Culture

Although the reputation of Champagne is well established, the history of Champagne wines and vineyards is poorly documented. However, a research team led by scientists from the CNRS and the Université de Montpellier at the Institut des sciences de l'évolution de Montpellier* has just lifted the veil on this history by analysing the archaeological grape seeds from excavations carried out in Troyes and Reims. Dated to between the 1st and 15th centuries AD, the seeds shed light on the evolution of Champagne wine growing, prior to the invention of the famous Champagne, for the first time. According to the researchers, "wild"** vines were cultivated throughout the period studied. Domestic varieties, coming from the south of Gaul, appeared as early as the 1st century and became the major grape varieties of the 2nd and 3rd centuries. This archaeological series was uninterrupted until around 1000 AD, when the wild vine and the southern varieties made a strong comeback. This period corresponds both to intense economic and societal changes and to global warming spanning a few hundred years. Northern grape varieties, more adapted to the cold, appeared more than 300 years later at the beginning of a colder climatic period***, supplanting the southern grape varieties. Published in Scientific Reports on January 27, 2021, these results pave the way for further global analysis that will allow a better understanding of the history of viticulture by combining biological, archaeological and historical data.

Linking molecular components through amide bonds is one of the most important reactions in research and the chemical industry. In the journal Angewandte Chemie, scientists have now introduced a new type of reaction for making amide bonds. Called an ASHA ligation, this reaction is fast, efficient, works under mild aqueous conditions, and is broadly applicable.

Amide bonds are the bond between a carbonyl carbon (C=O) and an organic nitrogen atom. It is amide bonds that link individual amino acids together into proteins and bind monomers into polyamide plastics like perlon and nylon. Many life-saving medicines such as taxol, lipitor and penicillin, as well as agrochemicals, biological conjugates, natural substances, and other products contain amide bonds. In addition to the classical method of production--the reaction of an acid group (-COOH) with an amino group (-NH(2))--a variety of different reactions have been developed for the formation of amide bonds. However, many of them are not broadly applicable due to a lack of chemoselectivity. They also require specialized coupling agents. New types of reactions are in demand.

A team led by Rajavel Srinivasan at Tianjin University (China) was searching for an efficient, sustainable method that starts with easily accessible materials and works fast. They chose a reaction between acylsilanes and hydroxylamines (a class of organic nitrogen compounds with an -N-O- linkage). Acylsilanes are a class of organic silicon compounds with a general structural formula of R(CO)-SiR(3). Their reactivity often differs completely from that of the related ketones. Although their chemistry is well known, they have previously rarely been used in the field of biomedical chemistry.

Based on their first letters, the reaction of acylsilanes with hydroxylamines is called an ASHA ligation. The driving force appears to be intramolecular migration of a silyl group from a carbon atom to an oxygen atom (Brook rearrangement), in which a strong Si-O bond is formed.

The researchers successfully tested the ligation with a broad palette of different molecular building blocks, including pharmaceutical agents, peptides, natural products, and other biologically active compounds. The reaction is chemoselective and works under mild conditions in an aqueous milieu. It produces high yields in the majority of cases and is tolerant toward most functional groups. New variants of ASHA ligation are in development for peptide synthesis as it did not work well.

However the simplicity and efficiency of the ASHA ligation should open pathways to new approaches in medicinal chemistry and chemical biology, such as fragment-based drug development, in which active substances are built up successively from small fragments.

Researchers at Vanderbilt University Medical Center (VUMC) and the University of Texas Medical Branch (UTMB) at Galveston have discovered what may be the Achilles' heel of the coronavirus, a finding that may help close the door on COVID-19 and possibly head off future pandemics.

The coronavirus is an RNA virus that has, in its enzymatic toolkit, a "proofreading" exoribonuclease, called nsp14-ExoN, which can correct errors in the RNA sequence that occur during replication, when copies of the virus are generated.

Using cutting-edge technologies and novel bioinformatics approaches, the researchers discovered that this ExoN also regulates the rate of recombination, the ability of the coronavirus to shuffle parts of its genome and even pull in genetic material from other viral strains while it replicates in order to gain evolutionary advantage.

