Culture

Diseases with a genetic cause could, in theory, be treated by supplying a correct version of the faulty gene. However, in practice, delivering new genetic material to human cells is difficult. A promising method for the delivery of such genes involves the use of DNA/lipid complexes (lipoplexes). Scientists at the University of Groningen have now used advanced simulations to investigate how these lipoplexes deliver DNA fragments into cells. The results, which were published in the journal eLife on 16 April, can be used to improve their efficiency.

The idea behind gene therapy is very simple: if a disease is caused by a particular version of a single gene, it could be cured by replacing this gene. For example, in cystic fibrosis, a mutation in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes the disease. Replacing it in mucosal cells with a copy that does not carry the mutation could reverse this.

Lipoplexes

However, our bodies are very good at destroying foreign DNA, so delivering a new gene inside a cell is difficult. Viruses are very good at delivering genetic material into cells, but they can also trigger the body's defences, creating an immune response that can make the patient sick and that in rare cases has even proved lethal. That is why scientists are now experimenting with lipid-based complexes, which are similar to cell membranes.

'These lipoplexes are taken up by cells in a structure called an endosome,' explains Bart Bruininks, a PhD student in the group of Siewert-Jan Marrink, Professor of Molecular Dynamics at the University of Groningen. Bruininks is the first author on the eLife paper. 'The problem is that endosomes digest material, so the DNA needs to escape quickly,' he explains. The lipoplex can fuse with the endosome membrane, allowing the DNA to enter the cell. 'This should happen as efficiently as possible to prevent degradation. That is why we want to know exactly how the lipoplex and the endosome membrane interact.'

Water channels

Studying this interaction through experiments is difficult. That is why Bruininks and his colleagues decided to simulate the interaction. 'Our group already has extensive experience in simulating membrane fusion.' Using a coarse grain molecular dynamics simulation, the fusion process between the lipoplex and the endosome membrane was visualized, as well as the subsequent escape of the DNA. 'These were very complex state-of-the-art simulations,' says Bruininks.

The lipoplex contains tiny water channels that contain the DNA. The lipids of the lipoplex fuse with the endosome's membrane. 'The lipids form a stalk-like connection and when both layers are fused, a pore opens up that connects the water channels to the cell's interior, allowing the DNA to escape,' says Bruininks. 'This picture of how the process works at the molecular level helps us to understand how to optimize it.' He predicts that poly-unsaturated fatty acids will speed up the fusion, allowing the DNA to escape into the cell's cytoplasm more quickly. 'This prediction could now be tested in the lab.'

Simple Science Summary

Some diseases that are caused by an error in a gene could be cured by inserting a properly functioning gene into the cells. However, placing new genes inside human cells is difficult. Viruses are efficient in shuttling genes into cells, but they can cause a dangerous immune response. That is why scientists are interested in using liposome complexes (lipoplexes), which are similar to cell membranes, as gene carriers. Scientists at the University of Groningen have now used advanced computer simulations to investigate how lipoplexes enter the cell and how they release the genes that they carry into the cells. The results will help them to optimize this process.

LAWRENCE, KANSAS -- David Slusky keeps hearing the same comments from other parents who are isolating with young children.

"They're telling their kids, 'Please don't do gymnastics on the stairs because this is not the week I want to take you to the hospital!' Many of us are trying to both avoid getting COVID-19 and anything that might send us to the hospital," said Slusky, associate professor of economics at the University of Kansas.

He believes Americans have now been reminded how dangerous this situation is ... even without a pandemic exacerbating matters.

"Because errors can happen or infections or complications, you don't want to be in a hospital unless you really need to be in one," he said. "I'm not recommending people set up ICUs in their garage. But if you have a condition where you can see a primary care provider and not go to the ER, that's ideal."

That's also the contention of his latest paper, "Office Visits Preventing Emergency Room Visits: Evidence from the Flint Water Switch," distributed by the Institute of Labor Economics.

Co-written with Shooshan Danagoulian and Daniel Grossman, the research looks at the infamous case of Flint, Michigan. In 2015, the city issued an advisory alerting residents to increased lead in drinking water after its water source was switched from Lake Huron to the Flint River. The result was thousands of children exposed to potentially toxic levels of lead, along with exposing a governmental conspiracy that led to 15 criminal indictments.

Slusky's analysis suggests that children were more likely to receive care from the same clinic following lead tests. Establishing such care reduced the likelihood parents would take them to emergency rooms for conditions treatable in an office setting.

"This is not only a paper about Flint," Slusky said.

"This is also a paper about overuse of the emergency room, and specifically overuse of the emergency room in a low-income population. These people are often the least medically connected, with the least time and least education to manage these kinds of complex problems."

His team used an algorithm created by New York University physicians that takes hospital discharges and categorizes them broadly into four categories: unpreventable emergencies, preventable emergencies, conditions requiring office visits and conditions that will resolve themselves.

"We use that to think about the number of avoidable visits happening in this diagnosis," he said.

In Flint, building a relationship with a primary care physician proved vital to the decision of whether parents would take their children to the ER for something that might be noncritical (such as high fever or diarrhea).

He said, "In a town where the emergency manager and governor misled you, the only person who took you seriously that your kid might be sick was your physician. So maybe you'll go to the doctor more now."

The connection between primary care and emergency care -- especially for those with low incomes -- is particularly relevant to the current pandemic.

