Culture

A new study by Johns Hopkins Medicine researchers of adults hospitalized for the eating disorder anorexia nervosa has strengthened the case for promoting rapid weight gain as part of overall efforts for a comprehensive treatment plan. The study findings, after analyzing data regarding 149 adult inpatients with anorexia nervosa in the Johns Hopkins Eating Disorders Program, stand in contrast to long held beliefs that patients would not tolerate a faster weight gain plan because it would be too traumatic.

In a report on the work published online Oct. 7 in the International Journal of Eating Disorders, researchers say a majority of patients not only tolerated the regimen, they also met their weight gain goals in weeks rather than months, they would recommend the program to others and they would be willing to repeat it, if needed.

A form of self-starvation, anorexia nervosa is a serious psychiatric disorder in which people feel fat or fear gaining weight despite being very underweight. Over time, people with anorexia experience physical, psychological and social complications with a high risk of long-term consequences that can include heart, kidney and liver damage, bone loss, depression and self-harm. Anorexia has one of the highest mortality rates of any psychiatric condition.

The investigators say their findings also suggest that inpatient eating disorder programs that focus on rapid weight gain can minimize a patient's time away from home, work and family, help curb treatment costs by reducing lengths of stay in a hospital or residential treatment program and be rated helpful by most patients.

"Treating anorexia is expensive due to the high cost of inpatient and residential treatment, and the cost of health care is important to both patients and health systems," says Angela Guarda, M.D., director of the Eating Disorders Program at The Johns Hopkins Hospital. Guarda is also the Stephen and Jean Robinson Associate Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. "Our findings suggest that a meal-based nutritional approach that emphasizes faster weight gain coupled with different types of behavioral therapy and meal support is well tolerated and achieves weight restoration in a majority of patients."

Earlier work by Guarda and others countered the belief that patients with anorexia need to gain weight slowly to avoid a potentially life threatening condition called re-feeding syndrome, which is a metabolic imbalance that can occur when severely malnourished people take in too much food or drink. Despite these safety studies, clinicians are still reluctant to implement rapid re-feeding strategies, combined with behavioral treatment approaches, because they fear that patients won't endure them. With the new study, Guarda and her team sought the patients' perception of the Johns Hopkins rapid re-feeding program.

For the study, researchers analyzed information gathered on 134 women and 15 men, averaging 35 years of age, who were treated and discharged from the integrated inpatient-partial hospitalization eating disorders program at The Johns Hopkins Hospital between February 2014 and June 2017. They were underweight when admitted to the program and placed on a regimen emphasizing faster weight gain, balanced meals and behavioral therapies designed to prevent relapses. The program aims to normalize eating and weight control behaviors, encourage healthier eating habits and help patients overcome their anxieties about eating a variety of foods.

More than 70% of the patients in the study reached a healthy body mass index (BMI). BMI is a measure of body fat based on height and weight. For most adults, a healthy BMI is between 18.5 and 24.9. Patients in the study achieved an average BMI of at least 19, which is within the healthy range, compared to an average of 16.1 at the beginning of the program. The average hospital stay was just 39 days, and patients gained 4 pounds per week on average -- "close to twice what many intensive treatment programs achieve, which means half as much hospital time is needed to reach a healthy weight," says Guarda.

Upon hospital discharge, patients were invited to complete an anonymous questionnaire to rate their satisfaction with the treatment. Some 107 participants (72%) completed the questionnaire. Overall, 71% of respondents said they would come back if they needed help with their eating disorder in the future, while 83% would recommend the program to others.

Like faster weight gain, Guarda explains, behavioral management is often criticized by clinicians as poorly tolerable by patients. However, the program's focus on behavior change was rated good or very good by 83% of the patients.

Participants also rated the degree to which they felt included in the treatment (78%), and their level of satisfaction with staff members (clinical nurses: 96%, occupational therapists: 99%, dietitians: 45%, social workers: 75%). Satisfaction with intervention factors (group therapies: 79%, family meetings and education: 63%) and environmental factors (comfort of units: 50%, presentation/taste of food: 36%) was also assessed.