These patterns of recombination, the researchers reported last week in the journal PLOS Pathogens, are conserved across multiple coronaviruses, including SARS-CoV-2, which causes COVID-19, and MERS-CoV, which causes a similar illness, Middle Eastern respiratory syndrome.

"The coronavirus exoribonuclease is therefore a conserved, important target for inhibition and attenuation in the ongoing pandemic of SARS-CoV-2, and in preventing future outbreaks of novel coronaviruses," concluded the paper's first author, Jennifer Gribble, a VUMC graduate student in the laboratory of Mark Denison, MD.

"If you can find a drug that prevents RNA recombination, you really shut down the virus," added Andrew Routh, PhD, assistant professor of Biochemistry and Molecular Biology at UTMB and, with Denison, the paper's co-corresponding author. "It's really intriguing in terms of what we understand about virus adaptation and evolution."

Previous studies have shown that coronaviruses are resistant to many nucleoside antiviral drugs, which work by introducing errors in the viral genetic code to block replication. The coronavirus proofreader corrects the errors so replication can proceed.

Only a few drugs are capable of circumventing the proofreader. They include an approved drug, remdesivir, and EIDD-2801 (molnupiravir), an investigational drug now in clinical trials. Both were developed with the help of VUMC scientists.

"Finding that the viral ExoN plays a key role in recombination is exciting," said Denison, director of the Division of Pediatric Infectious Diseases at VUMC who has studied coronaviruses for more than 30 years.

"Knocking out this function (in laboratory studies) leads to decreased recombination and a weaker virus," Denison said. "So we think it may be possible to block this process with drugs as well (and) that it may make other drugs like remdesivir and molnupiravir work even better and last longer."

In 2007 Denison and his colleagues discovered the coronaviruses proofreader. They also found that blocking the enzyme accelerated the rate of uncorrected errors -- mutations--and crippled its ability to cause disease in animals.

Several years later they discovered that remdesivir, an investigational antiviral drug, had highly potent activity against a wide range of coronaviruses, both in laboratory and animal tests. In October 2020 remdesivir was approved for emergency use in patients hospitalized with COVID-19.

For the past two years, Gribble and Routh have collaborated in an effort to understand the role of recombination in the replication of RNA viruses, which include influenza, polio, measles, hepatitis C, HIV and Ebola, as well as the coronaviruses.

Using computational software Routh had developed, which can scour virus-sequencing datasets for evidence of "recombination events," Gribble was studying recombination in model experimental viruses, such as coronaviruses that infect mice.

Once the pandemic hit, Routh, Gribble and their colleagues were quickly able to apply this approach to SARS-CoV-2 and other coronaviruses that cause disease in humans. Other VUMC co-authors were Laura Stevens, MS, Maria Agostini, PhD, Jordan Anderson-Daniels, PhD, James Chappell, MD, PhD, Xiaotao Lu, MS, and Andrea Pruijssers, PhD.

Recombination does not always result in a "fitter," potentially more virulent virus, Routh noted. If during recombination, for example, some of the genome is deleted, the result is a "defective" viral genome that can mix with, and disable, the more virulent strain.

Coronaviruses frequently produce defective genomes, the researchers found. "That could be useful," Routh said. "You might be able to exploit defective genomes as a way of making new vaccines ... or to perturb replication (of a more virulent strain) ... in the patient."

Much remains to be learned about recombination and the role that plays in the continued spread of evolving variants of SARS-CoV-2 around the world and the ability of anti-viral drugs and vaccines to stop it.

That's why basic science is so important, said Denison, who holds the Edward Claiborne Stahlman Chair in Pediatric Physiology and Cell Metabolism in the Vanderbilt University School of Medicine.

"We need to understand the capacity of all kinds of viruses to move between species and the mechanisms by which they cause disease," he said. "We need to make sure that there are fundamental things that we know about all identified viruses -- their genomic sequences, for example, and some basics about their biology."

That takes a lot of creativity, determination -- and money. Funding for this study was provided by National Institutes of Health grants AI108197, GM065086 and AI133952, the Dolly Parton COVID-19 Research Fund and the Elizabeth B. Lamb Center for Pediatric Research at Vanderbilt.

