Culture

A new test that measures the quantity and quality of inactive HIV viruses in the genes of people living with HIV may eventually give researchers a better idea of what drugs work best at curing the disease.

Currently no cure exists for HIV and AIDS, but antiretroviral therapy drugs, or ARTs, effectively suppress the virus to undetectable levels.

Published today in Cell Reports Medicine, the study discusses how a new test, developed jointly by scientists at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, will give researchers, and eventually doctors, an easier way to gauge how much HIV virus might reside in a patient's genome.

This latent HIV reservoir results from HIV's integration into DNA, specifically in the chromosomes of T lymphocytes and macrophages, said Dr. Florian Hladik. He is the paper's senior author and a UW research professor of obstetrics and gynecology. Viral integration into the host cell genome is a unique feature of retroviruses, he added.

Current tests are complicated, expensive, and sometimes give inaccurate readings of viral load, said Hladik.  The two existing tests are done through sequencing the viral DNA from patient cells or inducing functional viral outgrowth in vitro from patient cell cultures. Both are time-consuming and expensive and do not lend themselves easily to the testing of new drug candidates to cure HIV.

"Our laboratory test is a simpler way to quantify the reservoir of intact viruses" he said.

The evaluation of novel therapies to cure HIV infection relies on repeatedly measuring the number of cells that contain HIV DNA before, during and after treatment. Current assays do not give this information quickly enough or with enough accuracy to be useful in future clinical trials.  And some of the assays require several blood draws from each patient-subject.

The test works by using a new type of assay that takes advantage of the multiplexing capacity of droplet digital polymerase chain reaction (ddPCR). It probes each isolated DNA molecule not only for the presence of integrated HIV DNA, but also to determine whether the viral DNA is intact or defective.  Commercial software and custom analyses are used calculate the number of T cells containing intact HIV DNA in the genome.

"This gives us a lot more information about the particular virus in a person's body than previous PCR assays," added Claire Levy, a UW research technologist in OB-GYN and the paper's lead author. Previous assays, she said, were only partway effective - like searching for someone's information online and learning only their first name. To continue that analogy, the new assay would yield more information, such as full name, age and height.

In the case of HIV, this extra information about the virus helps scientists understand how it is behaving in the human body.

Practically, this new PCR assay will help researchers determine the effectiveness of a drug candidate being tested against HIV/AIDS by closely tracking how many cells with intact HIV DNA exist after each dose, Levy and Hladik explained.

"I can see a patient going to a doctor and adding this to the list of questions they might ask. Now they ask about their viral load and T-cell count. I hope in the future they may be able to ask how large their HIV reservoir might be," Hladik said. "What gets me excited is that one day, this number may tell them how long it will take to entirely eliminate HIV from their body."

Osaka, Japan - Humans are exposed to many types of bacteria daily, the majority of which are harmless. However, some bacteria are pathogenic, which means they can cause disease. An extremely common pathogenic bacterial infection is Helicobacter pylori (H. pylori) in the stomach, where it can lead to chronic inflammation (gastritis), ulcers, and even cancer. A group of researchers from Osaka University have determined a specific molecular mechanism that H. pylori uses to adapt to growing in the human stomach for long periods of time.

In a report published in Nature Communications, this group found that a small RNA molecule called HPnc4160 plays a key role in how H. pylori invades the stomach and leads to disease.

Previous studies showed that HPnc4160 is conserved in different strains of H. pylori, suggesting that it has an important function. Yet, the amount of this molecule produced in the bacteria is variable among strains. Genetic analysis revealed that a specific part of the H. pylori gene, called the T-repeat region, varied in length from strain to strain. The researchers became interested in how this region affected HPnc4160 expression. Additionally, they were curious how these fluctuations would allow some strains to colonize the human stomach more efficiently than others.

"Slight differences in the genetic sequence of H. pylori can sometimes give certain strains advantages over others that allow it to grow better," says lead author of the study Ryo Kinoshita-Daitoku. "We were interested in the genetic and molecular reasons behind why particular strains are more pathogenic and can live in the stomach for decades, leading to cancer development."

To address these questions, the researchers infected gerbils and mice with wild type (normal) H. pylori for 8 weeks, then extracted and genetically characterized the mutant strains that appeared. They discovered that strains with a higher number of T-repeats had lower expression of HPnc4160.

"We found that the H. pylori strains with low HPnc4160 levels were more infectious," explains Hitomi Mimuro, senior author. "When this RNA was completely absent, the amounts of several bacterial pathogenic factors significantly increased and the strain showed stronger colonization within the rodent stomach."

One of the pathogenic factors was the bacterial protein CagA, which is known as an oncoprotein because it can promote cancer development.

"Interestingly, we observed longer T-repeat regions, lower levels of HPnc4160, and higher levels of CagA in gastric cancer patients compared with those not suffering from cancer," describes Kinoshita-Daitoku.

These novel findings provide crucial information regarding the molecular and genetic landscape of highly pathogenic H. pylori and may assist in the development of innovative therapeutics for the treatment of H. pylori related illnesses, including gastric cancer.

Inserting lightweight optimization code in high-speed network devices has enabled a KAUST-led collaboration to increase the speed of machine learning on parallelized computing systems five-fold.