"Our program is solely meal-based and does not employ tube feeding," says Guarda. Occupational therapists and nursing and dietician staff members assist patients in preparing and portioning meals, and in eating food prepared by others in cafeteria and restaurant settings. "We want to help our patients translate what they're learning here to a more real world environment so they can stay healthy once back at home."

According to Guarda, most patients go to inpatient programs like the one at Johns Hopkins under pressure from family members, employers or a significant other, and they are often anxious and apprehensive about entering treatment. "At the beginning, they often don't see the need to be here," she says, "but these results show that for most patients, their overall perception is positive by the end of treatment."

Guarda says she's encouraged that the field of anorexia nervosa is gradually moving toward greater and more uniform accountability about outcomes. "The standard of care should be based on evidence. Uniform, transparent reporting of weight and behavioral outcomes by treatment programs is needed so that patients, their families and referring clinicians can be more informed about treatment programs," she says.

According to the National Eating Disorders Association, 0.9% of women and 0.3% of men will develop anorexia during their lifetime.

A team of Johns Hopkins University researchers has developed a new software that could revolutionize how DNA is sequenced, making it far faster and less expensive to map anything from yeast genomes to cancer genes.

The software, detailed in a paper published in Nature Biotechnology, can be used with portable sequencing devices to accelerate the ability to conduct genetic tests and deliver diagnoses outside of labs. The new technology targets, collects and sequences specific genes without sample preparation and without having to map surrounding genetic material like standard methods require.

"I think this will forever change how DNA sequencing is done," said Michael C. Schatz, a Bloomberg Distinguished Associate Professor of Computer Science and Biology and senior author of the paper.

The new process shrinks the time it takes to profile gene mutations, from 15 days or more to just three. That allows scientists to understand and diagnosis conditions almost immediately, while saving time and money by eliminating preparation and additional analysis.

"In cancer genomics there are a few dozen genes known to increase cancer risk, but with a standard sequencing run, you would have to sequence the whole genome just to read off those few genes," Schatz said, adding that adaptive sequencing allows researchers to "pick and choose which molecules we want to read and which can be skipped."

To provide a sense of how much this invention speeds up sequencing, Schatz relates it to finding a movie on Netflix. The older, standard method of sequencing would require someone to watch every second of every movie on Netflix to find what they want. Instead, adaptive sequencing eliminates hours of watching irrelevant content by quickly recognizing unwanted movies and skipping to the next entry.

The open-source software's algorithm was written by lead author Sam Kovaka, a Johns Hopkins doctoral student. Its acronymic name, UNCALLED, stands for a Utility for Nanopore Current Alignment to Large Expanses of DNA.

It took two years to code, develop and test the software, and another year to refine it enough to produce results worthy of publication, Kovaka said.

"UNCALLED allows for unprecedented flexibility in targeted sequencing," he added. "The fact that it's purely software-based means researchers can target any genomic region with no added cost compared to a normal sequencing run, and they can easily change targets just by running a different command."

The process identifies DNA molecules as they pass through tiny electrified holes, or "nanopores," inside devices called nanopore sequencers, which are smart phone-sized versions of the bulky machines used in labs. The software reads the data and checks it against a specified genome's reference sequence within a fraction of a second. Desired molecules are allowed to pass through the pore to be fully mapped. But if an undesirable molecule is detected, the software reverses the voltage in the nanopore, physically ejecting the molecule to make room for the next.

"It's like a nightclub doorman allowing desired guests on a list to enter while rejecting the rest with a Taser," Schatz explains.

The research team performed two demonstrations of UNCALLED.

The first showed that the software was able to enhance the sequencing of 148 genes known to increase cancer risk by quickly and accurately profiling all of their variants with just a single run through a portable sequencer. The software made it possible to catalogue in real time dozens of complex structural mutations in the cancer genes that a standard run would have missed.