CHAMPAIGN, Ill. -- Culture, civic-mindedness and privacy concerns influence how willing people are to share personal location information to help stem the transmission of COVID-19 in their communities, a new study finds. Such sharing includes giving public health authorities access to their geographic information via data gathered from phone calls, mobile apps, credit card purchases, wristband trackers or other technologies.

Reported in the International Journal of Geo-Information, the study will help public health officials better tailor their COVID-19 mitigation strategies to specific cultural contexts, the researchers said.

The scientists assessed survey responses from 306 people living in the United States and South Korea. Participants were recruited through social media and were younger and more highly educated than the general population of those countries. Conducted in late June and early July, the surveys asked participants to rate their privacy concerns, perceptions of social benefit and acceptance of a variety of COVID-19 mitigation efforts that involve collecting geographic data from individuals.

"For each method, we wanted to see how these factors influenced people's willingness to share their data," said Junghwan Kim, a graduate student in geography and geographic information science at the University of Illinois Urbana-Champaign who led the research with Mei-Po Kwan, a geography professor at The Chinese University of Hong Kong and Kim's doctoral adviser at the U. of I.

Understanding the factors that influence these decisions is key to designing effective public health campaigns, Kim said. What works in one society may not be viable in a different part of the world.

Participants answered questions about conventional contact tracing, where public health officials call those who test positive for the virus to interview them about where they've been and whom they've potentially exposed. Such methods are time-consuming and inefficient, however, so the researchers also asked participants to rate their attitudes toward public health efforts that collect geolocation information from their phones, track their credit card purchases, ask them to wear a wristband or require that they carry a "travel certificate" demonstrating that they have tested negative for COVID-19.

The surveys also asked subjects to rate how they felt about the public disclosure of location, gender and age information of those who tested positive for the virus, or for the sharing of the public locations they had visited without disclosure of their gender and age.

The team found that people were more concerned about - and less likely to accept - methods that collected more sensitive and private information.

"Not surprisingly, we saw that there is a trade-off relationship between privacy concerns and social benefits," Kim said. "So, there is more acceptance when a person's privacy concern is low and the perceived social benefits are high. We also found that people in South Korea have a significantly higher acceptance of most mitigation efforts than those in the U.S."

This higher acceptance may have to do with South Korea's previous experience with the Middle East respiratory syndrome, which is caused by a much deadlier coronavirus than the one that causes COVID-19, Kwan said. But it likely also is a reflection of South Korea's culture.

"Compared with people in the U.S., South Koreans have a stronger collectivist - rather than individualist - culture," she said. "They also have lower privacy concerns and perceive greater social benefits for COVID-19-mitigation measures."

"The results have important public health policy implications," the researchers wrote. For example, the use of phone-based or wristband GPS tracking "would not be effective in the U.S. and other countries where people's acceptance of these methods is very low." Other approaches, such as random phone calls to monitor people's compliance with quarantine orders or the use of travel certificates that verify a person's COVID-19-negative status, would likely work better in such societies.

King's College London researchers have found evidence that minocycline, a widely used antibiotic with anti-inflammatory properties, gave greater improvement in depressive symptoms in patients with treatment resistant depression with low-grade peripheral inflammation.

Improvement in depressive symptoms
In a four-week randomised clinical MINDEP (MINocycline in DEPression) trial, 39 patients with major depressive disorder were recruited from services linked to South London and Maudsley NHS Foundation Trust (SLaM) and via public advertisement.

The trial took place at the NIHR / Wellcome Trust King's Clinical Research Facility at King's College Hospital. The patients, who were taking their routine antidepressant treatment, were split into two groups, one group took daily a placebo (sugar pill) tablet while the other group took daily minocycline alongside their routine treatment for 4 weeks.
Both groups showed similar, significant improvement in depressive symptoms as measured by the Hamilton Depression (HAM-D) Rating Scale. However, patients with higher C-reactive protein (CRP) levels, indicating low-grade inflammation, showed greater improvement in their depressive symptoms when taking minocycline.