This "in-network aggregation" technology, developed with researchers and systems architects at Intel, Microsoft and the University of Washington, can provide dramatic speed improvements using readily available programmable network hardware.

The fundamental benefit of artificial intelligence (AI) that gives it so much power to "understand" and interact with the world is the machine-learning step, in which the model is trained using large sets of labeled training data. The more data the AI is trained on, the better the model is likely to perform when exposed to new inputs.

The recent burst of AI applications is largely due to better machine learning and the use of larger models and more diverse datasets. Performing the machine-learning computations, however, is an enormously taxing task that increasingly relies on large arrays of computers running the learning algorithm in parallel.

"How to train deep-learning models at a large scale is a very challenging problem," says Marco Canini from the KAUST research team. "The AI models can consist of billions of parameters, and we can use hundreds of processors that need to work efficiently in parallel. In such systems, communication among processors during incremental model updates easily becomes a major performance bottleneck."

The team found a potential solution in new network technology developed by Barefoot Networks, a division of Intel.

"We use Barefoot Networks' new programmable dataplane networking hardware to offload part of the work performed during distributed machine-learning training," explains Amedeo Sapio, a KAUST alumnus who has since joined the Barefoot Networks team at Intel. "Using this new programmable networking hardware, rather than just the network, to move data means that we can perform computations along the network paths."

The key innovation of the team's SwitchML platform is to allow the network hardware to perform the data aggregation task at each synchronization step during the model update phase of the machine-learning process. Not only does this offload part of the computational load, it also significantly reduces the amount of data transmission.

"Although the programmable switch dataplane can do operations very quickly, the operations it can do are limited," says Canini. "So our solution had to be simple enough for the hardware and yet flexible enough to solve challenges such as limited onboard memory capacity. SwitchML addresses this challenge by co-designing the communication network and the distributed training algorithm, achieving an acceleration of up to 5.5 times compared to the state-of-the-art approach."

While pollinators such as bees and butterflies provide crucial ecosystem services today, little is known about the origin of the intimate association between flowering plants and insects.

Now, a new amber fossil unearthed by researchers from the Nanjing Institute of Geology and Palaeontology of the Chinese Academy of Sciences (NIGPAS) and the University of Bristol sheds light on some of the earliest pollinators of flowering plants.

The study was published in Nature Plants on April 12.

Two hundred million years ago the world was as green as today, overgrown with dense vegetation, but it was not as colorful. Flowering plants (angiosperms) that make up over 80% of all plant species today, only began to diversify in the Cretaceous, about 125 million years ago.

Some scientists have attributed the huge evolutionary success of angiosperms to their mutualistic relationships with insect pollinators, but fossil evidence of Cretaceous pollinators has so far been scarce.

In this study, the paleontologists describe a new fossil beetle species named Pelretes vivificus from mid-Cretaceous amber originating from northern Myanmar. The new species lived in the Burmese Cretaceous rainforest some 99 million years ago. Its closest relatives are short-winged flower beetles (Kateretidae) that today occur in Australia, visiting a diverse range of flowers and feeding on their pollen.

"Pelretes vivificus is associated with clusters of pollen grains, suggesting that short-winged flower beetles visited angiosperms in the Cretaceous. Some aspects of the beetle's anatomy, such as its hairy abdomen, are also adaptations associated with pollination," said Prof. CAI Chenyang, a paleontologist from NIGPAS.

The Hukawng Valley in northern Myanmar is one of the richest amber deposits known. "Besides the unparalleled abundance of fossil insects, the amber dates back to the mid-Cretaceous, right when angiosperms were taking off," said Erik Tihelka, entomologist and paleontologist at the University of Bristol. Cretaceous amber fossils provide an important source of evidence for understanding the biology of early angiosperms.

While Pelretes is not the first pollinating beetle to be described from Cretaceous amber, this unique specimen preserves a bizarre clue about its diet. The fossil is associated with beetle coprolites - fossil fecal pellets - that provide a very unusual but important insight into the diet of short-winged flower beetles in the Cretaceous.

The fossil fecal pellets are completely composed of pollen, the same type that is found in clusters surrounding the beetle and attached to its body, which suggest that Pelretes visited angiosperms to feed on their pollen. This finding provides a direct link between early flowering plants in the Cretaceous and their insect visitors; it shows that these insect fossils were not just incidentally co-preserved with pollen, but that there was a genuine biological association between the two.

"The pollen associated with the beetle can be assigned to the fossil genus Tricolpopollenites. This group is attributed to the eudicots, a living group of derived angiosperms, that includes the orders Malpighiales and Ericales," said Dr. LI Liqin, fossil pollen specialist from NIGPAS.

"This shows that pollinators took advantage of early angiosperms soon after their initial diversification and visited a diverse range of groups by the mid-Cretaceous," said Prof. CAI.

While the new Coronavirus will, hopefully, be effectively controlled sooner rather than later, its latest namesake is here to stay - a small caddisfly endemic to a national park in Kosovo that is new to science.

Potamophylax coronavirus was collected near a stream in the Bjeshkët e Nemuna National Park in Kosovo by a team of scientists, led by Professor Halil Ibrahimi of the University of Prishtina. After molecular and morphological analyses, it was described as a caddisfly species, new to science in the open-access, peer-reviewed Biodiversity Data Journal.