Then the team demonstrated how the software could selectively sequence certain species collected from an environment, such as microbes living on skin or those in pond water. By rejecting molecules from known microbes (such as E. coli), the software was able to efficiently sequence the remaining molecules, which revealed a less-understood yeast genome.

UNCALLED can operate on standard hardware used for nanopore sequencing without requiring special reagents or accelerators. The selection of genes or genomes to sequence is controlled entirely in the software and can be changed at any time.

As medical research progresses, traditional treatment protocols are being rapidly exhausted. New approaches to treat diseases that do not respond to conventional drugs are the need of the hour. In search for these approaches, science has turned to a wide range of potential answers, including artificial nucleic acids. Artificial or xeno nucleic acids are similar to naturally occurring nucleic acids (think DNA and RNA) -- but are produced entirely in the laboratory.

Xeno nucleic acids are essential for the development of nucleic acid-based drugs. To be effective, they need to be able to stably bind to natural RNA (a cellular single-stranded version of the DNA, which is essential for all body processes). However, it is unclear how, if at all, RNA hybridizes with these xeno nucleic acids. A new study by researchers from Japan sheds light on this mechanism, opening doors to the development of potentially revolutionary nucleic acid-based drugs.

In their experimental study published in Communications Chemistry, the team of the researchers was able to determine three-dimensional structures of RNA hybridization with the artificial nucleic acids serinol nucleic acid (SNA) or L-threoninol nucleic acid (L-aTNA), two of the few xeno nucleic acids capable of binding and forming duplexes with natural RNA effectively. This study was the outcome of collaboration among researchers at the Graduate School of Engineering of Nagoya University, the Graduate School of Pharmaceutical Sciences of Nagoya City University, the Exploratory Research Center on Life and Living Systems (ExCELLS) of the National Institutes of Natural Sciences, and the Graduate School of Engineering of Osaka University.

Natural nucleic acids like DNA and RNA have a sugar-phosphate "backbone" and nitrogen-based components; while the nitrogen-based components in SNA and L-aTNA remain the same, they have an amino acid-based backbone instead. SNA and L-aTNA have advantages over other artificial nucleic acids because of their simple structure, easy synthesis, excellent water solubility, and high nuclease resistance. These characteristics make them more suitable for developing nucleic acid drugs. "Since SNA and L-aTNA can bind to natural nucleic acids, we wanted to know what the key to stabilize the duplex structure between SNA or L-aTNA and RNA," states Dr. Yukiko Kamiya, the lead scientist on the study, "and therefore, we started to work on determining the three-dimensional structure."

They found that intra-molecular (within-molecule) interactions are important for keeping the helical (twisted) double-stranded structures formed of acyclic nucleic acids and RNA stable. While helical structures of natural nucleic acids are A-type, meaning that they twist towards the right, these synthetic duplex structures seemed to align in a perpendicular pattern, resulting in larger areas between each turn of the helix. In addition, they obtained triple-stranded structures consisting of L-aTNA or SNA and RNA, through "Hoogsteen base pair" interactions, as shown in Figure 1.

These findings question a lot of things we have so far believed to be fundamental in biology. Ribose, the sugar in the backbone of natural nucleic acids, doesn't seem to be necessary for forming a stable duplex, contrary to the currently accepted knowledge. Then why did nature select ribose? "This is perhaps better answered through future studies looking at the helical structure," says Dr. Kamiya.

For now, her team is happy that their findings open up more drug development avenues. "The structural understanding of these duplexes can help us come up with novel designs of nucleic acid-based drugs. We hope that through these findings, the development of nucleic acid drugs will accelerate," she says.

These insights, of course, go beyond medical applications. Nucleic acids are the blueprints of the "construction" of all living organisms, but we realize that many of their secrets are still uncovered. These findings shed light on a small but significant chapter of nucleic acids.