"Ideally, we don't want individuals who don't need to be there in the emergency room, especially to keep them from infecting others or getting infected themselves. As we increase testing capacity and try to test more of the population and get them back to work, an established and stronger relationship with a primary care provider is crucial," he said.

A KU faculty member since 2015, Slusky specializes in the economics of infrastructure, environment and insurance. Much of his research has addressed the dilemma of lowering health care spending while raising health.

"Right now we're not getting great stuff and we're spending a lot. Giving people health insurance doesn't actually save money, though it is a very good way to get them healthy. So part of this is changing what we care about. And part of it is giving people a broader menu of options, so you can call a nurse at two o'clock in the morning instead of just heading to the ER."

Ultimately, Slusky believes the Flint study can help the health care industry examine a variety of different policies so that parents can determine the best way - both medically and financially -- to help their sick children.

"We need to save our emergency resources for when we actually need them," he said. "And we need to ensure people are aware of and comfortable with other options so they only use emergency resources when needed."

Scientists have understood quite well why so many poisonous or distasteful animals have brightly colored bodies - the colors send a message to the predators: "don't eat me, or you'll get sick and die." These permanent warning signals became textbook examples of "aposematism": use of conspicuous signals to warn predators. But not all animals show their warning colors all the time. Some toxic animals actually hide the warning colors, showing them only at the very last moment when they are about to be attacked (thus called "switchable aposematism"). Also, some other prey animals never advertise their distastefulness and defend themselves after attack only by chemicals creating a perception of bad taste in the predators. Scientists do not fully understand the reasons for such a diversity of prey behaviors.

In a recent report in PeerJ, a Korean-Polish team composed of Woncheol Song and Piotr Jablonski from the Seoul National University and Polish Academy of Sciences, and Sang-im Lee from DGIST, has presented the first comprehensive computer simulation (ApoSim) to understand the evolution of the diversity of warning signals. The ApoSim model interface was built within a user friendly NetLogo framework and it can be used by anyone interested in simulation of biological evolution. A you tube video shows an example of how changing the predator learning speed may change the evolutionary outcome.

According to Dr. Woncheol Song, evolutionary biologists have paid disproportionate attention to the permanent aposematism. "It is relatively easy to understand why poison dart frogs have yellow color, giant hornets have bright orange-and-black stripes, etc. These animals gain the benefits of constantly warning the predators to avoid being eaten, but also increase the chance of detection by predators that are not deterred by the poison. However, when prey have choices to either show or hide the warning signal and of when to do it, it is not a simple matter. You need to weigh the costs and benefits of how and when to present the warning signals," points out Dr. Song.

The integration of the extremely diverse forms of animal behavior into one framework was not easy. "A praying mantis posturing to strike, a rattlesnake producing the alarm sound, a ladybug releasing foul-odored hemolymph, a cuttlefish flashing like a neon-sign, and a skunk raising its striped tail - their messages are all the same, to tell you stay away from them. But they are also different from each other in countless ways. However, if you want to conduct theoretical studies with them, you have to put them in the same formula. It is like doing sums of apples and oranges while convincing other scientists that it is a good idea," Dr. Song recalls the difficulty of model-building process. The researchers considered energy costs, timing, anatomy and physiology, detectability, memorability, and many other properties of prey aposematic behaviors, as well as predators' learning processes. Finally, the authors successfully created a simplified artificial digital world that reasonably captures the diversity of permanent and switchable aposematism, and can be used by anybody without prior programming experience.

The model was run over 88 thousand times in order to find out which aposematic behavior is the best depending on how fast the predators are learning, how high is the proportion of predators that have not yet learned to avoid the defended prey, how easy it is to detect a prey, how easy it is to detect a prey after the warning is displayed and the signal intensity is increased, how hard it is for the prey to develop and keep the ability to switch signals. The outcome of the simulations brought new discoveries as well as confirmed some of the already existing ideas. For example, one may argue that there are multiple types of predators in the ecosystem. If some predators are not deterred by the warning and attack the prey anyway, the prey may be better protected by withholding the warning to avoid detection by those predators. This is but one simple example that can be visualized and understood by using the new model.

"We have not only demonstrated that the predator mix can drive the evolution of switchable aposematism, but we have also evaluated several other equally-compelling hypotheses, all of them interacting in a five-dimensional parameter space defined by properties of prey and predators. There have been many ideas published since the time of Darwin, but only a few of them have been thoroughly examined. Now, each of them can be explored in the digital world provided in this model, and the model results can be integrated with findings made in nature, like the recent studies conducted by us on the spotted lanternfly [https://www.eurekalert.org/pub_releases/2016-05/lobe-wda051916.php; https://www.eurekalert.org/pub_releases/2019-02/lobe-yaw020819.php]," Dr. Piotr Jablonski commented when asked about the importance of the new "ApoSim" model's availability to the research community. "The model will also serve as a new educational tool in teaching evolution," added Dr. Sang-im Lee, whose experience in undergraduate teaching of evolution in Korea indicated the need for new educational tools.

For years, speculation about the poor quality of vital agricultural supplies in the African nation of Uganda has focused on questions of deliberate tampering with products - adding rocks to bags of seed in order to charge more money for the heavier product, for instance. But in a recent publication, two UConn researchers found no evidence of deliberate adulteration - but plenty of proof that mismanagement and inadequate infrastructure pose a significant problem for Ugandan farmers.

