointed to the current Coronavirus pandemic as evidence that companies needed forward-thinking, however unprecedented the current situation.

"Investments in innovation are initially expensive with research, development and implementation costs, but they are necessary components for a company wishing to grow.

"Although nobody could have foreseen the events of 2020, it is plain to see that those who have been able to adapt business models and services to a socially distant population have generally fared better through the pandemic.

"Being able to adapt to whatever the 'new normal' could look like will require investment in innovation like never before - and it is important that managers have the licence to do this."

Astronomers have taken a step towards understanding how the Moon might have formed out of a giant collision between the early Earth and another massive object 4.5 billion years ago.

Scientists led by Durham University, UK, ran supercomputer simulations on the DiRAC High-Performance Computing facility to send a Mars-sized planet - called Theia - crashing into the early Earth.

Their simulations produced an orbiting body that could potentially evolve into a Moon-like object.

While the researchers are careful to say that this is not definitive proof of the Moon's origin, they add that it could be a promising stage in understanding how our nearest neighbour might have formed.

The findings are published in the journal Monthly Notices of the Royal Astronomical Society.

The Moon is thought to have formed in a collision between the early Earth and Theia, which scientists believe might have been an ancient planet in our solar system, about the size of Mars.

Researchers ran simulations to track material from the early Earth and Theia for four days after their collision, then ran other simulations after spinning Theia like a pool ball.

The simulated collision with the early Earth produced different results depending upon the size and direction of Theia's initial spin.

At one extreme the collision merged the two objects together while at the other there was a grazing hit-and-run impact.

Importantly, the simulation where no spin was added to Theia produced a self-gravitating clump of material with a mass of about 80 per cent of the Moon, while another Moon-like object was created when a small amount of spin was added.

The resulting clump, which settles into an orbit around the post-impact Earth, would grow by sweeping up the disc of debris surrounding our planet.

The simulated clump also has a small iron core, similar to that of the Moon, with an outer layer of materials made up from the early Earth and Theia.

Recent analysis of oxygen isotope ratios in the lunar samples collected by the Apollo space missions suggests that a mixture of early Earth and impactor material might have formed the Moon.

Lead author Sergio Ruiz-Bonilla, a PhD researcher in Durham University's Institute for Computational Cosmology, said: "By adding different amounts of spin to Theia in simulations, or by having no spin at all, it gives you a whole range of different outcomes for what might have happened when the early Earth was hit by a massive object all those billions of years ago.

"It's exciting that some of our simulations produced this orbiting clump of material that is relatively not much smaller than the Moon, with a disc of additional material around the post-impact Earth that would help the clump grow in mass over time.

"I wouldn't say that this is the Moon, but it's certainly a very interesting place to continue looking."

The Durham-led research team now plan to run further simulations altering the mass, speed and spinning rate of both the target and impactor to see what effect this has on the formation of a potential Moon.

Co-author Dr Vincent Eke, of Durham University's Institute for Computational Cosmology, said: "We get a number of different outcomes depending upon whether or not we introduce spin to Theia before it crashes into the early Earth.

"It's particularly fascinating that when no spin or very little spin is added to Theia that the impact with the early Earth leaves a trail of debris behind, which in some cases includes a body large enough to deserve being called a proto-Moon.

"There may well be a number of possible collisions that have yet to be investigated that could get us even closer to understanding just how the Moon formed in the first place."

Everyday life for the more than 46 million people around the world who suffer from type 1 diabetes could become much easier and safer.

Researchers from the University of Copenhagen and biotech firm Gubra have developed a new insulin molecule that, in the future, will ensure that diabetics receive just the right amount of insulin.

The insulin on the market today is unable to identify whether a patient with type 1 diabetes needs a small or large effect from the insulin, which lowers blood sugar.

"That is why we have developed the first step towards a kind of insulin that can self-adjust according to a patient's blood sugar level. This has tremendous potential to vastly improve the lives of people with type 1 diabetes," explains Professor Knud J. Jensen, of the University of Copenhagen's Department of Chemistry, one of the researchers behind a new study on this new insulin.

Effective in rats

The researchers behind the study developed a type of insulin with a built-in molecular-binding that can sense how much blood sugar is in the body. As blood sugar rises, the molecule becomes more active and releases more insulin. As blood sugar drops, less is released.

"The molecule constantly releases a small amount of insulin, but varies according to need," says Knud J. Jensen, who continues:

"It will give type 1 diabetes patients a safer and easier treatment. Today, a person with type 1 diabetes must inject themselves with insulin many times throughout the day and frequently monitor their blood sugar level by pricking their finger with a blood glucose meter. This here, allows a person to inject the new insulin molecule less often over the course of a day and thereby think about it less," says Knud J. Jensen.

Although the new 'automated' insulin is a major advance towards better diabetes treatment, it will be a while before the revolutionary insulin becomes a part of diabetics' everyday lives.