New Curtin University research has found southern Australian long-finned pilot whales are able to mimic the calls of its natural predator and food rival - the killer whale, as a possible ploy to outsmart it.

The study is the first published research analysing the calls of long-finned pilot whales in the Southern Hemisphere, which were recorded in the Great Australian Bight, off WA and SA, between 2013 and 2017.

The research, published in Scientific Reports, also found evidence of 'duetting', which is common in birds and primates but very rarely reported in aquatic mammals, and which suggests the whale's sophisticated acoustic communication system is more complex than previously thought.

Lead author Rachael Courts from Curtin's Centre for Marine Science and Technology said the study of long-finned pilot whales off southern Australia showed what appeared to be mimicry of a call of the Australian killer whale.

"This mimicry may be a clever strategy employed by the whales in order to disguise themselves from predators including killer whales. It may also allow them to scavenge food remnants from killer whales, undetected," Ms Courts said.

"Duetting refers to coordinated and patterned singing by two animals and is related to social bonding and coordination of behaviour.

"Some long-finned pilot whale calls were found to be remarkably similar to those of the same species in the Northern Hemisphere, which is surprising as non-equatorial aquatic mammals such as these are not expected to cross the equator for large-scale migrations, meaning the last contact the two hemispheres' populations could have had would have been more than 10,000 years ago.

"Our findings therefore raise the question of how far these two populations' home ranges really extend and now that we have some of their call repertoire documented, we can monitor home ranges with remote underwater sound recorders such as those used by many countries, including Australia."

Professor Christine Erbe, Director of Curtin's Centre for Marine Science and Technology, said the research was not only the first to be published on the calls of long-finned pilot whales off southern Australia but also the first in the entire Southern Hemisphere. Previous studies have only focussed on waters off the US, Canada and Europe.

"Our research discovered three unique vocalisations recorded from southern Australian long-finned pilot whales, which have not been reported for the species," Professor Erbe said.

"These were very complex multi-component calls much like killer whale calls, but given this is the first southern hemisphere study, we don't know how common the calls might be in other Southern Hemisphere pilot whales. This aspect could be the focus of future research."

A team of scientists from Hokkaido University has suggested that marimo maintain their characteristic spherical shape due to the rarity of the formation of reproductive cells.

The marimo is the aggregative form of the freshwater alga Aegagropila linnaei. In Japan, Lake Akan in Hokkaido is the best known habitat of the marimo. It is so emblematic of the lake and surrounding region that it has been designated as a special national monument. However, due to decades of deforestation and pollution, the marimo populations in Lake Akan have steeply dropped and have not recovered, despite a number of protective measures.

In the current study, Professor Isamu Wakana and Professor Masashi Ohara of Hokkaido University have discovered that A. linnaei rarely produces its reproductive cells, called zoospores, suggesting that such rarity contributes to the formation of the characteristic spherical appearance of marimo. Their findings, published in the journal Aquatic Botany, contribute to the ongoing efforts to understand the reproduction of the marimo and, hence, its conservation.

A. linnaei is a filamentous alga commonly found in two forms: free-floating and epilithic (attached to rocks); the extremely rare third form, spherical aggregates called marimo, is known from only two locations in the world: Lake Akan, Japan, and Lake Myvatn, Iceland. The means by which this alga transitions between the three forms is still under investigation. In this study, the scientists decided to investigate the reproductive behavior of the marimo and examine if it had any relation to the forms of A. linnaei.

All three forms of A. linnaei are found in Lake Akan. Between May and October in 2017 and 2018, the scientists sampled five different locations across the lake: Churui and Kinetanpe for aggregative forms, Takiguchi for free-floating forms, and Jyagaiwa and Shurikomabetsu for epilithic forms. The number of zoospores (the reproductive cells) from fifty filaments of each of the different forms were counted.