Ironically, the study of this new insect was impacted by the same pandemic that inspired its scientific name. Although it was collected a few years ago, the new species was only described during the global pandemic, caused by SARS-CoV-2. Its name, P. coronavirus, will be an eternal memory of this difficult period.

In a broader sense, the authors also wish to bring attention to "another silent pandemic occurring on freshwater organisms in Kosovo's rivers," caused by the pollution and degradation of freshwater habitats, as well as the activity increasing in recent years of mismanaged hydropower plants. Particularly, the river basin of the Lumbardhi i Deçanit River, where the new species was discovered, has turned into a 'battlefield' for scientists and civil society on one side and the management of the hydropower plant operating on this river on the other.

The small insect order of Trichoptera, where P. coronavirus belongs, is very sensitive to water pollution and habitat deterioration. The authors of the new species argue that it is a small-scale endemic taxon, very sensitive to the ongoing activities in Lumbardhi i Deçanit river. Failure to understand this may drive this and many other species towards extinction.

Interestingly, in the same paper, the authors also identified a few other new species from isolated habitats in the Balkan Peninsula, which are awaiting description upon collection of further specimens. The Western Balkans and especially Kosovo, have proved to be an important hotspot of freshwater biodiversity. Several new insect species have been discovered there in the past few years, most of them being described by Professor Halil Ibrahimi and his team.

Many women "risk" allowing natural grey hair to show in order to feel authentic, a new study shows.

Researchers from the University of Exeter surveyed women who chose not to dye their grey hair, and found a "conflict" between looking natural and being seen as competent.

Participants in the study - mostly from English-speaking countries - belonged to online groups whose members allow their natural grey hair to show, and the researchers noted "solidarity and sisterhood" among these women.

"We are all constrained by society's norms and expectations when it comes to appearance, but expectations are more rigorous for women - especially older women," said lead author Vanessa Cecil, of the University of Exeter.

"The 'old woman' is an undesirable character in Western societies, being seen as incompetent or unpleasant - if she is seen at all.

"In our study, we wanted to understand why some women choose natural grey hair.

"In the face of impossible standards to be natural and remain youthful forever, these women are doing what they can to retain status.

"Although many reported negative consequences such as being ignored or treated as less competent, they also felt happier to be 'flying my natural flag'.

"We also found that women chose to compensate for going grey by using other beauty practices - so embracing grey isn't the same as embracing looking old.

"Grey-haired and youthfully glamorous is one thing, but in Western societies it's still not OK to look old."

Responses from the 80 participants, members of two Facebook groups about transitioning to natural grey hair, suggested the key trade-off was between authenticity and being seen as competent.

Women reported being shamed - including by family and friends - for being too natural ("let oneself go") but also wanted to avoid looking as if they have tried too hard to conceal their age ("mutton dressed as lamb").

Those who were supported by partners, family and friends had an "easier time" of the transition to grey, Cecil said.

Many women have chosen natural grey hair during COVID lockdowns - both because hairdressers have been closed and due to spending less time in public, including at work.

"This appears to have accelerated a shift that was already happening, with more and more women choosing not to dye their hair," Cecil said.

In 2018, Pompeu Fabra University launched its Planetary Wellbeing initiative, a long-term institutional strategy spurred by the United Nations Sustainable Development Goals (SDG) and based on the Planetary Health project promoted by the Rockefeller Foundation and The Lancet.

Fifteen academics and public officials, led by the three directors of the initiative, Josep Maria Antó, scientific director of ISGlobal; Josep Lluís Martí, UPF vice-rector for innovation projects, and Jaume Casals, UPF rector, are the authors of an academic article published in the journal Sustainabilty, in which they present the Planetary Wellbeing initiative.

Josep Lluís Martí: "The article is a presentation to the world of the Planetary Wellbeing initiative and an ambitious commitment by UPF to invite other universities and research centres to collaborate in this strategic agenda for the future".

The article involves the participation of several proponents of the initiative from different departments of the University, as well as research institutions in France, the United Kingdom and the United States, including two prestigious international researchers: Howard Frumkin, one of the world's leading experts in Planetary Health, and Marc Fleurbaey, one of the most renowned international economists in the field of wellbeing and climate change.

We live in a time of pressing planetary challenges, many of which threaten catastrophic change to the natural environment and require massive and novel coordinated scientific and societal efforts on an unprecedented scale. In this context, UPF understands that Universities and other academic institutions have the opportunity and responsibility to assume a leading role in an era when the destiny of the planet is precisely in the hands of human beings.

Josep Lluís Martí, UPF vice-rector for innovation projects and co-author, explains that the article is the first 'concept paper' drafted in the framework of the University's Planetary Wellbeing initiative: "This paper seeks to explain what we might understand by Planetary Wellbeing, why it was decided to extend the original term of Planetary Health to the field of wellbeing, and why universities and research centres should undertake a commitment to the UN's SDG in its three main areas of activity: teaching, research and knowledge transfer".

The article describes how UPF is responding to these challenges, and thus it provides an example of how higher education institutions might meet their responsibility in confronting those challenges through conceptualization of the underlying sustainable aim of the transformation required in the existing institution.