Author Dr Valeria Mondelli, Clinical Reader in Psychoneuroimmunology at Institute of Psychiatry, Psychology & Neuroscience, King's College London, and Principal Investigator of the trial said: "Our findings are very exciting because we are showing that patients with increased levels of C reactive protein (an inflammatory biomarker) show a good response in terms of reduction of depressive symptoms following treatment with minocycline. Of the many patients with depression who do not respond to usual antidepressant treatment, we have shown in previous studies that in at least two thirds of patients this could be due to the increased levels of inflammation. Now, with this study, we are identifying a potential new effective treatment for these patients."

Predicting response
Patients underwent a blood sample to measure biological markers and a clinical assessment at the baseline visit and within 14 days the trial ending.

Researchers also found that levels of two biological markers, CRP and IL-6, can be used to predict minocycline response in depression. The study identified a specific threshold of CRP levels which is associated with the antidepressant effect of minocycline treatment. Another inflammatory marker, interferon-gamma, was reduced by the treatment with minocycline but not by placebo, suggesting specific pathways mediating the effects of minocycline on depressive symptoms.

Dr Mondelli added "We also identified the threshold of CRP levels that is associated with response to this anti-inflammatory treatment. This is very important as we may be able to identify with an easy blood test those patients who are going to benefit from treatment with an anti-inflammatory medication which is already used for other medical conditions and therefore easily available."

Dr Maria Antonietta Nettis, lead author and Clinical Research Associate at Institute of Psychiatry, Psychology & Neuroscience, King's College London said: "Integrating the measurement of biological markers such as CRP in patients' first assessments could help identifying potential responders to minocycline, which could be a relatively safe and well-tolerated addition to treatment in immune-related depression.

Although replications in larger samples are needed, we believe our study has a potentially important clinical impact, as we moved a step towards the identification of personalized treatments for Major depressive disorder (MDD)."

(Boston)--Researchers from Boston University School of Medicine (BUSM) have identified proteins that are essential for the viability of whole genome doubled tumor cells, yet non-essential to normal cells that comprise the majority of human tissue.

"Exploiting these vulnerabilities represents a highly significant and currently untapped opportunity for therapeutic intervention, particularly because whole genome doubling is a distinguishing characteristic of many tumor types," said corresponding author Neil J. Ganem, PhD, associate professor of pharmacology and medicine, section of hematology and medical oncology, at Boston University School of Medicine (BUSM).

The vast majority of human cells are diploid, meaning that they possess two copies of each chromosome (one from each parent). Numerous cell cycle controls exist to ensure that this state is maintained across successive cell divisions. Despite these controls, errors can occur that result in a whole genome doubling (WGD), in which a diploid cell transitions to a tetraploid state (where cells have four copies of each chromosome, instead of two). WGD cells are oncogenic, and their contribution to tumor development is quite significant: Computational analyses from the Ganem lab have revealed that approximately 35 percent of all solid tumors arise from cells that have experienced a WGD event.

While WGD confers traits that favor tumor formation, it also imposes numerous physiological stresses upon cells. This led Ganem and his colleagues to hypothesize that WGD tumor cells must acquire specific genetic alterations that enable them to tolerate the numerous defects imparted by a doubled cellular and genomic content, and that these tumor cells may therefore possess specific dependencies not present in normal diploid cells.

Using sequencing data from approximately 10,000 primary human cancer samples and data from nearly 600 cancer cell lines, the researchers found that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. They identified several genes that are specifically required for the viability of WGD cells, including KIF18A, which is non-essential in normal diploid cells but becomes completely essential in WGD cancer cells.

"Currently, WGD status of cancer patients is not reported clinically because it does not inform treatment options. However, our study suggests that WGD cancer cells, based on their unique cellular physiology, may be specifically sensitive to a whole new variety of therapeutics. These findings may therefore validate the inclusion of WGD status as a new variable in future personalized medicine options," explained Ryan Quinton, an MD/PhD student in Ganem's lab who was the lead author on the study.

These findings appear online in Nature.

The Asia Pacific Consortium on Osteoporosis (APCO) has today launched the first pan-Asia Pacific clinical practice standards for the screening, diagnosis, and management of osteoporosis, targeting a broad range of high-risk groups.

Published in Osteoporosis International today, 'The APCO Framework' comprises 16 minimum clinical standards set to serve as a benchmark for the provision of optimal osteoporosis care in the region.