"We've tested the insulin molecule on rats and it has proven itself effective. The next step is to develop the molecule so that it works more rapidly and accurately. And finally, to test it in humans -- a process that can take many years. But it is certainly worth pinning one's hopes on," explains Professor Jensen.

An idea that sprouted in the United States

The idea to create a kind of insulin that self-adjusts to a patient's needs occurred many years ago, while Professor Jensen was living in the United States. This is where a friend of his with type 1 diabetes recounted to him a story:

"My author friend Jan Sonnergaard told me about a married couple who had been dancing one night. The man had type 1 diabetes and was feeling unwell. The wife thought to stabilise his blood sugar by giving him insulin. Unfortunately, the insulin eventuated in her husband's death. I wanted to make certain that this kind of tragedy would never be repeated," says Knud J. Jensen, concluding:

"The difficult thing with diabetes is that insulin always works the same way. It lowers blood sugar, even though that might not be what a patient requires. This is what we seek to address with our new molecule."

Researchers from the University of Helsinki have developed a novel bioinformatics pipeline called Lazypipe for identifying viruses in host-associated or environmental samples.

The pipeline was developed in close collaboration between virologists and bioinformaticians. The researchers believe they have succeeded to address many challenges typically encountered in viral metagenomics.

Previously, the Viral Zoonooses Research Unit, led by Professor Olli Vapalahti, has published two examples of novel and potentially zoonotic viral agents that were identified with Lazypipe from wild animals that can serve as vectors. A new ebolavirus was identified from faeces and organ samples of Mops condylurus bats in Kenya, and a new tick-borne pathogen Alongshan virus from ticks in Northeast Europe.

"These examples demonstrate the efficacy of Lazypipe data analysis for NGS libraries with very different DNA/RNA backgrounds, ranging from mammalian tissues to pooled and crushed arthropods," says Dr. Teemu Smura.

Covid-19 heightens the need to detect new viruses rapidly

The current Coronavirus pandemic heightens the need to rapidly detect previously unknown viruses in an unbiased way.

"The detection of SARS-CoV-2 without reference genome demonstrates the utility of Lazypipe for scenarios in which novel zoonotic viral agents emerge and can be quickly detected by NGS sequencing from clinical samples," says Dr. Ravi Kant.

In early April, the research group tested libraries of SARS-CoV-2 positive samples with Lazypipe.

"We confirmed that the pipeline detected SARS-CoV-2 in 9 out of 10 libraries with default settings and without SARS-CoV-2 reference genome," says Dr. Ilja Pljusnin.

"Lazypipe could play a crucial role in prediction of emerging infectious diseases," adds Assoc. Prof. Tarja Sironen.

Psoriasis has always been a common disease. Historically, its causes were obscure and surrounded by stigma; it wasn't until recently that scientists categorized it as an autoimmune condition. Indeed, modern scientific research shows that the body's own T-cells, macrophages and dendritic cells are responsible for attacking healthy skin tissue, triggering inflammation and proliferation of skin cells, and resulting in the characteristic red, painful plaque-like lesions experienced by psoriasis patients.

But although these immune-mediating cells have been identified as the primary culprits for the breakdown of healthy skin, their roles do not fully clarify the underlying cause. What makes these cells behave so abnormally?

Based on their existing knowledge of the cellular and genetic pathways linked with the disease, Professor Kazumitsu Sugiura and Dr. Soichiro Watanabe from Fujita Health University, Japan, along with their colleagues, attempted to find out. Their study helped them clarify the role of another potential culprit in the formation of psoriasis lesions: neutrophils. Their findings are published in Scientific Reports.

The most common type of white blood cell, neutrophils are known to be associated with various other chronic and autoimmune conditions, such as rheumatoid arthritis and lupus. Neutrophils have pro-inflammatory effects: once activated, they travel to the site of infection and effectively undergo cell death. During this process, they burst open and release their contents, forming what scientists call "neutrophil extracellular traps" (NETs), a web of proteins and genetic information from the nucleus of the former cell.

NETs have reportedly been found in psoriasis lesions. However, the mechanisms linking the formation of NETs and severe skin inflammation are unknown. Prof Sugiura explains: "NETs and neutrophils can induce inflammation through various mechanisms; we aim to clarify the role of NET signaling and possibly prevent the development of severe psoriasis-like lesions".

A precursor to the activation of NETs in psoriasis is a group of signaling proteins called IL-36 cytokines, whose role in recruiting various white blood cells and inducing inflammation is well acknowledged. For instance, a mutation in the Il36rn gene that causes a deficiency of the IL-36 receptor antagonist (IL-36Ra) protein, allows IL-36 to act uninhibited, leading to inflammation, inducing the proliferation of epidermal cells and increasing neutrophil count in psoriasis-like lesions in the mutant mice, in a condition known as DITRA. This results in skin cells keratinizing (hardening) in the manner seen in psoriasis lesions.