But the article goes further as it is an invitation for others to join in to work towards this shared goal. According to Josep Lluís Martí, publishing in Sustainability, one of the top international scientific journals in this field, "represents a presentation to the world of the Planetary Wellbeing initiative and an ambitious commitment by UPF to invite other universities and research centres to collaborate in this strategic agenda for the future".

How does the University understand the concept of Planetary Wellbeing and what implications does it have?

The Planetary Wellbeing initiative defines this concept as "the highest attainable standard of wellbeing for human and non-human beings and their social and natural systems". Developing the potential of these new concepts involves substantial theoretical and empirical effort in many different fields, all of them interrelated by the crosscutting challenges of global complexity, interdisciplinarity, and urgency. "Close collaboration of science, humanities, and culture is more desperately needed now than ever before in the history of humankind", the authors assert.

"Close collaboration of science, humanities and culture is more desperately needed now than ever before in the history of humankind".

Josep Lluís Martí is of the opinion that "the concept of planetary wellbeing, as we understand it at UPF, provides a particularly fruitful framework in which to develop this threefold commitment to the SDG in the areas of research, teaching and knowledge transfer, and its own research agenda aimed at finding solutions for the major urgent, complex planet-wide challenges that humanity faces today, such as climate change, the pandemic and sustainability".

The article examines how the Planetary Wellbeing initiative applies the three challenges that need to be addressed in order to succeed: conceptual, knowledge and implementation and governance. The conceptual challenges refer to the rules, that is, to set a regulative ideal for all humanity and for the planet; the knowledge ones, to the opportunity for new research to stimulate connections between different scientific disciplines on issues relevant to the future of the planet; and those of implementation and governance, to the various actions needed to address, for example, climate change, and will be decisive for the future of humanity.

What actions has UPF got underway?

The article reviews the various transformative educational initiatives implemented and planned by the University, which in 2019 made a "Declaration of Climate Emergency" as part of its institutional sustainability strategy, which has contributed to an initial assessment of its carbon footprint and establishing several specific ambitious goals to reduce this footprint.

An annual plenary meeting, an annual call for internal research seed funding, the organization of several annual conferences and international research meetings, the design of new courses and specific, interdisciplinary programmes on Planetary Wellbeing, such as a MOOC (Massive Open Online Course), a master's degree (jointly with the UOC and ISGlobal), and a minor; the awarding of a prize for the best master's degree thesis and for the best doctoral thesis on Planetary Wellbeing, and the organization of public talks and dialogues, are some of the actions that UPF has initiated.

Universities have a central role not only in developing much needed research on the complex issues concerning Planetary Wellbeing but also in teaching and promoting the view that a new kind of science and approach to such issues is needed", the authors conclude.

A shared set of systems in the brain may play an important role in controlling the retrieval of facts and personal memories utilised in everyday life, new research shows.

Scientists from the University of York say their findings may have relevance to memory disorders, including dementia, where problems remembering relevant information can impact on the daily life of patients.

Researchers say the findings may also have important implications for the development of a new generation of artificial intelligence systems, which use long-term memory in solving computational problems.

The brain's long-term memory stores are categorised into two: factual memory and memory of personal experiences.

Together, these two long-term memory stores help us understand and respond to the world around us.

Decades of clinical and experimental research has shown that these two memory stores are represented across two separate brain regions.

But the new study suggests that a shared set of brain regions play an important role in controlling the successful retrieval of weak memories.

Using functional magnetic resonance imaging technology, researchers studied how these regions were shown to increase their activity when participants were asked to retrieve fact memories and personal memories.

Lead researcher Dr Deniz Vatansever, formerly of the University of York and now working for the Institute of Science and Technology for Brain-inspired Intelligence, Fudan University said: "The new research suggests that despite their functional differences, successfully retrieving weak information from these two memory systems might be dependent upon a shared brain mechanism.

"Our memories allow us to make sense and flexibly interact with the world around us. Although in most cases, our strongly encoded memories might be sufficient for the task at hand, remembering to pack a beach towel for an upcoming seaside holiday, this strong memory may be irrelevant in other instances, such as when packing for a business trip. As such, we need to tightly control the retrieval of relevant memories to solve different tasks under different circumstances. Our results indicate that this control process might be shared across both factual and personal memory types."

Senior author Prof. Elizabeth Jefferies from the Department of Psychology, University of York, said: "In order to generate appropriate thoughts and behaviours, we have to draw on our memory stores in a highly flexible way. This new study highlights control processes within the brain that allow us to focus on unusual aspects of the meanings of words and to retrieve weakly encoded personal experiences. This control over memory allows us to be creative and to adapt as our goals or circumstances change."

Researchers at the University of Toronto have found that a calorie labelled is not the same as a calorie digested and absorbed, when the food source is almonds.

The findings should help alleviate concerns that almonds contribute to weight gain, which persist despite the widely recognized benefits of nuts as a plant-based source of protein, vitamins and minerals.

"Nuts have generally been thought of as healthy the last two decades, but the messaging around nuts has often come with a disclaimer that they are high in fat and energy," said John Sievenpiper, principal investigator on the study and an associate professor in the departments of nutritional sciences and medicine at the Temerty Faculty of Medicine.