"For whatever reason, there's very little research in Africa on the food supply chain," says Nathan Fiala, Assistant Professor in UConn's Agricultural and Resource Economics department. Part of Fiala's work has been aimed at improving our understanding of these supply chains, so when an organization contacted him and co-author and PhD student Alicia Barriga to further investigate this concerning trend, they were eager to learn more.

Barriga explains that in Uganda, as in some other Sub-Saharan African and developing countries elsewhere, small-scale farmers rely on agriculture for subsistence. The local government and non-governmental organizations (NGOs) have made efforts to improve agricultural technology and production to ultimately reduce hunger. Overall food security has improved in Uganda, yet it remains uneven across the country, and there are vulnerabilities, especially in regards to weather and internal conflict, says Barriga. For example, in 2019 several districts reported acute an food crisis due to heavy rain, pests, and diseases.

Fiala says that Uganda's supply chain is an interesting one to study because food security and food insecurity are so evident in the country.

"People in Uganda don't eat three meals a day seven days a week generally," he says. "We see lots of skipping of meals, and people oftentimes only eat one or two times a day, generally due to food insecurity and poverty."

In the fertile land of Uganda, Fiala says, you can plant seeds pretty much anywhere and the seeds will grow. Despite this, food productivity remains low, and previous studies revealed discrepancies in the quality of agricultural supplies like seeds and fertilizers.

Agricultural inputs like seeds, fertilizers, and herbicides oftentimes show signs of corruption from other materials. Barriga says that seeds, for example, can be mixed with rocks, dirt, or sand in order to bulk the bags up.

Fiala explains that authors of previous studies surmised the discrepancies were due to adulteration of the product, and as often happens, people jumped to the conclusion that the supplies were being purposefully corrupted. This explanation prevails despite lack of evidence of tampering.

To investigate these claims, Fiala and Barriga sampled along the seed supply chain in a method called a "mystery shopper approach" from seed sellers all the way to the farmer. The seeds were then tested for purity, germination, rigor, and DNA similarity. What they found was surprising.

"We found absolutely no evidence of adulteration. What it looks like is that along the supply chain the materials are being handled improperly. The discrepancies we see in the quality of the supplies is likely due to mismanagement," says Fiala.

"For example, if you get a bag of fertilizer and throw it into the back of a truck and transport it to the north of the country where it's hot and you don't have a refrigerated truck, the fertilizer can lose half its nitrogen. This loss is just through transportation, not adulteration."

The mishandling of the supplies is not malicious or deliberate -- these supplies are being handled this way because there is simply no infrastructure in place to handle them properly. For instance, access to refrigerated trucks or buildings may be minimal or non-existent.

"We use the words 'corruption' and 'adulteration' when we don't really know what that is, and it is hard to distinguish deliberate actions from just incompetence and mismanagement," he says. "When researchers say corruption they are combining corruption and mismanagement together."

Fiala also points out that there remains a market for fertilizer and seed. If the supplies were all bad, it is reasonable to conclude the market would have disappeared.

"The answer is the supplies are not that bad on average but there is high variation, which can be bad news if you are a farmer," he says.

Though this research could have major policy implications, Fiala says it is unlikely to lead to efforts in the near term to improve the supply chain and food security for Ugandan citizens anytime soon.

"I have spoken to the Ugandan government about this and they are really interested in this work but they have no money and there is no political will to react," he says. "The economic return to government is low, and focus is on things like manufacturing and economic growth. Most people don't see the last-mile farmer as a way to improve growth. This will probably only get worse due to the COVID-19 crisis."

Washington, DC - April 17, 2020 - Genetic variability in the human immune system may affect susceptibility to, and severity of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease (COVID-19). The research is published today, April 17 in the Journal of Virology, a publication of the American Society for Microbiology.

Individual genetic variation may explain differences in the strength of immune responses. Certain immune system genes, called human leukocyte antigen genes that are involved in recognizing pathogens, vary from person to person. Variations can influence how well the immune system recognizes a given pathogen. Poor recognition of SARS-CoV-2 could cause a person to be more vulnerable to the virus.

"In particular, understanding how variation in HLA [a component of the immune system containing multiple genes] may affect the course of COVID-19 could help identify individuals at higher risk from the disease," according to the authors of the new study.

The authors show that individual HLA, haplotype, and full genotype variability likely influence the capacity to respond to SARS-CoV-2 infection, and note that certain alleles in particular could be associated with more severe infection, as has previously been shown with SARS-CoV.

"This is the first study to report global distributions of HLA types and haplotypes with potential epidemiological ramifications in the setting of the current pandemic," write the authors, from Oregon Health & Science University, Portland, and the Portland VA Research Foundation.

"HLA typing can be fast and inexpensive," the authors write. "Pairing HLA typing with COVID-19 testing where feasible could improve assessment of viral severity in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination."

The genetic material--DNA-- of plants and animals (within the latter humans) is stored inside the cell, and DNA packing is guaranteed by proteins called histones. Furthermore, histones play a key role in regulating the activation of gene expression and its timing: a given stimulus modifies a histone, making it allow or repress the expression of a gene. The Cell Signaling laboratory at IRB Barcelona, ??led by Eulàlia de Nadal and Francesc Posas, has identified more than 200 regions (amino acids) in histones that, under cellular stress, undergo modifications to regulate the response to this condition.