Armed with this theoretical knowledge, Prof. Sugiura and team studied two groups of mice: one healthy (wild type) and another with the aforementioned Il36rn gene mutation. They induced psoriasis-like lesions using imiquimod, a drug known to stimulate IL-36 signaling and subsequent immunological response. After examining the lesions, they found that mutant mice suffered more severe inflammation than the wild type. A more detailed histological analysis revealed that the mutant mice also had significantly higher neutrophil counts and NET concentrations than the wild type. The scientists went one step further and examined the mRNA levels of target cytokines known to be involved in psoriasis formation to elucidate the IL-36 pathway, thereby linking cause and effect.

Having identified these complex cellular mechanics, the scientists made a list of potential targets to block the inflammation pathway and prevent psoriasis. They injected the diseased mice with Cl-amidine, a drug which specifically targets and inhibits PAD4--an enzyme responsible for the formation of NETs. After only three days of treatment, they found the lesions, as well as the levels of inflammatory cells and IL-36 signaling proteins, significantly reduced.

Although further research and human clinical trials will be required to confirm the safety and effectiveness of potential psoriasis treatments, Prof. Sugiura and his colleagues are hopeful. Dr. Soichiro Watanabe says, "By providing mechanistic insights into the involvement of neutrophils in psoriasis pathogenesis, our study provides new directions for developing novel promising therapeutic approaches, potentially revolutionizing the quality of life of thousands of people suffering from particularly severe forms of psoriasis."

A new study suggests that COVID-19 guidance in Sweden may have reduced people's risks of having a heart attack.

By using anonymous location data from mobile phones, researchers developed an aggregate picture of the activities of the Swedish population and mapped it against attendances at the country's 29 emergency cardiac angiography units.

Cardiac angiography is used to treat blockages to the heart's blood vessels.

On those days when the location data revealed people were staying close to home, the proportion of patients going to hospital for emergency heart treatment dropped from an average of 63 patients a day in pre-COVID years to an average of 55 patients a day during the first wave of the pandemic - from 1 March to 5 May 2020. At its lowest point, in the early part of April, the drop in patients was 38 percent.

A downloadable graph shows the relative drop in patients attending the cardiac angiography units. The decline was seen from early March. The Swedish public health authorities advised people aged 70-plus to stay at home from 16 March. (Please see details in Notes to editors).

In comparison, when the location data showed people were active at work or were going shopping or being physically active, the proportionate number of attendances at the heart units rose.

Chris Gale, Professor of Cardiovascular Medicine at the University of Leeds, was one of the scientists involved in the study. He said: "This was a statistical analysis so cause-and-effect cannot be directly determined, but it has identified a number of interesting associations.

"Although Sweden was not locked down, people aged 70 or more were urged to stay at home and that could have reduced exposure to some of the events that are known to trigger a heart attack such as stress, intense physical activity, air pollution and exposure to some viruses."

The study - the Effects of movement trends on acute coronary syndrome during the COVID-19 pandemic - published in the Journal of Internal Medicine, is one of the first scientific investigations to use aggregated mobility data from map services from mobile devices to help explain how COVID-19 and the health messages around the virus may have affected people's health.

The findings in detail

A baseline measure was set for the location activity data based on daily averages from pre-COVID times. Variation from that baseline was measured as a percentage increase or decrease. The following associations were observed with the data from the angiography clinics:

A 10 percent increase in activity relating to retail and recreation was associated with a 15 per cent increase in heart attack and angina cases - collectively known as acute coronary syndrome (ACS) - seen at the angiography clinics.

A 10 percent increase in activity around grocery and pharmacy was linked to a 14 percent increase in ACS cases.

A 10 percent increase in activity around workplace was associated with a 12 percent increase in ACS cases.

A 10 percent increase in activity in the home category was linked to a 38 percent decline in ACS cases.

The analysis using Apple data produced comparable results.

The researchers say the decline in people attending hospital with a heart attack was seen in other countries including the UK, where it is believed people might not have sought emergency medical treatment out of fear of contracting COVID-19 or because they did not want to overwhelm hard-pressed NHS services.

But the researchers say there is no evidence in Sweden that there were bed shortages, higher mortality from heart disease or changes in quality of care in hospitals - factors which might have suggested people were becoming ill but had decided not to seek emergency help.

They said in the paper: "Self-isolation, working from home, and less rigorous recreational activities may have decreased stress and exertion-induced acute cardiac syndrome in individuals at risk and can possibly explain the decline in incidence of myocardial infarction (heart attack) as the association between psychological stress and physical exertion and incidence of myocardial infarction/ACS is well established."

The researchers say that messaging about hand hygiene and social distancing has reduced the spread of other respiratory conditions such as flu which could also trigger heart problems.