Developed by APCO members representing key osteoporosis stakeholders, and multiple medical and surgical specialities, this set of clear, concise, relevant and pragmatic clinical standards aims to support national societies, guidelines development authorities, and health care policy makers with the development of new guidelines, and to encourage the revision of existing guidelines.

According to the Framework lead author, APCO Chairperson, and Director of the Osteoporosis and Bone Metabolism Unit at Singapore General Hospital, Dr Manju Chandran, Singapore, APCO employed a 5IQ analysis and the well-established Delphi Consensus process to analyse the 18 clinical practice guidelines currently available in the Asia Pacific region, to inform the development of The APCO Framework.

"Utilising a comprehensive, four-round Delphi consensus method enabled our APCO members who work in vastly different health care systems, to reach a remarkable level of consensus on a benchmark set of clinical standards for the provision of quality osteoporosis care for the Asia Pacific region."

The APCO Framework offers clinicians structured, well-articulated, and readily accessible clinical practice guidelines that define:

Individuals to be identified for assessment;

Investigations required;

Relevant indications for treatment;

Appropriate selection of interventions to be made;

The guidance and information patients need for self-care;

Integration of healthcare systems for optimal provision of care; and

The need, and methods for monitoring and improving the quality of osteoporosis care.

"Implementation of The APCO Framework, or a similar set of standards of care informed by the Framework, is expected to significantly reduce the burden of osteoporosis not only in the Asia Pacific region, but also worldwide. We hope that the Framework can serve as a stimulus for harmonisation of guidelines in other regions that have similar socio-economic diversity and heterogeneity of health care resources," Dr Chandran said.

Globally, the population aged 65 years or over increased from six per cent in 1990, to nine per cent in 2019.[1] This proportion is projected to rise to 16 per cent by 2050,1 meaning one in six people worldwide will be aged 65 years or over by 2050.[1] The number of people aged 60 years and over in the Asia-Pacific region - home to more than a third of the world's population aged 65 years and over, and to more elderly people than any other region [2] - is predicted to triple between 2010 and 2050, reaching a staggering 1.3 billion people.[3]

Osteoporotic fractures among Asia-Pacific populations are expected to increase exponentially, not only because of the region's rapidly aging population, but also due to mounting urbanisation, and the subsequent increase in sedentary lifestyles.[4]

Despite the presence of generally safe and effective treatments for osteoporosis, as many as five in six patients presenting to their primary care physician (PCP), or to a hospital with a fragility fracture, will not be assessed for osteoporosis, nor appropriately managed to prevent further fracture.[5]

According to Medical Director of Osteoporosis Australia, and APCO Executive Committee member, Professor Peter Ebeling AO, Australia, as many as half of those who have sustained a hip fracture, have already experienced a previous fracture at other skeletal sites.

"In fact, a prior fracture at any site is associated with a doubling of future fracture and mortality risk. The unfortunate ramifications of the gross under-diagnosis and under-treatment of osteoporosis is that a large number of people sustain further debilitating secondary fractures, which places a substantial, but importantly, preventable burden on already strained healthcare systems," said Prof Ebeling.

A fragility fracture, which occurs every three seconds worldwide, [6] compromises quality of life and loss of independence. [6,7] Concerningly, one-in-four patients who sustain a hip fracture die within a year, and less than half of those who survive, regain their previous level of function.[8,9] In 2010, an estimated 158 million people aged 50 years and above were at high risk for osteoporotic fracture - a figure which is set to double by 2040.[10]

According to International Osteoporosis Foundation (IOF) CEO and APCO Executive Committee member, Dr Philippe Halbout, Switzerland, these alarming statistics, coupled with the anticipated, exponential rise in osteoporotic fractures among Asia-Pacific populations, warrant a standardised set of minimum clinical standards for the region.

"Anecdotal evidence to date reveals significant inconsistencies in osteoporosis clinical practice guidelines in the Asia Pacific region, which vary widely in scope and recommendations. This was confirmed when we analysed the 18 guidelines."

"Implementation of the minimum clinical standards proposed by The APCO Framework, and reform of existing guidelines, will support clinical improvement initiatives, while also paving the way for a more holistic approach to osteoporosis care, and ultimately, greater consistency across all national and regional clinical practice guidelines in the region," Dr Halbout said.