Also, they have observed that stress of distinct nature, such as that caused by excess heat or salinity, leads to different histone modifications, thereby pointing to a "personalized" adaptation response to each type of stress. The study has been carried out on the yeast Saccharomyces cerevisiae, a model organism widely used in biomedicine.

"The histone modifications that regulate gene expression under normal conditions are being widely studied," says Eulàlia de Nadal. "However, little was known about the role of histones in responses to cellular stress, which have to be rapid and highly dynamic. Information about this role is important because the regulation of histones is associated with a wide range of diseases," she concludes.

Details about the modifications: heat and salt stress

Histones can undergo distinct modifications through the addition of different chemical groups. As well as identifying the key points of the amino acid sequence at which the modifications take place, the group of researchers has described in detail some of the modifications that occur in response to salt and heat stress. They have provided details of the modification, how it occurs and how it influences gene regulation.

On the basis of these results, the laboratory is to develop two lines of research. On the one hand, the researchers will address other specific modifications that occur in response to stress. And, on the other hand, to understand which mechanisms are relevant in different diseases, they will study how these modifications correlate with those that take place in human cells.

Two new species of viruses have been identified in blood samples taken from patients in Brazil's northern region who had similar symptoms to those of dengue or Zika, such as high fever, severe headache, rash and red skin spots. One belongs to the genus Ambidensovirus and was found in a sample collected in the state of Amapá. The other belongs to the genus Chapparvovirus and was found in blood from the state of Tocantins. The study was supported by São Paulo Research Foundation - FAPESP. The results are published in the journal PLOS ONE.

"What surprised us most was finding an Ambidensovirus in a human sample. Viral species in this genus have been described only in insects, shellfish and other invertebrates. Never in mammals," said Antonio Charlys da Costa, a postdoctoral fellow at the University of São Paulo's Medical School (FM-USP) and one of the authors of the study.

According to Costa, different species of Chapparvovirus have been described in other mammals but, again, never in humans. "However, we don't yet know whether these viruses were active in the patients, let alone whether they caused the symptoms," he told.

For Eric Delwart, a senior investigator at the Vitalant Research Institute in the United States and supervisor of the project, scientists can use these findings to investigate whether novel viruses are present in other people in the region or in other populations and whether there is a risk of dissemination.

"So far no evidence has been found that these viruses have spread or that they're pathogenic," Delwart said. "However, it's scientifically interesting that Ambidensovirus has been detected in human hosts. The discovery shows how little we know about the ability of certain viruses to infect different kinds of cells."

Delwart also stressed the importance of reanalyzing existing clinical samples in epidemiological studies of potential emerging viruses. In the study discussed here, the samples analyzed were originally collected by central public health laboratories (LACENs) in several states across Brazil as part of their routine surveillance activities.

Viral diversity

The identification of the new species was possible thanks to a technique known as metagenomics, which entails the concomitant sequencing of all the genetic material in an entire blood, urine, saliva or fecal sample, including each of the microbes that exist within it. The technique can also be used, for example, to study all the bacteria and fungi in the soil of a region or to map the different species in a person's gut microbiota. Once all the nucleic acids in a sample have been extracted and sequenced, bioinformatics tools are used to compare the results with known genome sequences described in databases.

Costa learned the methodology during his PhD research, while he was on an internship at Delwart's laboratory. The supervisor in Brazil was Ester Sabino, a professor at FM-USP who headed the university's Institute of Tropical Medicine (IMT-USP) between 2015 and 2019.

The PLOS ONE article reports the results of analyses of 781 samples collected between 2013 and 2016. Anelloviruses were found in 80% of patients, while 19% contained type 1 human pegiviruses (HPgV-1). Neither genus is thought to cause significant pathologies. In 17%, the researchers detected parvovirus B19, which causes erythema infectiosum (slapped cheek syndrome or fifth disease), a common childhood ailment characterized by a mild fever and rashes on the face, arms, legs and trunk.

The viral species that had never been described, both belonging to the family Parvoviridae, were found in only two of the samples. The plasma samples were provided by the LACENs for Amapá, Tocantins, Paraíba, Maranhão, Mato Grosso do Sul, Piauí and Maranhão states.

"The study continues, and altogether we've received 20,000 samples for analysis. They send us samples that test negative for dengue, Zika and chikungunya. In our lab at IMT-USP, we perform molecular tests to detect other known flaviviruses [which cause yellow fever or West Nile fever, for example], alphaviruses [including Mayaro virus and several species that cause encephalitis] and enteroviruses [which can cause respiratory diseases and hand-foot-and-mouth syndrome, among others]. If we find none, we move on to the metagenomic analysis," Costa said.

The aim of the project, he added, is to describe the viral diversity found in Brazil and identify species that may be causing diseases in humans unnoticed amid outbreaks of disease caused by arboviruses.

A study published in the journal Clinical Infectious Diseases in 2019, for example, reported on a hidden outbreak of parvovirus B19 during a dengue epidemic in 2013-14. The principal investigator was the virologist Paolo Zanotto, a professor at the University of São Paulo. The study was supported by FAPESP.

"This is a significant case from a public health standpoint. If it infects pregnant women, parvovirus B19 can cause severe problems in their fetuses," Costa said.