Dr Moman Mohammad, from Lund University, Sweden, who led the study, said: "The results give a first insight into how data from mobile devices may provide a rapid measure of how the behaviour of a population might change and how that can influence the spread of disease - and possibly, enable us to predict the level of future hospitalisations.

"We know that a stroke can be triggered by the same events that trigger a heart attack. During the first wave of the pandemic, there is evidence that the number of people experiencing a stroke also declined."

TAMPA, Fla. (December 3, 2020)- A team of researchers at the University of South Florida Department of Surgery has made a key discovery as to why we become more susceptible to heart disease as we age. The human body, especially the heart, is dependent on the mitochondria, the part of the cell responsible for producing energy to maintain organ function. The protein, Sesn2, is located inside the mitochondria and plays a pivotal role in protecting the heart from stress.

Dr. Ji Li, professor of surgery and molecular pharmacology and physiology, and his colleagues found levels of Sesn2 diminish over time, which weakens the heart and can cause it to lose functionality. His group's study published in "Redox Biology," reports that an insufficient level of Sesn2 is the reason older individuals are at greater risk of heart attack and other heart complications. This indicates stabilizing the protein could be the answer to maintaining a healthy heart.

It's common for people who've experienced cardiac arrest to have a stent inserted into a blood vessel to relieve obstruction or are prescribed medications designed to prevent blood clots. While they may offer rapid relief, these treatments can cause further injury to the heart. There are currently no known treatments available to prevent those potential side effects. Li's group, which includes the University of Louisville, found focusing on Sesn2 can keep mitochondria functional integrity, offsetting such complications.

Through biochemical analysis and high-powered microscopes, they could see Sesn2 deficiency caused cells to die in older mice, inducing heart attack. Li is now in the process of confirming their findings on human hearts provided by LifeLink, which helps facilitate organ donations for transplantation and research. Li expects to have those results available in the next couple of years.

"The age-related Sesn2 is a critical player in mitochondria," Li said. "Maintaining the cardiac Sesn2 levels could make the heart energic and against age-related heart disease."

The uncovering of Sesn2's significance helps advance the development of new therapeutic treatments. Li says the method would likely be a familiar one. Gene therapy or pharmacological approach could be considered to maintain the cardiac Sesn2 signaling pathway to strengthen the heart in aging.

Neuroscientists have provided clear visual evidence that a region of the human brain known as the ventral striatum kicks in during decision-making to weigh the costs versus the benefits of making a physical effort.

Nature Human Behavior published the research by scientists at Emory University. It gives the first detailed view of ventral striatum activity during three phases of effort-based decision-making -- the anticipation of initiating an effort, the actual execution of the effort and the reward, or outcome, of the effort.

"It's important to understand the neural mechanisms underlying motivation," says Shosuke Suzuki, first author of the study and an Emory graduate student of psychology. "Our work has wide implications for treatment of disorders related to reduced motivation, such as depression, schizophrenia and PTSD. It may also help enhance motivational programs for everything from education to athletics and public health."

"The willingness to expend effort is something crucial to our survival and something that we use every day," adds Michael Treadway, senior author of the study and Winship Distinguished Research Professor in Emory's Department of Psychology and Department of Psychiatry and Behavioral Science. "We've identified two closely overlapping, but nevertheless distinct, areas of the ventral striatum involved with different phases of effort-based decision-making. And we've provided a concrete neuroimaging tool to measure the sensitivity of signals associated with these phases that others can apply to their own data."

For example, Treadways says, the new method could provide a window into how a drug is affecting the brains of patients suffering from motivational deficits, compared to controls.

Treadway's lab focuses on understanding the molecular and circuit-level mechanisms of psychiatric symptoms related to mood disorders, anxiety and decision-making.

The ventral striatum, located deep within the brain's cerebral hemispheres, is an area associated with movement and mediating rewarding experiences and motivation.

Neuroimaging has consistently shown that the ventral striatum activates during decision-making to encode the potential value of rewards relative to costs, such as wait times and probability. The ventral striatum helps you decide whether to pay more for "next-day" delivery or choose "free, one-week" delivery to receive a package.

Neuroimaging studies had previously failed, however, to detect a strong value signal in the ventral striatum for decisions that require a physical effort. If you want more coffee, but the pot is empty, is it worth getting up and brewing some more?

"It was a mystery why this brain region encoded the value of a reward versus time and probability but did not appear to do so for physical effort," Suzuki says. "It's been a paradox in the neuroimaging literature."

Previous research on rodents showed that the ventral striatum is critical for motivating an animal to work for rewards like food. Animal research also shows evidence for two opposing signals in the ventral striatum. An activation signal prepares an animal to work and a discounting signal helps an animal select rewards that require the least effort. These signals help animals work for what they need, while also making sure they don't work more than they have to.