"We still see that caveat in the media and on the internet today, and it has been part of many clinical guidelines, although that is changing," said Sievenpiper, who is also a staff physician and scientist at St. Michael's Hospital, Unity Health Toronto.

"Other researchers have shown that there is a bioaccessibility issue with nuts, that a calorie labelled may not be a calorie absorbed. This study quantifies that effect with almonds in a relevant population," Sievenpiper said.

The journal Mayo Clinic Proceedings published the findings today.

The researchers found that after digestion, about 20 per cent of calories derived largely from fat in almonds remained unabsorbed, which they observed in stool samples. That translated to about two per cent less energy absorbed from the diet overall among study participants.

A person eating the same amount of almonds in a daily diet of 2,000 to 3,000 calories would absorb 40 to 60 calories less than would be predicted by Atwater factors, on which many food labels are based. That could result in weight loss up to 2.9 kilograms or 6.3 pounds over a year, assuming no compensation in the form of increased intake or decreased energy expenditure.

Participants in the study did not gain weight, which is consistent with the majority of high-quality trials that measure nut consumption and weight gain, some of which show an association with weight loss, Sievenpiper said.

The researchers used a randomized crossover trial to study 22 women and men with high cholesterol, who underwent a series of three, month-long dietary interventions separated by a week-long washout period.

All study participants consumed an NCEP Step-2 diet (low in saturated fat and cholesterol, part of the U.S. National Cholesterol Education Program). The three dietary interventions were full-dose almonds (75 grams per day or three quarters of a cup); half-dose almonds plus half-dose muffins; and full-dose muffins as a study control.

Nutritional makeup of the muffins matched the almonds in amount of protein, fibre and fats.

"One unique aspect of this study is that it assessed people with high cholesterol, who are at greater risk for cardiovascular disease," said Stephanie Nishi, a doctoral student in nutritional sciences at the time of the study who is now a postdoctoral fellow at the University of Rovira i Virgili in Spain.

"That has not been done in this population before, and it's important because this group typically gets many messages to eat more nuts, owing to the evidence for nut consumption and heart health," Nishi said.

Nishi and Sievenpiper both said there is a big gap between the number of nuts people are recommended to consume and how many they actually eat, generally and in populations at risk for cardiovascular and other disease.

Further barriers stemming from concerns about weight gain are counter-productive, they said.

Diabetes Canada recently adjusted their guidelines based in part on the study's findings, and to avoid the stigma around nuts and weight gain, said Sievenpiper, who has contributed to guidelines for patients with diabetes and other metabolic disorders, and for cardiovascular disease.

A recent study finds U.S. companies that have a substantial number of employees in foreign jurisdictions with lower tax rates are more likely than their peers to "artificially" locate earnings in those jurisdictions - and the Internal Revenue Service (IRS) is less likely to challenge these complex tax-planning activities.

"Many politicians seek to encourage domestic employment and discourage sending jobs overseas," says Nathan Goldman, co-author of the study and an assistant professor of accounting in North Carolina State University's Poole College of Management. "To do that, they'll need to address elements of corporate tax policy that effectively encourage corporations to ramp up their percentage of foreign employees."

The researchers were interested in determining how foreign employment affected income shifting by large companies, and tax uncertainty regarding the foreign transactions of those companies. Income shifting is when companies artificially locate earnings in a low-tax jurisdiction. For example, one form of income shifting is when a company alters intercompany pricing by charging unusual prices to transfer income from the part of the company that earned the money to the part of the company that is based in a low-tax jurisdiction - particularly when there is no reason to do so other than to avoid taxes. Tax uncertainty refers to the likelihood that an IRS audit will result in the company having to pay more in taxes.

For this study, the researchers looked at data from 815 large, multinational companies based in the U.S. The researchers collected financial data on all of the companies for each year between 2000 and 2016. During that time period, all of the companies had at least one year during which they recorded at least $100 million in foreign sales. The average firm in the sample, during the average year, had 18,763 employees, of which 8,499 were employed outside the U.S.

The researchers used empirical models that allowed them to identify whether companies were recording unusually high profit margins in low-tax jurisdictions relative to the U.S. - which would suggest that companies were engaging in income shifting.

The researchers found companies that had a higher percentage of foreign employees were more likely to have unusually high profit margins overseas. In addition, those companies recorded fewer unrecognized tax benefit reserves on their financial statements, which reflects lower tax uncertainty. In other words, companies appear to be facing less scrutiny from the IRS related to their aggressive tax planning activities.

"Think of it this way: If a company only has a few employees in a low-tax jurisdiction and claims a huge profit there, the IRS is likely going to single that company out - the amount of profit is out of scale with the size of the operation," Goldman says. "But if a company has a lot of employees in that jurisdiction, the profits appear more reasonable, and the relevant business activities are less likely to get singled out by the IRS for a rigorous audit.

"One of the takeaways here is that the tax code effectively encourages companies to increase the percentage of their employees who work in foreign jurisdictions that have low tax rates. Not just because of a higher U.S. tax rate, but because the company is better able to substantiate the economic substance of their transactions, resulting in a higher likelihood of defending these aggressive tax planning activities in an IRS audit."