Next steps

Further detailed studies will be required to determine whether the two novel viruses described are a human health hazard.

"We tried and failed to infect cell cultures in the lab, either because these viruses don't infect the type of cell used in the experiment or because the viral particles contained in the samples we analyzed were no longer viable. We don't know," Costa said.

However, the group obtained a second sample of the virus identified in the patient from Tocantins (a chapparvovirus) and is now developing a serological test. "The idea is to see whether this patient and their family have antibodies against this microorganism, in which case they were infected in the past and produced a response against the virus," Costa said.

Researchers at the University of Illinois at Urbana-Champaign have used molecular dynamics simulations to understand how sodium dodecyl sulfate causes protein unfolding. SDS is commonly used in labs to separate proteins and determine their molecular weights. However, it is still unclear how SDS influences protein structure.

The paper "Protein unfolding by SDS: the microscopic mechanisms and the properties of the SDS protein assembly" was published in Nanoscale.

"Our study uncovered the microscopic details of how these interactions occur in several millionths of a second," said David Winogradoff, a postdoctoral research associate in the Aksimentiev group. "We were physically representing every single atom that was present in the system, and we did it at high temperatures to speed up the process of SDS binding to the protein as well as the unfolding."

The researchers used several supercomputers to create simulations of the SDS-protein interactions. "Using these different supercomputers we were able to complete our studies over the period of a week instead of a year," said Aleksei Aksimentiev, a professor of biological physics and a faculty member of the Beckman Institute for Advanced Science and Technology.

The simulations helped them to understand how SDS causes protein unfolding and to what extent the proteins unfold. "Our studies show that there are areas of proteins that are exposed and areas that are wrapped around SDS, like beads on a string," Aksimentiev said.

Although the simulations provide detailed insights into the interactions, they were too short to probe the balance between the SDS bound to the unfolded proteins and the SDS dissolved in the surrounding solution. "The molecular dynamics method allows us to provide fine molecular details that are inaccessible to other techniques," Winogradoff said.

"SDS has been used for a long time. Our study enables new applications of SDS as an unfolding agent to facilitate protein sequencing," Aksimentiev said. "We want to know how the SDS molecules are arranged on the proteins so that we can drive these chains through a nanopore and read the sequence."

For millennia, metallurgists have been meticulously tweaking the ingredients of steel to enhance its properties. As a result, several variants of steel exist today; but one type, called martensitic steel, stands out from its steel cousins as stronger and more cost-effective to produce. Hence, martensitic steels naturally lend themselves to applications in the aerospace, automotive and defense industries, among others, where high-strength, lightweight parts need to be manufactured without boosting the cost.

However, for these and other applications, the metals have to be built into complex structures with minimal loss of strength and durability. Researchers from Texas A&M University, in collaboration with scientists in the Air Force Research Laboratory, have now developed guidelines that allow 3D printing of martensitic steels into very sturdy, defect-free objects of nearly any shape.

"Strong and tough steels have tremendous applications but the strongest ones are usually expensive -- the one exception being martensitic steels that are relatively inexpensive, costing less than a dollar per pound," said Dr. Ibrahim Karaman, Chevron Professor I and head of the Department of Materials Science and Engineering. "We have developed a framework so that 3D printing of these hard steels is possible into any desired geometry and the final object will be virtually defect-free."

Although the procedure developed was initially for martensitic steels, researchers from the Texas A&M said they have made their guidelines general enough so that the same 3D printing pipeline can be used to build intricate objects from other metals and alloys as well.

The findings of the study were reported in the December issue of the journal Acta Materialia.

Steels are made of iron and a small quantity of other elements, including carbon. Martensite steels are formed when steels are heated to extremely high temperatures and then rapidly cooled. The sudden cooling unnaturally confines carbon atoms within iron crystals, giving martensitic steel its signature strength.

To have diverse applications, martensitic steels, particularly a type called low-alloy martensitic steels, need to be assembled into objects of different shapes and sizes depending on a particular application. That's when additive manufacturing, more commonly known as 3D printing, provides a practical solution. Using this technology, complex items can be built layer by layer by heating and melting a single layer of metal powder along a pattern with a sharp laser beam. Each of these layers joined and stacked creates the final 3D-printed object.

However, 3D printing martensitic steels using lasers can introduce unintended defects in the form of pores within the material.

"Porosities are tiny holes that can sharply reduce the strength of the final 3D-printed object, even if the raw material used for the 3D printing is very strong," said Karaman. "To find practical applications for the new martensitic steel, we needed to go back to the drawing board and investigate which laser settings could prevent these defects."

For their experiments, Karaman and the Texas A&M team first chose an existing mathematical model inspired from welding to predict how a single layer of martensitic steel powder would melt for different settings for laser speed and power. By comparing the type and number of defects they observed in a single track of melted powder with the model's predictions, they were able to change their existing framework slightly so that subsequent predictions improved.

After a few such iterations, their framework could correctly forecast, without needing additional experiments, if a new, untested set of laser settings would lead to defects in the martensitic steel. The researchers said this procedure is more time-efficient.

"Testing the entire range of laser setting possibilities to evaluate which ones may lead to defects is extremely time-consuming, and at times, even impractical," said Raiyan Seede, a graduate student in the College of Engineering and the primary author of the study. "By combining experiments and modeling, we were able to develop a simple, quick, step-by-step procedure that can be used to determine which setting would work best for 3D printing of martensitic steels."