The presence of these signals had never been tested in humans. The Emory researchers theorized that as the physical cost to perform a task rises, the activation signal would drive an increase in activity in the ventral striatum, while the discounting signal would drive a decrease. They proposed that the simultaneous firing of these two signals -- the cost of effort versus the activation of effort itself -- is what made it harder to detect the value signal in previous studies.

An additional complication to detecting brain activation associated with physical effort is the fact that neuroimaging requires participants to lie still within a functional Magnetic Resonance Imaging (fMRI) machine while their brains are scanned.

To get around these issues, the researchers designed fMRI experiments that would allow participants to remain in a supine position and would also separate the neural signals involving effort from the one associated with the cost of the effort.

For the first set of experiments, the researchers created a virtual maze. As their brains were scanned, study participants were presented with maze navigation tasks that required different levels of effort. In one condition, the participants watched themselves move through the virtual maze passively. In another condition, they simply pressed a button on a handheld device to move through the maze. A third condition required the higher effort of repeatedly and rapidly pressing the button to move through the maze. Each maze, when successfully completed, rewarded them with a nominal dollar amount.

During a second experiment, the neural activity of participants was measured as they made a series of choices between two options, with varying amounts of reward and effort required for each option. The effort and reward amounts were presented sequentially to try to isolate the effort-activation signal during the anticipation of various effort demands.

The results showed that two distinct regions of the ventral striatum fired in response to different phases of physical effort and effort-based decision making, with some overlap. Activity in an anterior region was mainly associated with reward and effort costs, while activity in a dorsal region was mainly associated with initiation of effortful movement. And this activity related to effortful movement was distinct from activity in another region, called the putamen, which was associated with initiation of simple movement.

The researchers now hope to build upon this increased awareness for how the brain encodes signals related to motivation.

"Our current paper provides a paradigm for how to measure brain activity for effort-based decisions associated with assigned tasks," Suzuki says. "Now we're developing experiments to identify specific modes of signaling when people spontaneously initiate action. That may give us a better measure of how the brain operates when people do things because they want to do them, in real-life situations. Getting sensitive measurements for how people normally decide to expend effort may help us develop better treatments for people suffering motivational deficits related to depression or other illnesses."

A researcher at the University of Tartu described new associations between Neandertal DNA and autoimmune diseases, prostate cancer and type 2 diabetes.

Modern humans migrated out of Africa more than 60,000 years ago and met and interbred with Neandertals and other archaic human groups. As a consequence, we can find that a few percent of the genomes of people outside of Africa contain traces of archaic ancestry. Large-scale resources with genetic and medical data are needed to find out how this archaic remains affect modern human health. Most previous studies have examined European population-specific cohorts. However, the Neandertal DNA content is quite different between Europeans and Asians and our knowledge limited about non-European Neandertal DNA. A new study by Senior Research Fellow of Evolutionary and Population Genomics Michael Dannemann analyzed Neandertal associated phenotypes in an Asian cohort and compared it to those discovered in a European cohort.

This study provides evidence that the impact of Neandertal DNA on the immune system has not been population-specific. "My findings show that while the Neandertal DNA in European and Asian populations differ they both contain variants that increase the risk of autoimmune diseases like dermatitis, Graves' disease and rheumatoid arthritis," said Dannemann.

Another disease for which associations were found in both populations was prostate cancer. Dannemann said that the difference is here that this gene variant had a protective effect which means it reduces the risk for prostate cancer.

Of particular interest were the Neandertal associations with type 2 diabetes, a disease influencing many people today. The result of this study showed that Neandertal-linked associations were only found in Asians and showed evidence for an over-proportional effect on this disease given the Neandertal DNA content in this population.

However, given the different associated archaic variants in both European and Asian cohorts, the results of this study also suggest that the effects of how Neandertal DNA influences immunity might be population-specific. "This is highlighting the importance of studying a wider range of ancestries to help us to ascertain how the phenotypic legacy of Neandertals influences modern humans today," added Dannemann.

The Gaia space telescope has measured the acceleration of the Solar System when it orbits the center of our Milky Way galaxy. The Solar System motion relative to the stars agrees with the results by Finnish astronomers in the 19th century.

Moreover, the observational data by Gaia improves satellite navigation. Finnish researchers are participating in this massive endeavor, that results in three-dimensional mapping of our galaxy, to be completed in 2024.

Today, Dec. 3, 2020, the European Space Agency (ESA) released observational data from the Gaia telescope (Gaia Early Data Release 3 or EDR3), in continuation to the DR1 and DR2 releases of the years 2016 and 2018. Gaia accrues accurate knowledge about, for example, the Milky Way stars, distant extragalactic quasars, and the asteroids of our Solar System.

Quasars are bright, star-like objects that allow for the determination of planet Earth's orientation in space. With the help of their precise positions measured by Gaia, a new high-precision reference system can be constructed for defining the positions of stars, Solar System objects, and also satellites.