MINNEAPOLIS/ST.PAUL (04/12/2021) — A new probe into the lingering impacts of the COVID-19 pandemic revealed correlations to six unhealthy eating behaviors, according to a study by the University of Minnesota Medical School and School of Public Health. Researchers say the most concerning finding indicates a slight increase or the re-emergence of eating disorders, which kill roughly 10,200 people every year — about one person every 52 minutes.

U of M Medical School’s Melissa Simone, PhD, a postdoctoral research fellow in the Department of Psychiatry and Behavioral Sciences, collaborated with School of Public Health professor and head of the Division of Epidemiology and Community Health, Dianne Neumark-Sztainer, PhD, MPH, to learn from study participants in Neumark-Sztainer’s Project EAT between April and May 2020.

“The COVID-19 pandemic has resulted in the rapid implementation of public health policies to reduce transmission of the virus. While these protections are necessary, the disruptions to daily life associated with the ongoing pandemic may have significant negative consequences for the risk of eating disorders and symptoms,” said Simone, who is the lead author of the study. “Eating disorders have one of the highest mortality rates across all psychiatric health concerns, and therefore, it is important to try to make links between the consequences of the pandemic and disordered eating behaviors.

The study aimed to understand potential associations between stress, psychological distress, financial difficulties and changes in eating behaviors during the COVID-19 pandemic through the analysis of both qualitative and quantitative data. Simone’s findings, published in theInternational Journal of Eating Disorders, found six key themes of eating behavior changes:

Mindless eating and snacking;
Increased food consumption;
Generalized decrease in appetite or dietary intake;
Eating to cope;
Pandemic-related reductions in dietary intake;
And, a re-emergence or marked increase in eating disorder symptoms.

Approximately 8% of those studied reported extreme unhealthy weight control behaviors, 53% had less extreme unhealthy weight control behaviors and 14% reported binge eating. The study revealed that these outcomes were significantly associated with poorer stress management, greater depressive symptoms and moderate or extreme financial difficulties.

“There has been a lot of focus on obesity and its connection with COVID-19. It is also important to focus on the large number of people who have been engaging in disordered eating and are at risk for eating disorders during and following the pandemic,” said Neumark-Sztainer, who is the principal investigator of Project EAT. “The majority of the young adults in our study are from diverse ethnic/racial and lower income backgrounds, who often do not receive the services they need. To ensure health inequities do not increase, we need to meet the needs of these populations.”

Simone added, “The economic consequences of the COVID-19 pandemic will likely persist long beyond the dissemination of a vaccine. Because our findings suggest that moderate or severe financial difficulties may be linked with disordered eating behaviors, it is essential that eating disorder preventive interventions and treatment efforts be affordable, easily accessible and widely disseminated to those at heightened risk. As such, online or mobile-based interventions may prove to be effective and accessible modes for targeted intervention efforts.”

This study was funded by the National Heart, Lung, and Blood Institute (R01HL116892, R35HL139853: Principal Investigator: D. Neumark-Sztainer), the National Center for Advancing Translational Sciences (TL1R002493, UL1TR002494), and the National Institute of Mental Health (T32MH082761).

BOSTON - (April 12, 2021) - A new source of energy expending brown fat cells has been uncovered by researchers at the Joslin Diabetes Center, which they say points towards potential new therapeutic options for obesity. According to the new report, published today by Nature Metabolism, the key lies in the expression of a receptor called Trpv1 (temperature-sensitive ion channel transient receptor potential cation subfamily V member 1) -- a protein known to sense noxious stimuli, including pain and temperature.

Specifically, the authors point to smooth muscle cells expressing the Trpv1 receptor and identify them as a novel source of energy-burning brown fat cells (adipocytes). This should translate into increased overall energy expenditure - and ultimately, researchers hope, reduced weight.

Brown fat or brown adipose tissue is a distinct type of fat that is activated in response to cold temperatures. Its primary role is to produce heat to help maintain body temperature and it achieves that by burning calories. This has raised the prospect that such calorie burning can be translated into weight loss, particularly in the context of obesity.

"The capacity of brown and beige fat cells to burn fuel and produce heat, especially upon exposure to cold temperatures, have long made them an attractive target for treating obesity and other metabolic disorders," said senior author Yu-Hua Tseng . "And yet, the precise origins of cold-induced brown adipocytes and mechanisms of action have remained a bit of a mystery."

The source of these energy-burning fat cells was previously considered to be exclusively related to a population of cells that express the receptor Pdgfrα (platelet derived growth factor receptor alpha). However, wider evidence suggests other sources may exist. Identifying these other sources would then open up potential new targets for therapy that would get around the somewhat uncomfortable use of cold temperatures to try to treat obesity.

The team initially investigated the general cellular makeup of brown adipose tissue from mice housed at different temperatures and lengths of time. Notably, they employed modern single cell RNA sequencing approaches to try to identify all types of cells present. This avoided issues of potential bias towards one particular cell type - a weakness of previous studies, according to the authors.

"Single cell sequencing coupled with advanced data analysis techniques has allowed us to make predictions in silico about the development of brown fat," said co-author Matthew D. Lynes. "By validating these predictions, we hope to open up new cellular targets for metabolic research."