Seede also noted that although their guidelines were developed to ensure that martensitic steels can be printed devoid of deformities, their framework can be used to print with any other metal. He said this expanded application is because their framework can be adapted to match the observations from single-track experiments for any given metal.

"Although we started with a focus on 3D printing of martensitic steels, we have since created a more universal printing pipeline," said Karaman. "Also, our guidelines simplify the art of 3D printing metals so that the final product is without porosities, which is an important development for all type of metal additive manufacturing industries that make parts as simple as screws to more complex ones like landing gears, gearboxes or turbines."

AUSTIN, Texas -- After a wild couple of months of equity market volatility, many mutual fund investors are now cautiously exploring how best to rebalance their portfolios. As they do so, new research from the McCombs School of Business at The University of Texas at Austin says they should keep an important factor in mind: taxable capital gains.

McCombs finance professor Clemens Sialm compared tax burdens and mutual fund performance in a new study published in the April 2020 issue of The Journal of Finance. The results showed a direct correlation in tax rates and performance, indicating that tax-efficient funds provide higher gains for investors and, therefore, more income for shareholders.

"The average equity mutual fund generates quite a bit of tax burden," Sialm said. "Most investors don't consider taxes as much as they should. So, in the coming months, as many investors make many portfolio adjustments meant to maximize their long-term objectives, they would be wise to rethink this issue," he said. "Harvesting losses can help offset future capital gain realizations, for example."

Short-term capital gains on stocks held for less than a year get taxed at rates as high as 37%. Holding stocks more than a year brings the top rate down to 20%.

"Often, it's fairly easy to avoid a higher tax rate on a capital gain," Sialm said. "If I've held a stock for 11 months, it's better to wait one more month to sell it."

In order to see whether minimizing taxes had negative effects on fund performance, Sialm and Hanjiang Zhang of Washington State University looked at U.S. equity mutual funds with more than $10 million in assets from 1990 to 2016. During that period, tax rates rose and fell between a high of 43% and a low of 15%. To calculate the bite taken by capital gains, the researchers used the rates in effect when a fund sold a stock.

What they found proved their theory. Low-tax funds actually outperformed the average fund, both before and after taxes. A 1.18% drop in a fund's tax burden boosted its return 0.55% before taxes and 0.99% after taxes.

"Tax-managed funds aren't sacrificing performance," Sialm said.

What made the tax-efficient funds do so well, Sialm found, is better all-around management. Funds that had lower tax burdens also displayed better stock-picking abilities. They also showed lower trading costs - presumably because they traded less often.

"They have a more sophisticated and more holistic approach," he said. "They take taxes and trading costs into account, and they have better stock-selection abilities."

Based on this research, fund shoppers should look at both fees and taxes when making decisions. The researchers said one way to tamp down taxes is to shop for certain kinds of funds - ones that tend to hold stocks for longer than a year:

Tax-managed funds, which reduce capital gains by balancing them against losses. Their after-tax returns were 0.81% better than similar funds that weren't tax managed.

Momentum funds, which buy stocks while they're rising and sell when they start to fall. "If you have a winning stock, you hold on to it longer," Sialm said. "If it's a losing stock, you sell it and take the capital loss."

Index funds, which try to match indexes like the Standard & Poor's 500. They hang onto a stock for as long as it's part of the index.

In a paper published in Science Advances, an international team of researchers have examined traits of marine megafauna species to better understand the potential ecological consequences of their extinction under different future scenarios.

Defined as the largest animals in the oceans, with a body mass that exceeds 45kg, examples include sharks, whales, seals and sea turtles.

These species serve key roles in ecosystems, including the consumption of large amounts of biomass, transporting nutrients across habitats, connecting ocean ecosystems, and physically modifying habitats.

Traits, such as how large they are, what they eat, and how far they move, determine species' ecological functions. As a result, measuring the diversity of traits allows scientists to quantify the contributions of marine megafauna to ecosystems and assess the potential consequences of their extinction.

The team of researchers - led by Swansea University's Dr Catalina Pimiento - first compiled a species-level trait dataset for all known marina megafauna to understand the extent of ecological functions they perform in marine systems.

Then, after simulating future extinction scenarios and quantifying the potential impact of species loss on functional diversity, they introduced a new index (FUSE) to inform conservation priorities.

The results showed a diverse range of functional traits held by marine megafauna, as well as how the current extinction crisis might affect their functional diversity.

If current trajectories are maintained, in the next 100 years we could lose, on average, 18% of marine megafauna species, which will translate in the loss of 11% of the extent of ecological functions. Nevertheless, if all currently threatened species were to go extinct, we could lose 40% of species and 48% of the extent of ecological functions.

Sharks are predicted to be the most affected, with losses of functional richness far beyond those expected under random extinctions.

Dr Catalina Pimiento, who led the research from Swansea University said:

"Our previous work showed that marine megafauna had suffered an unusually intense period of extinction as sea levels oscillated several million years ago. Our new work shows that, today, their unique and varied ecological roles are facing an even larger threat from human pressures."

Given the global extinction crisis, a crucial question is to what extent nature holds a back-up system. In the event of extinction, will there be remaining species that can perform a similar ecological role?