Neurons, the fundamental units of the brain, are complex computers by themselves. They receive input signals on a tree-like structure - the dendrite. This structure does more than simply collect the input signals: it integrates and compares them to find those special combinations that are important for the neurons' role in the brain. Moreover, the dendrites of neurons come in a variety of shapes and forms, indicating that distinct neurons may have separate roles in the brain.

A simple yet faithful model

In neuroscience, there has historically been a tradeoff between a model's faithfulness to the underlying biological neuron and its complexity. Neuroscientists have constructed detailed computational models of many different types of dendrites. These models mimic the behavior of real dendrites to a high degree of accuracy. The tradeoff, however, is that such models are very complex. Thus, it is hard to exhaustively characterize all possible responses of such models and to simulate them on a computer. Even the most powerful computers can only simulate a small fraction of the neurons in any given brain area.

Researchers from the Department of Physiology at the University of Bern have long sought to understand the role of dendrites in computations carried out by the brain. On the one hand, they have constructed detailed models of dendrites from experimental measurements, and on the other hand they have constructed neural network models with highly abstract dendrites to learn computations such as object recognition. A new study set out to find a computational method to make highly detailed models of neurons simpler, while retaining a high degree of faithfulness. This work emerged from the collaboration between experimental and computational neuroscientists from the research groups of Prof. Thomas Nevian and Prof. Walter Senn, and was led by Dr Willem Wybo. "We wanted the method to be flexible, so that it could be applied to all types of dendrites. We also wanted it to be accurate, so that it could faithfully capture the most important functions of any given dendrite. With these simpler models, neural responses can more easily be characterized and simulation of large networks of neurons with dendrites can be conducted," Dr Wybo explains.

This new approach exploits an elegant mathematical relation between the responses of detailed dendrite models and of simplified dendrite models. Due to this mathematical relation, the objective that is optimized is linear in the parameters of the simplified model. "This crucial observation allowed us to use the well-known linear least squares method to find the optimized parameters. This method is very efficient compared to methods that use non-linear parameter searches, but also achieves a high degree of accuracy," says Prof. Senn.

Tools available for AI applications

The main result of the work is the methodology itself: a flexible yet accurate way to construct reduced neuron models from experimental data and morphological reconstructions. "Our methodology shatters the perceived tradeoff between faithfulness and complexity, by showing that extremely simplified models can still capture much of the important response properties of real biological neurons," Prof. Senn explains. "Which also provides insight into 'the essential dendrite', the simplest possible dendrite model that still captures all possible responses of the real dendrite from which it is derived," Dr Wybo adds.

Thus, in specific situations, hard bounds can be established on how much a dendrite can be simplified, while retaining its important response properties. "Furthermore, our methodology greatly simplifies deriving neuron models directly from experimental data," Prof. Senn highlights, who is also a member of the steering committe of the Center for Artifical Intelligence (CAIM) of the University of Bern. The methodology has been compiled into NEAT (NEural Analysis Toolkit) - an open-source software toolbox that automatizes the simplification process. NEAT is publicly available on GitHub.

The neurons used currently in AI applications are exceedingly simplistic compared to their biological counterparts, as they don't include dendrites at all. Neuroscientists believe that including dendrite-like operations in artificial neural networks will lead to the next leap in AI technology. By enabling the inclusion of very simple, but very accurate dendrite models in neural networks, this new approach and toolkit provide an important step towards that goal.

This work was supported by the Human Brain Project, by the Swiss National Science foundation and by the European Research Council.

Among infectious diseases that have caused pandemics and epidemics, smallpox stands out as a success story. Smallpox vaccination led to the disease's eradication in the twentieth century. Until very recently, smallpox vaccine was delivered using a technique known as skin scarification (s.s.), in which the skin is repeatedly scratched with a needle before a solution of the vaccine is applied. Almost all other vaccines today are delivered via intramuscular injection, with a needle going directly into the muscle, or through subcutaneous injection to the layer of tissue beneath the skin. But Thomas Kupper, MD, chair of the Department of Dermatology, and colleagues, had reason to suspect that vaccines delivered by skin scarification may offer better protection against respiratory diseases. In a study published in Npj vaccines, Kupper and co-authors present results from preclinical studies suggesting skin scarification may help generate lung T cells and provide protection against infectious diseases, with implications for prevention of COVID-19.