"The knowledge accrued by Gaia affects the precision of satellite navigation in the future. The satellite positions and Earth orientation in space are determined in a reference frame tied to the directions of quasars. The precision and state of the art of the reference frame are critical for the precision in navigation," says Professor Markku Poutanen at the Finnish Geospatial Research Institute FGI, National Land Survey of Finland.

The precise observations of quasars resulted, for the first time, in a successful computation of the acceleration of the Solar System.

"The acceleration of the Solar System towards the center of the Milky Way, as measured by Gaia, is (2.32±0.16) x 10-10 m/s2 or, roughly, two one-hundred-billionth parts of the gravitational acceleration caused by the Earth on its surface, " summarizes Astronomy Professor Karri Muinonen at the Department of Physics, University of Helsinki, also Research Professor at the Finnish Geospatial Research Institute FGI.

Gaia in the research of asteroids

Gaia's data processing is carried out within the European DPAC network (Data Processing and Analysis Consortium) with more than 300 researchers. Solar System researchers at the University of Helsinki take part in the Gaia data processing in several different ways.

"We are responsible for the daily computation of orbits for asteroids discovered by Gaia. Based on these computations, ground-based follow-up observations are organized," describes Muinonen.

"Before data releases, we take part in the validation of Gaia observations of asteroid positions, brightnesses, and spectra. Our research with Gaia data focuses on asteroid orbits, rotation periods and pole orientations, masses, shapes, and surface structural and compositional properties. In the computation of collision probabilities for near-Earth asteroids, the precision of reference frames is completely central," continues Muinonen.

Asteroid observations by Gaia were published in DR2 in spring 2018 (14 099 asteroids). In the forthcoming DR3 release in spring 2022, there will be position and brightness data for tens of thousands of asteroids and, for the first time, asteroid spectra will also be released.

Years of work and billions of stars

The EDR3 data has been collected by Gaia from the end of July 2014. The data includes, for example, position and brightness data of 1,81 billion stars and color data of 1,55 billion stars from the time period of 34 months. Furthermore, the data more than triples the number of quasars observed for precise reference frames to 1,61 million.

EDR3 is a remarkable improvement, in terms of both numbers and precisions, as compared to the earlier releases. The newest release gives hints about the gigantic nature of the forthcoming DR3 release in spring 2022 and the final DR4 release after 2024.

Gaia observes astronomical objects systematically in the so-called L2 Lagrange point some 1,5 million kilometers from the Earth in the anti-sun direction. Gaia observes about two billion stars with a precision, at best, of one hundred millionths of a degree. The result will be a three-dimensional map of our galaxy.

Stellar motion in the future

Based on the Gaia data, researchers' have modeled the motion of stars in the Milky Way. They have produced an animation for the motion of 40 000 randomly selected stars on the sky 1.6 million years into the future.

"In the animation, short and long trails describe changes in stellar positions with 80 000 years. The former are mostly related to distant stars, whereas the latter are solely due to the nearby stars. Every now and then, short trails expand into long ones, and long trails shrink into short ones. This is also related to the changing distances of the stars," says Muinonen.

In the end of the animation, stars appear to be removed from the left and collected to the right. This is due to the Solar System's motion relative to the stars. A similar phenomenon can be seen when moving from a center of a forest islet to its boundary: the trees in the front gradually disappear whereas they seem to be collected in the back.

"This shows the average motion of the Solar System with respect to the surrounding stars. From the Finnish point of view, it is intriguing that the motion documented by Gaia agrees with the pioneering research about the Solar System's motion by Friedrich Wilhelm August Argelander (1799-1875) in the 19th century at the Helsinki Observatory," concludes Muinonen.

Argelander was the first astronomer, who unequivocally calculated the direction of Solar System motion in space. He worked at the Observatory, University of Helsinki, then the Imperial Alexander University. He had made the observations at the Turku Observatory in 1827-1831 before the observatory moved to Helsinki. In Helsinki, he compiled the stellar catalog entitled "DLX stellarum fixarum positiones mediae ineunte anno 1830" that, as the title says, included the precise positions of 560 stars.

Movement of quasars is actually the movement of Solar System

More accurately, the apparent stellar streams include the information about the motion of the stars and the Solar System about the center of the Milky Way. The Gaia quasar observations allow for the determination of the acceleration related to this orbital motion.

Gaia has measured the apparent motions of quasars on the sky. These motions are tiny, about one thousandth part of the motion of stars 3000 light years from us. The apparent stream of quasars is directed toward the center of the Milky Way, that is, in the direction where the acceleration of the Solar System is pointing. Gaia has, in essence, measured the absolute motion of the Solar System relative to the distant universe. This motion derives from the gravitational forces by the Milky Way and all other objects in the universe.