Dr John Griffin, a co-author on the study from Swansea University adds:

"Our results show that, among the largest animals in the oceans, this so-called "redundancy" is very limited - even when you roll in groups from mammals to molluscs. If we lose species, we lose unique ecological functions. This is a warning that we need to act now to reduce growing human pressures on marine megafauna, including climate change, while nurturing population recoveries."

Ionic channels -integral proteins in the cell membrane- are essential in several processes such as cardiac activity, nervous transmission, cell proliferation and the regulation of blood pressure. A study which has now been published in Science Advances describes for the first time the membrane traffic and association mechanisms of the Iks cardiac currents, a flow of potassium ions through ionic channels in the cell membrane which is decisive for the right cardiovascular function.

These molecular mechanisms that are related to the cardiac physiology have been characterized by a team of experts from the Laboratory of Molecular Physiology of the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB), under the supervision of Professor Antonio Felipe, from the Department of Biochemistry and Molecular Biomedicine.

Other participants in the study are experts from the Faculty of Medicine and Health Sciences and the Institute of Neurosciences (UBNeuro) of the UB; the August Pi i Sunyer Biomedical Research Institute (IDIBAPS); the Alberto Sols Biomedical Research Institute (CSIC-UAM); the Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV); the University of Exeter (United Kingdom) and the National Institute of Health in Bethesa (NHI).

Ionic channels: frontiers in cell membranes

Voltage-gate potassium channels (Kv) regulate the transmission of the nervous impulse and the potential of cardiac action through the passing of K ions across the plasmatic membrane that surrounds the cells.

The activity of these potassium channels is fundamental in processes related to the synaptic transmission, brain physiology and cardiac action potential. Although its physiological function seems to be clear in electric cells, "its role is uncertain in other type of cells that may be detected", notes Professor Antonio Felipe.

In particular, the Kv7.1 channel and its regulatory subunit KCNE1 generate the Iks current in the heart, an electrical flow that takes part in the repolarization of the heart tissue and intervenes in the QT interval of the cardiac action potential. When this interval is altered, long or short QT-, serious cardiac pathologies can appear (cardiac arrythmia, sudden death, etc.).

"Knowing the nature and functioning of these proteins is essential to understand, diagnose, and treat these pathologies, which represent a great social impact", notes Antonio Felipe.

Kv7.1-KCNE1 complex: unconventional processing mechanism

The new study describes how the Kv7.1 channel is placed in the cell membrane through an unknown and unconventional mechanism which involves an alternative route that avoids the classic route of Golgi apparatus, an organelle formed by a system of flattened cisterns in the cell cytoplasm. Also, the regulatory subunit KCNE1 follows a traditional processing mechanism through this cell organelle, which is related to the biosynthesis and transport of essential molecules for cell physiology.

The new study describes how the Kv7.1 (KCNQ1) channel and its regulatory subunit KCNE1 are related in specific dominions of the endoplasmic reticulum, a system formed by a complex network of membranes and related to the synthesis and transport of proteins.

These specialized dominions are located near the cell surface and are contact projections between the endoplasmic reticulum and the cell membrane (endoplasmic reticulum-plasma membrane junctions, ER-PM). ). These cell regions are assembly areas in the Kv7.1 channel (KCNQ1) with its regulatory subunit KCNE1 and are used as a previous step to the translocation of this protein complex to the plasmatic membrane so that this ionic channel develops its essential physiological function.

"This exclusive unconventional mechanism described in the new study explains the location of this ionic channel in specific regions of the cells in the cardiac muscle -such as T tubules- and its function in signalling pathways of calcium during the cardiac action potential", concludes Professor Antonio Felipe.

Abnormal levels of stress hormones such as adrenaline and cortisol are linked to a variety of mental health disorders, including depression and posttraumatic stress disorder (PTSD). MIT researchers have now devised a way to remotely control the release of these hormones from the adrenal gland, using magnetic nanoparticles.

This approach could help scientists to learn more about how hormone release influences mental health, and could eventually offer a new way to treat hormone-linked disorders, the researchers say.

"We're looking how can we study and eventually treat stress disorders by modulating peripheral organ function, rather than doing something highly invasive in the central nervous system," says Polina Anikeeva, an MIT professor of materials science and engineering and of brain and cognitive sciences.

To achieve control over hormone release, Dekel Rosenfeld, an MIT-Technion postdoc in Anikeeva's group, has developed specialized magnetic nanoparticles that can be injected into the adrenal gland. When exposed to a weak magnetic field, the particles heat up slightly, activating heat-responsive channels that trigger hormone release. This technique can be used to stimulate an organ deep in the body with minimal invasiveness.

Anikeeva and Alik Widge, an assistant professor of psychiatry at the University of Minnesota and a former research fellow at MIT's Picower Institute for Learning and Memory, are the senior authors of the study. Rosenfeld is the lead author of the paper, which appears today in Science Advances.

Controlling hormones

Anikeeva's lab has previously devised several novel magnetic nanomaterials, including particles that can release drugs at precise times in specific locations in the body.

In the new study, the research team wanted to explore the idea of treating disorders of the brain by manipulating organs that are outside the central nervous system but influence it through hormone release. One well-known example is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response in mammals. Hormones secreted by the adrenal gland, including cortisol and adrenaline, play important roles in depression, stress, and anxiety.