As well as identifying the previously known Pdgfrα-source of energy burning brown fat cells, their analysis of the single cell RNA sequencing data suggested another distinct population of cells doing the same job - cells derived from smooth muscle expressing Trpv1*. The receptor has previously been identified in a range of cell types and is involved in pain and heat sensation.

Further investigations with mouse models confirmed that the Trpv1-positive smooth muscle cells gave rise to the brown energy-burning version of fat cells especially when exposed to cold temperatures. Additional experiments also showed that the Trpv1-positive cells were a source for beige fat cells that appear in response to cold in white fat, further expanding the potential influence of Trpv1-expressing precursor cells.

"These findings show the plasticity of vascular smooth muscle lineage and expand the repertoire of cellular sources that can be targeted to enhance brown fat function and promote metabolic health," added lead author.

Brown adipose tissue is the major thermogenic organ in the body and increasing brown fat thermogenesis and general energy expenditure is seen as one potential approach to treating obesity, added Shamsi.

"The identification of Trpv1-expessing cells as a new source of cold-induced brown or beige adipocytes suggests it might be possible to refine the use of cold temperatures to treat obesity by developing drugs that recapitulate the effects of cold exposure at the cellular level," said Tseng.

The authors note that Trpv1 has a role in detecting multiple noxious stimuli, including capsaicin (the pungent component in chili peppers) and that previous studies suggest administration in both humans and animals results in reduced food intake and increased energy expenditure.

Tseng added: "Further studies are now planned to address the role of the Trpv1 channel and its ligands and whether it is possible to target these cells to increase numbers of thermogenic adipocytes as a therapeutic approach towards obesity."

Histones are tiny proteins that bind to DNA and hold information that can help turn on or off individual genes. Researchers at Karolinska Institutet have developed a technique that makes it possible to examine how different versions of histones bind to the genome in tens of thousands of individual cells at the same time. The technique was applied to the mouse brain and can be used to study epigenetics at a single-cell level in other complex tissues. The study is published in the journal Nature Biotechnology.

"This technique will be an important tool for examining what makes cells different from each other at the epigenetic level," says Marek Bartosovic, post-doctoral fellow at the Department of Medical Biochemistry and Biophysics, Karolinska Institute. "We anticipate that it will be widely implemented by the broad biomedical community in a wide variety of research fields."

Even though all cells in our bodies contain exactly the same genetic information written in DNA, they read and execute this information differently. For example, a neuron in the brain reads the DNA differently than a skin cell or a fat cell. Epigenetics play a crucial role in the interpretation of the genetic information and allows the cells to execute specialized functions.

Modification of histones is one type of epigenetic information. Histones are attached to DNA like beads on a string and decorate it as "epigenetic stickers". These stickers label which genes should be turned on or off. All together this system coordinates to ensure that thousands of genes are switched on or off at the right place and time and in the right cell.

To better understand how cells become different and specialized, it is important to know which parts of the DNA are marked by which histone "stickers" in each individual organ and in each individual cell within that organ. Until recently, it was not possible to look at histone modifications of an individual cell. To examine the histone modifications in one specific cell type, a very high number of cells and cumbersome methods of cell isolation would be required. The final epigenetic histone profile of one cell type would then be an averaged view of thousands of cells.

In this study, the researchers describe a method that introduces a new way of looking at histone modifications in unprecedented detail in a single cell and at a large scale. By coupling and further optimizing other epigenomic techniques, the researchers were able to identify gene regulatory principles for brain cells in mice based on their histone profile.

"Our method--single-cell CUT&Tag--makes it possible to examine tens of thousands of single cells at the same time, giving an unbiased view of the epigenetic information in complex tissues with unparalleled resolution," Gonçalo Castelo-Branco, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institute, says. "Next, we would like to apply single-cell CUT&Tag in the human brain, both in development and in various diseases. For instance, we would like to investigate which epigenetic processes contribute to neurodegeneration during multiple sclerosis and whether we would be able to manipulate these processes in order to alleviate the disease."

What exactly happens when the corona virus SARS-CoV-2 infects a cell? In an article published in Nature, a team from the Technical University of Munich (TUM) and the Max Planck Institute of Biochemistry paints a comprehensive picture of the viral infection process. For the first time, the interaction between the coronavirus and a cell is documented at five distinct proteomics levels during viral infection. This knowledge will help to gain a better understanding of the virus and find potential starting points for therapies.

When a virus enters a cell, viral and cellular protein molecules begin to interact. Both the replication of the virus and the reaction of the cells are the result of complex protein signaling cascades. A team led by Andreas Pichlmair, Professor of Immunopathology of Viral Infections at the Institute of Virology at TUM, and Matthias Mann, Head of the Department of Proteomics and Signal Transduction at the Max Planck Institute of Biochemistry, has systematically recorded how human lung cells react to individual proteins of the covid-19 pathogen SARS-CoV-2 and the SARS coronavirus, the latter of which has been known for some time.