What makes the elderly and people with underlying conditions more vulnerable to COVID-19? According to a new study led by McGill University researchers, clues can be found in the proteins involved in initiating infection, as the virus binds to host cells of different animals. Greater cellular oxidation with aging and sickness may explain why seniors and people with chronic illness get infected more often and more severely.

Over 60 million people have been infected and around 1.5 million have died from COVID-19. The virus is disrupting economies and food supply chains all over the world. Understanding why some animals get infected and others do not could be the key to unlocking new treatments and therapies. In a study published in Computational and Structural Biotechnology Journal, researchers analyzed available protein sequences of the virus and host cell receptors across different spices to find out why.

"We know that the virus can infect humans, cats, dogs and ferrets but not bovine and swine. Also, COVID-19 hits the elderly and people with underlying conditions more severely than the young and healthy ones. Until now reasons for this were unclear," says McGill Professor Jaswinder Singh.

The research was conducted by a multidisciplinary team of scientists led by Professor Singh. The team includes Professor Rajinder Dhindsa (McGill University), Professor Baljit Singh (University of Calgary) and Professor Vikram Misra (University of Saskatchewan).

How COVID-19 infects cells

Once inside a host cell, the virus hijacks the cell's metabolic machinery to replicate and spread. The virus's protein spikes attach to a protein receptor on the surface of the host cell called ACE2, fusing the membranes around the cell and the virus together. This process allows the virus to enter the cell and co-opt its protein-making machinery to make new copies of itself. The copies then go on to infect other healthy cells.

In analyzing the proteins and their amino acid building blocks, the researchers found that animals susceptible to the virus have a few things in common. Such animals like humans, cats, and dogs have two cysteine amino acids that form a special disulfide bond held together by an oxidizing cellular environment. This disulfide bond creates an anchor for the virus. "Our analysis suggests that greater cellular oxidation in the elderly or those with underlying health conditions could predispose them to more vigorous infection, replication and disease," says co-author Rajinder Dhindsa, an emeritus professor of biology at McGill University.

In the case of animals resistant to the virus, like pigs and cows, one of these two cysteine amino acids is missing, and the disulfide bond cannot be formed. As a result, the virus cannot anchor on to the cell.

According to the researchers, preventing the anchor from forming could be the key to unlocking new treatments for COVID-19. One strategy, they suggest, could be to disrupt the oxidizing environment that keeps the disulfide bonds intact. "Antioxidants could decrease the severity of COVID-19 by interfering with entry of the virus into host cells and its survival afterwards in establishing further infection," says Professor Singh.

In terms of next steps, the researchers say CRISPR technology could be used to edit protein sequences and test out their theory. The researchers are also looking into other proteins near the ACE2 receptor that may facilitate entry of the virus to see if they behave the same way.

DALLAS - Dec. 3, 2020 - A team led by UT Southwestern has derived a new "intermediate" embryonic stem cell type from multiple species that can contribute to chimeras and create precursors to sperm and eggs in a culture dish.

The findings, published online this week in Cell Stem Cell, could lead to a host of advances in basic biology, regenerative medicine, and reproductive technology.

Cells in early embryos have a range of distinct pluripotency programs, all of which endow the cells to create various tissue types in the body, explains study leader Jun Wu, Ph.D., assistant professor of molecular biology. A wealth of previous research has focused on developing and characterizing "naïve" embryonic stem cells (those about four days post-fertilization in mice) and "primed" epiblast stem cells (about seven days post-fertilization in mice, shortly after the embryo implants into the uterus).

However, says Wu, there's been little progress in deriving and characterizing pluripotent stem cells (PSCs) that exist between these two stages - largely because researchers have not been able to develop a paradigm for maintaining cells in this intermediate state. Cells in this state have been thought to possess unique properties: the ability to contribute to intraspecies chimeras (organisms that contain a mix of cells from different individuals of the same species) or interspecies chimeras (organisms that contain a mix of cells from different species) and the ability to differentiate into primordial germ cells in culture, the precursors to sperm and eggs.

For this study, the researchers successfully created intermediate PSCs, which they named "XPSCs" from mice, horses, and humans.

Wu says that these results could eventually lead to an array of advances in both basic and applied research. For example, looking at gene activity in XPSCs from different species and interspecies chimeras could help researchers understand which signatures have been conserved through evolution. Examining the communication between cells in chimeras may help scientists identify strategies that could be used to accelerate the development of tissues and organs from stem cells used for transplantation. And using chimera-derived primordial germ cells to create sperm and eggs could aid in preserving endangered animal species and advancing infertility treatments.

"These XPSCs have enormous potential. Our study helps open the door to each of these possibilities," says Wu, who is a Virginia Murchison Linthicum Scholar in Medical Research.