"Some disorders that we consider neurological may be treatable from the periphery, if we can learn to modulate those local circuits rather than going back to the global circuits in the central nervous system," says Anikeeva, who is a member of MIT's Research Laboratory of Electronics and McGovern Institute for Brain Research.

As a target to stimulate hormone release, the researchers decided on ion channels that control the flow of calcium into adrenal cells. Those ion channels can be activated by a variety of stimuli, including heat. When calcium flows through the open channels into adrenal cells, the cells begin pumping out hormones. "If we want to modulate the release of those hormones, we need to be able to essentially modulate the influx of calcium into adrenal cells," Rosenfeld says.

Unlike previous research in Anikeeva's group, in this study magnetothermal stimulation was applied to modulate the function of cells without artificially introducing any genes.

To stimulate these heat-sensitive channels, which naturally occur in adrenal cells, the researchers designed nanoparticles made of magnetite, a type of iron oxide that forms tiny magnetic crystals about 1/5000 the thickness of a human hair. In rats, they found these particles could be injected directly into the adrenal glands and remain there for at least six months. When the rats were exposed to a weak magnetic field -- about 50 millitesla, 100 times weaker than the fields used for magnetic resonance imaging (MRI) -- the particles heated up by about 6 degrees Celsius, enough to trigger the calcium channels to open without damaging any surrounding tissue.

The heat-sensitive channel that they targeted, known as TRPV1, is found in many sensory neurons throughout the body, including pain receptors. TRPV1 channels can be activated by capsaicin, the organic compound that gives chili peppers their heat, as well as by temperature. They are found across mammalian species, and belong to a family of many other channels that are also sensitive to heat.

This stimulation triggered a hormone rush -- doubling cortisol production and boosting noradrenaline by about 25 percent. That led to a measurable increase in the animals' heart rates.

Treating stress and pain

The researchers now plan to use this approach to study how hormone release affects PTSD and other disorders, and they say that eventually it could be adapted for treating such disorders. This method would offer a much less invasive alternative to potential treatments that involve implanting a medical device to electrically stimulate hormone release, which is not feasible in organs such as the adrenal glands that are soft and highly vascularized, the researchers say.

Another area where this strategy could hold promise is in the treatment of pain, because heat-sensitive ion channels are often found in pain receptors.

"Being able to modulate pain receptors with this technique potentially will allow us to study pain, control pain, and have some clinical applications in the future, which hopefully may offer an alternative to medications or implants for chronic pain," Anikeeva says. With further investigation of the existence of TRPV1 in other organs, the technique can potentially be extended to other peripheral organs such as the digestive system and the pancreas.

Annals of Internal Medicine News
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Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.
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SARS-CoV-2 Isolation from Ocular Secretions of a Patient With COVID-19 in Italy With Prolonged Viral RNA Detection
Researchers from the National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy present the early detection of infectious SARS-CoV-2 in ocular fluids from the first confirmed Covid-19 case in Italy. Read the full text: http://annals.org/aim/article/doi/10.7326/M20-1176.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Concetta Castilletti, PhD, can be reached through Salvatore Curiale at salvatore.curiale@inmi.it.
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MISSOULA - The edge. Every athlete, from the professional to the weekend warrior, strives to obtain that ever-elusive element that leads to victory - sometimes sparing no expense to get there.

A lighter bike, a better training regimen, the newest shoes.

A recently released study from the University of Montana, however, has discovered that common "edge," sports nutrition products, are no more effective at promoting recovery in female athletes as regular, carbohydrate-rich, often less-expensive potato-based foods.

"Athletes are vulnerable to strategic marketing. We are easily swayed," said UM Research Professor Brent Ruby, a veteran endurance athlete who knows all too well the allure of sports powders and gels.

As director of UM's Montana Center for Work Physiology and Exercise Metabolism, Ruby and his team have done extensive work in the field of athletic performance and examining the role that post-exercise carbohydrate nutrition plays in the replenishing of spent muscle mass. The center's 2015 study that showed a McDonald's Happy Meal is just as effective for exercise recovery as commercial nutrition products garnered national attention.

Again, always the edge.

The difference in the latest study is the inclusion and focus on female recreational athletes.

"There's been a great deal of research into what sets the stage for muscle recovery after exercise," Ruby said. "But women have been poorly represented in these studies. It is common to only study men and then make broad recommendations, which is wrong."

With funding from the Alliance for Potato Research & Education, Ruby's team established and employed a study similar to the McDonald's research, this time looking at muscle recovery between male and female recreational athletes using potato products and sports supplements.

Eight men and eight women participated in the study, which involved 90 minutes of intense cycling followed by rest, recovery and refueling and a 20-kilometer time trial. After a lot of sweat was spent, blood drawn and muscles biopsied, the results showed that muscles in both men and women replenish carbohydrate stores similarly - and just as well with regular foods as with sports supplements.

Ruby hopes these new results - published in the European Journal of Applied Physiology - will help female athletes, as well as male, make better-informed choices about their refueling programs. This article is online at https://rdcu.be/b3zkg.

"Endurance athletes love to talk about how hard they train and how special their diet is," Ruby said. "But we need to take a deep breath. It doesn't have to be complicated. As long as you are getting adequate carbohydrates, your diet can be as diverse as you want it to be."