A detailed interaction map

To this end, more than 1200 samples were analyzed using the state-of-the-art mass spectrometry techniques and advanced bioinformatic methods. The result is a freely accessible dataset that provides information on which cellular proteins the viral proteins bind to and the effects of these interactions on the cell. In total, 1484 interactions between viral proteins and human cellular proteins were discovered. "Had we only looked at proteins, however, we would have missed out on important information", says Andreas Pichlmair. "A database that only includes the proteome would be like a map containing just the place names but no roads or rivers. If you knew about the connections between the points on that map, you could gain much more useful information."

According to Pichlmair, important counterparts to the network of traffic routes on a map are protein modifications called phosphorylation and ubiquitination. Both are processes in which other molecules are attached to proteins, thereby altering their functions. In a listing of proteins, these changes are not measured, so that there is no way of knowing whether proteins are active or inactive, for example. "Through our investigations, we systematically assign functions to the individual components of the pathogen, in addition to the cellular molecules that are switched off by the virus," explains Pichlmair. "There has been no comparable mapping for SARS-CoV-2 so far," adds Matthias Mann. "In a sense, we have taken a close look at five dimensions of the virus during an infection: its own active proteins and its effects on the host proteome, ubiquitinome, phosphoproteome and transcriptome."

Insights into how the virus works

Among other things, the database can also serve as a tool to find new drugs. By analyzing protein interactions and modifications, vulnerability hotspots of SARS-CoV-2 can be identified. These proteins bind to particularly important partners in cells and could serve as potential starting points for therapies. For example, the scientists concluded that certain compounds would inhibit the growth of SARS-CoV-2. Among them were some whose antiviral function is known, but also some compounds which have not yet been studied for efficacy against SARS-CoV-2. Further studies are needed to determine whether they show efficacy in clinical use against Covid-19.

"Currently, we are working on new anti Covid-19 drug candidates, that we have been able to identify through our analyses," says Andreas Pichlmair. "We are also developing a scoring system for automated identification of hotspots. I am convinced that detailed data sets and advanced analysis methods will enable us to develop effective drugs in a more targeted manner in the future and limit side effects in advance."

April 12, 2021 - For critically ill COVID-19 patients treated with extracorporeal membrane oxygenation (ECMO), the risk of death remains high - but is much lower than suggested by initial studies, according to a report published today by Annals of Surgery. The journal is published in the Lippincott portfolio by Wolters Kluwer.

The findings support the use of ECMO as "salvage therapy" for COVID-19 patients with acute respiratory distress syndrome (ARDS) or respiratory failure who do not improve with conventional mechanical ventilatory support, according to the new research by Ninh T. Nguyen, MD, Chair of the Department of Surgery, University of California, Irvine Medical Center (UCIMC) and colleagues. "Our findings refute previous reports of futility for ECMO therapy in the setting of COVID-19," states Fabio Sagebin, MD, of the UCIMC Division of Cardiothoracic Surgery.

Extracorporeal membrane oxygenation is a life-sustaining therapy for carefully selected patients with respiratory or circulatory failure. Requiring specialized equipment and highly trained professionals, ECMO is mainly provided at large medical centers.

While some hospitals have been using ECMO therapy for COVID-19 patients with severe ARDS, there is a "paucity of data" on outcomes, according to the authors. Initial case series reported "exceedingly high" mortality rates: over 90 percent.

Dr. Nguyen and colleagues used the nationwide Vizient hospital database to analyze outcomes of 11,182 patients with COVID-19 and ARDS who received ECMO between April and September 2020. The patients were treated at 155 US medical centers; numbers of patients treated with ECMO ranged from 1 to 38 per hospital. The majority of patients were under the age of 50 years (57.9 percent) with about 37 percent aged 51 to 64 years. Only about five percent were aged 65 years or older.

For these ECMO-treated COVID-19 patients with ARDS, the overall rate of in-hospital death was 45.9 percent. Although high, that is roughly half the mortality rate reported in smaller ECMO studies from early in the pandemic. It's also comparable to the 39 percent death rate in a recent analysis of about 1,000 patients from the Extracorporeal Life Support Organization registry (largely treated at higher-volume ECMO centers).

For patients in the new study, average length of hospital stay was lengthy: 37 days, including 29 days in the intensive care unit. The in-hospital mortality rate increased with age: from about 25 percent for patients aged up to 30 years, to 42 percent for those aged 31 to 50 years, 53 percent for those aged 51 to 64, and 74 percent for those aged 65 or older.

The researchers performed a subset analysis comparing patients aged 18 to 64 who were treated with (1,113 patients) or without ECMO (16,343 patients). In-hospital mortality was 44.6 percent for the ECMO-treated patients compared to 37.9 percent for those treated without ECMO.

"Our data showed that patients with COVID-19 and ARDS treated with conventional ventilatory support had a high risk of death and patients selected for ECMO, which is a higher risk group, had a similarly high rate of death," according to Dr. Sagebin. "The data suggests that in appropriately selected patients, we can save lives with this therapy."

The researchers note some limitations of their database study, including the lack of data regarding the extent and severity of ARDS or response to ventilatory support measures.

Dr. Nguyen states: "Although ECMO therapy appears to show a benefit, it is a costly and resources intensive therapy including long length of hospitalization that is not readily available at most medical centers. In the setting of a pandemic when the number of severely ill patients outpaced the availability of limited resources, then this therapy will require appropriate selection of patients that would be most likely to benefit."