"We have known for years that this technique was a good way to generate T cells that would home to the skin, but our study shows that skin scarification is also an effective way to generate T cells that home to the lungs," said Kupper. "Vaccine development today is focused on selecting the best antigen(s) for T cells and B cells. But for a vaccine to work to its full potential, it also needs to direct T cells to where they are needed most. For respiratory pathogens, that means getting T cells to the lungs."

Historically, smallpox vaccines used live vaccinia virus (VACV). More recently, the Food and Drug Administration has approved the use of modified vaccinia Ankara (MVA), a modern alternative that lacks about 10 percent of the parent genome and cannot replicate in human cells, thus avoiding the serious side effects seen with VACV. MVA, as a smallpox vaccine, is injected subcutaneously.

Kupper and colleagues set out to determine if the skin scarification route of immunization with MVA could provoke a more effective T cell response than other routes of immunization. The team inoculated mice using either skin scarification, intramuscular, subcutaneous, or intradermal injection. Skin scarification generated more T cells, produced greater numbers of lung-specific T cells and provided superior protection against lethal viral doses than the others.

"We used to think that lung-homing T cells could only be generated by direct lung infection, but here we find overlap between T cells appearing after lung infection and T cells generated through skin scarification," said Kupper.

The authors note that their work is preclinical -- until clinical trials are conducted in humans, it's unknown if the phenomenon seen in the mouse model can be replicated in people. But the work has spurred the Kupper lab to explore the potential for using the MVA vector and skin scarification technique to develop more powerful -- and, potentially universal -- vaccines against other infectious illnesses such as influenza and coronaviruses.

"We have known for a while that you can program T cells to go where you want them to go in the body -- if you want protective T cells in the lungs, this is one way to achieve that. It is a serendipitous finding, but it seems to work very well," said Kupper.

In 2016, a team led by UCLA's Martin Monti reported that a 25-year-old man recovering from a coma had made remarkable progress following a treatment to jump-start his brain using ultrasound.

Wired U.K. called the news one of the best things that happened in 2016. At the time, Monti acknowledged that although he was encouraged by the outcome, it was possible the scientists had gotten a little lucky.

Now, Monti and colleagues report that two more patients with severe brain injuries -- both had been in what scientists call a long-term "minimally conscious state" -- have made impressive progress thanks to the same technique. The results are published online in the journal Brain Stimulation.

"I consider this new result much more significant because these chronic patients were much less likely to recover spontaneously than the acute patient we treated in 2016 -- and any recovery typically occurs slowly over several months and more typically years, not over days and weeks, as we show," said Monti, a UCLA professor of professor of psychology and neurosurgery and co-senior author of the new paper. "It's very unlikely that our findings are simply due to spontaneous recovery."

The paper notes that, of three people who received the treatment, one -- a 58-year-old man who had been in a car accident five-and-a-half years prior to treatment and was minimally conscious -- did not benefit. However, the other two did.

One is a 56-year-old man who had suffered a stroke and had been in a minimally conscious state, unable to communicate, for more than 14 months. After the first of two treatments, he demonstrated, for the first time, the ability to consistently respond to two distinct commands -- the ability to drop or grasp a ball, and the ability to look toward separate photographs of two of his relatives when their names were mentioned.

He also could nod or shake his head to indicate "yes" or "no" when asked questions such as "Is X your name?" and "Is Y your wife's name?"

Small but significant improvement

In the days following the second treatment, he also demonstrated, for the first time since the stroke, the ability to use a pen on paper and to raise a bottle to his mouth, as well as to communicate and answer questions.

"Importantly," Monti said, "these behaviors are diagnostic markers of emergence from a disorder of consciousness."

The other patient who improved is a 50-year-old woman who had been in even less of a conscious state for more than two-and-a-half years following cardiac arrest. In the days after the first treatment, she was able, for the first time in years, according to her family, to recognize a pencil, a comb and other objects.

Both patients showed the ability to understand speech.