Wu notes that developing XPSCs presented a special challenge because the conditions that keep naïve PSCs in a stable state are exactly the opposite from those that stabilize primed PSCs. While culture conditions for naïve PSCs must activate a WNT cell-signaling pathway and suppress the FGF and TGF-ß pathways, the conditions to maintain primed PSCs must suppress WNT and activate FGF and TGF-ß.

Aiming for the preferred environment for XPSC derivation, Wu and his colleagues placed cells from early mouse embryos into cultures containing chemicals and growth factors that activate all three pathways. These lab-grown cells were extremely stable in culture and able to multiply without developing any further for approximately two years.

Additional experiments showed that these cells met the expectations researchers have long strived to meet of contributing to chimeras and directly differentiating into primordial germ cells. Wu and his colleagues made intraspecies chimeras of mice using cells derived from mice with different coat colors by injecting the cells into early mouse embryos. They also tracked the contributions of the XPSCs by tagging the cells with a fluorescent protein and then identifying them throughout the resulting offspring's body.

Wu's team made interspecies chimeras by injecting horse XPSCs into early mouse embryos and allowing the embryos to develop in mice for several days. Surprisingly, although horses have a comparatively long gestational period - nearly a year - the researchers found that these foreign cells had contributed to mouse organ development, indicating that signals from the mouse cells determine organ developmental timelines.

Like XPSCs from other species, the human cells showed that they were capable of differentiating into a variety of tissues if culture conditions allowed them to progress in development, as well as directly form primordial germ cells in a dish.

Over a quarter of all proteins in a cell are found in the membrane, where they perform vital functions. To fulfil these roles, membrane proteins must be reliably transported from their site of production in the cell to their destination and correctly inserted into the target membrane. Researchers from the Heidelberg University Biochemistry Center (BZH) have succeeded in determining the three-dimensional structure of a molecular machine responsible for the correct placement of an important membrane protein family - the so-called "tail-anchored" membrane proteins, or TA proteins for short.

An adult human consists of an estimated 100 billion cells. Each one contains countless proteins, the architects and players in life that perform a broad range of functions. A major portion of the proteins in a cell are membrane proteins, i.e. components of the fine membranes (from the Latin membrana) that envelop every cell as well as its small organs, the organelles. Membrane proteins can form channels or pores and perform fundamental tasks such as transport of substances and signal transmission. Therefore, the correct insertion of a membrane protein is crucial for it to fulfil its biological role and, in turn, for the proper function of the cell. But what ensures that the protein ends up at the right membrane and is integrated at the right spot?

Specific signal sequences, small sections of proteins that act like "post codes", are vital for delivery to the correct location and proper insertion into the membrane. They are detected by molecular sorting machines that deliver the protein to its destination. In some proteins, the signal sequence is found at the end of the molecule, known to scientists as "tail-anchored" or TA membrane proteins. This vital membrane protein family is involved in many cellular processes, including membrane fusion and apoptosis, or programmed cell death.

BZH researchers led by Prof. Dr Irmgard Sinning recently determined the three-dimensional structure of the molecular machine that inserts the TA proteins into the membrane of the endoplasmic reticulum (ER) - an important distribution network inside the cell that is connected to all other organelles. For their structural analyses, the BZH scientists used cryo-electron microscopy (cryo-EM), a method recognised by the Nobel Prize for Chemistry in 2017. "This type of high-resolution structural information is essential to understand the final steps of the protein insertion process into the ER membrane," explains Prof. Sinning, who directs a research group at the BZH.

The GET insertion machine is responsible for the correct insertion of TA proteins into the ER membrane. GET stands for "guided entry of tail-anchored membrane proteins". This insertion machine, which has barely changed over the course of evolution from yeast to man, consists of three protein building blocks. Two are located in the ER membrane where they form a kind of cavity (Get1 and Get2). The third one (Get3) is located outside the membrane, acting as the TA protein deliverer. All three components of the GET insertion machine are essential for the correct insertion of the TA protein into the target membrane. Get2 takes the protein from the deliverer and essentially "pushes" it towards the cavity in the interior of the membrane. The Heidelberg researchers uncovered this unexpected detail concerning the interaction between Get2 and Get3 during their analysis of the protein structure. They also showed that two copies of the insertion machine always work closely together to make the integration process more efficient. "The GET insertion machine provides the TA proteins with an energetically favourable route into the membrane," states Prof. Sinning.

"Small membrane proteins like those found in the GET insertion machine are a challenge for structural biology, so our research required innovative ideas," adds structural biologist Dr Melanie McDowell. Only in recent years have technical improvements in cryo-EM allowed structures of increasingly smaller protein complexes to be identified in ever greater detail. Heidelberg University therefore established a cryo-EM network (HDcryoNet), making the structural analysis of small membrane protein complexes like the GET insertion machine possible. Prof. Sinning and Dr McDowell believe that their new data provide a crucial missing puzzle piece required to complete the picture of protein transport in the cell and protein insertion into membranes.