The formation of zoospores with four flagella (spores) was observed, for the first time, in epilithic and aggregate forms from mid-August to early-September. However, the level of formation was very low (maximum 1.3%), particularly in aggregative forms. Zoospore formation was not observed in the free-floating forms.

A. linnaei has been known to produce zoospores (with two flagella) very rarely under cultured condition, but the current study has verified that zoospore (with four flagella) formation occurs regularly in summer in the natural environment, albeit at a very low level. Since the formation of zoospore can lead to fragmentation of aggregates, the low percentages of produced zoospores appear to maintain the aggregative form, the marimo. This is a breakthrough in the understanding of the formation of marimo. However, this work was unable to verify the presence of zoospores with two flagella; confirming their formation and their role in the life cycle are vital.

Isamu Wakana is an acknowledged expert on the subject of marimo. He is currently a Technical Committee Member of the Kushiro International Wetland Centre, where his expertise is critical to the conservation of marimo in Lake Akan.

The Bolson tortoise (Bolson Gopherus flavomarginatus) is the largest land reptile in North America. It lives mainly in dry areas, in particular, in the Chihuahua desert in northern Mexico. In recent decades, its numbers have fallen by 50%, driving the International Union for Conservation of Nature to include it on its red list and it has been classified as endangered. Land tortoises are prone to suffering from a wide range of diseases that can deplete their numbers even more, therefore understanding potential pathogenic organisms could help in advancing conservation strategies.

This was the task set for a research team made up of members from different universities and Mexican entities, including Zoology Professor Francisco Sánchez Tortosa from the University of Córdoba, given his knowledge and experience in conservation biology. Specifically, in this research study, published in Biology, the bacteria present in Ornithodoros turicata ticks were analyzed. These ticks are parasites on tortoises and can transmit diseases to them.

In order to carry out the research, 45 Bolson tortoises were captured at the Mapimí Biosphere Reserve in Mexico, out of which 11 had ticks on their shell or their skin. 17 adult ticks were collected to analyze the bacteria they carried, by means of next generation sequencing.

In the analyses, a large number of potentially pathogenic bacteria was found. This could be due to the large variety of guests found on these kinds of ticks that act as hosts. These live in the big burrows built by the tortoises and used by other animal species such as rodents, birds and other reptiles, that they are parasites on as well.

Among the most numerous bacteria detected are Proteobacteria, Actinobacteria and Firmicutes. Of these, two documented bacteria were registered as pathogens, Mycoplasma spp and Pasteurella testudinis. In addition, A. marginale pathogenic bovine bacteria and A. kovis pathogenic ovine bacteria were detected, as well as A. phagocytophilum, Coxiella burnetii and Neoehrlichia sp zoonoctic bacteria.

According to Professor Francisco Sánchez Tortosa, these results could be interpreted in two ways. On the one hand, this research could lead us to believe that these ticks, and in turn these tortoises, carry diseases that could spread to other animal species, such as livestock, and ultimately, to humans. "That would be an erroneous and catastrophic interpretation as it could lead to a campaign against it that could end in this species's extinction", he asserts.

On the other hand, his vision is more optimistic. "Jumps from one species to another are very uncommon. Now we have this information, but these pathogens have been living with all the other fauna for thousands of years and nothing has ever happened. If we were to perform this research with other animal species, we would surely find similar results. This research is simply a tool in order for us to better understand natural processes and help conserve this species of tortoise, not the other way around", he explains.

The tortoises with parasites did not show evident signs of disease, so further research is needed to understand the tortoises' defense mechanisms against diseases that can be transmitted by ticks, and their characteristics as guests.

A study by University of Tartu researchers indicates that the sensitivity of tests used to detect viral antibodies in a blood sample may differ significantly. The combination of several tests may give the best result.

At the onset of COVID-19 symptoms, first, the nasopharyngeal swab is taken to verify the presence of the virus. But if the aim is to determine whether an asymptomatic person has been in contact with the virus or, vice versa, to know which acute disease the person recently suffered from, a test detecting antibodies in a blood sample comes helpful.

Antibodies are produced in the human body as a counteraction to viral proteins to prevent the virus from replicating and spreading in the body. Usually, it takes a couple of weeks after infection for the antibodies to emerge. Different parts of the virus induce the development of different antibodies. In the case of coronavirus, for instance, there can be antibodies against the spike protein of the virus, against the proteins of the receptor binding domains as well as against the nucleocapsid.

Different types of antibodies are produced, but the IgG antibodies stay in the body for the longest. "When we ever suffer from a disease, usually the IgG antibodies are the ones to stay in our body," explained Epp Sepp, Senior Research Fellow in Medical Microbiology at the University of Tartu, one of the authors of the article published in Plos One.

One use for tests detecting viral antibodies in a blood sample is in large studies trying to ascertain the percentage of the population that has been exposed to the virus. This was also done in spring in the pilot seroepidemiological study in Estonia led by the University of Tartu.

To detect antiviral antibodies, tests are used that detect the presence of antibodies to different proteins or their combinations. There are now hundreds of coronavirus antibody tests, which, unfortunately, are not universally suitable for all patients.

Test sensitivity varies significantly

The study was conducted in cooperation between the University of Tartu, Synlab and Kuressaare Hospital in Saaremaa (Saaremaa is the island in Estonia with the biggest corona outbreak during the first virus wave - editor remark). In the study nine coronavirus antibody tests that were most widely used during the outbreak in spring were analysed. Seven of them were by major producers and two were laboratory tests developed at the University of Tartu by the research group led by Professor Pärt Peterson.

The study involved 97 patients from Saaremaa with a confirmed case of COVID-19. The IgG antibodies to coronavirus were determined by nine tests and the test results were compared based on the patients' symptoms (cough, headache, tiredness, difficulty breathing, diarrhoea, etc.) and the time between the onset of the disease and the antibody test. The majority of studied patients had COVID-19 symptoms, except for about one fifth of them.

The study revealed that in general, the sensitivity of the tests was lower than the producers had stated. As was expected, the rapid test included in the study at the request of the Health Board had the lowest sensitivity.

In half of the patients, all nine antibody tests gave a positive result. In two patients, none of the tests detected coronavirus antibodies. This implies that antiviral antibodies might not even emerge in some COVID-19 patients. For the rest of the patients, the test results varied. Analysis of the correlation of the results indicated that in some patients, the prevailing antibodies were those against the nucleocapsid while in others antibodies against the spike protein prevailed.

Finding a reliable combination is crucial

Some tests worked equally well for asymptomatic patients and those with many symptoms. In the case of some tests, the results were highly dependent on the time of taking the sample and the number of symptoms. For instance, for some tests, the positivity rate in asymptomatic COVID-19 cases was about two times lower than in polysymptomatic ones. The best diagnostic sensitivity in detecting antibodies was achieved by combining several antibody tests, for instance, a test detecting antibodies to the spike protein with the test detecting antibodies to the nucleocapsid.

"In the everyday work of Synlab, we are using the Abbott test that is sensitive to antibodies to the nucleocapsid. If that gives a borderline negative result in a patient, we will analyse this sample again using another test sensitive to antibodies to the spike protein. If the result is positive, we will trust that. My experience has shown that antibodies to the nucleocapsid disappear faster and antibodies to the spike protein last for longer," explained the lead author of the study Paul Naaber, Senior Research Fellow in Medical Microbiology at the University of Tartu.

According to researchers, there is no one perfect test that works well in all cases. To get the most reliable result, the tests may need to be combined. "This is a very important piece of knowledge for planning major seroepidemiological studies. Our analysis showed that had we relied solely on the information written on the package by the producer, the studies in which the tests were used could have led to a completely different result. In spring, only a few published studies had compared tests, so we took it upon ourselves. Objective measurements indicate that test sensitivity may be significantly lower than stated on the package," Naaber explained.

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."