"What is remarkable is that both exhibited meaningful responses within just a few days of the intervention," Monti said. "This is what we hoped for, but it is stunning to see it with your own eyes. Seeing two of our three patients who had been in a chronic condition improve very significantly within days of the treatment is an extremely promising result."

The changes the researchers saw are small, but Monti said even the smallest form of communication means a way to reconnect. One powerful moment during the study was when the wife of the 56-year-old man showed him photos and asked whether he recognized who he saw.

"She said to us, 'This is the first conversation I had with him since the accident,'" Monti said. "For these patients, the smallest step can be very meaningful -- for them and their families. To them it means the world."

Using acoustic energy

The scientists used a technique called low-intensity focused ultrasound, which uses sonic stimulation to excite the neurons in the thalamus, an egg-shaped structure that serves as the brain's central hub for processing. After a coma, thalamus function is typically weakened, Monti said.

Doctors use a device about the size of a saucer creates a small sphere of acoustic energy they can aim at different brain regions to excite brain tissue. The researchers placed the device by the side of each patient's head and activated it 10 times for 30 seconds each in a 10-minute period. Each patient underwent two sessions, one week apart.

Monti hopes to eventually translate the technology into an inexpensive, portable device so the treatment could be delivered not only at state-of-the-art medical centers, but also at patients' homes, to help "wake up" patients from a minimally conscious or vegetative state.

The treatment appears to be well tolerated; the researchers saw no changes to the patients' blood pressure, heart rate or blood oxygen levels, and no other adverse events. Monti said the device is safe because it emits only a small amount of energy, less than a conventional Doppler ultrasound.

While the scientists are excited by the results, they emphasize that the technique is still experimental and likely will not be available to the public for at least a few years. For now, there is little that can be done to help patients recover from a severe brain injury that results in either a chronic vegetative state or a minimally conscious state, Monti said.

Monti said his team is planning additional studies to learn exactly how thalamic ultrasound modifies brain function; he hopes to start those clinical trials once the researchers and patients are assured of being safe from COVID-19.

The study's lead author is Josh Cain, a UCLA graduate student in psychology, and a co-senior author is Caroline Schnakers, a former UCLA researcher who is now assistant director of research at Casa Colina Hospital and Centers for Healthcare in Pomona, California. The work was funded by the Tiny Blue Dot Foundation and the Dana Foundation.

Understanding the terminology

People in a coma appear as if they are under general anesthesia; their eyes are closed, and they do not wake up even if someone tries to rouse them. Some people do eventually recover from a coma and regain significant cognitive function. Others move into a puzzling condition called a vegetative state in which they are awake -- that is, their eyes open and close as if they are waking up and falling asleep -- but they show no signs of consciousness.

A minimally conscious state is a condition in which people are awake (they wake up and fall asleep periodically) but show subtle signs that they are conscious -- for example, the ability to blink their eyes in response to a command.

LOS ALAMOS, N.M., January 27, 2021--A new 3D analysis shows that wildland fires flare up in forests populated by similar-sized trees or checkerboarded by large clearings and slow down where trees are more varied. The research can help fire managers better understand the physics and dynamics of fire to improve fire-behavior forecasts.

"We knew fuel arrangement affected fire but we didn't know how," said Adam Atchley, lead author on a Los Alamos National Laboratory-led study published today in the International Journal of Wildland Fire. "Traditional models that represent simplified fuel structures can't account for complex wind and varied fire response to actual forest conditions. Our study incorporated a varied, 3D forest and wind behavior. Adding diverse tree sizes and shapes slowed fire quite a bit, as did adding small gaps between trees. By examining the physics of fire-fuel behavior, we are able to see fundamentally how forest structure affects behavior."

The study for the first time links generalized forest characteristics that can be easily observed by remote sensing and modeled by machine learning to provide insight into fire behavior, even in large forested areas.

Understanding how wildland fire behaves is necessary to curb its spread, and also to plan safe, effective prescribed burns. However, data is limited, and most studies are too simplistic to accurately predict fire behavior. To predict how fire will move through a forest, it is necessary to first paint an accurate picture of a typical forest's diversity with varying density, shapes, and sizes of trees. But this is computationally expensive, so most studies target homogenous forests that rarely occur in nature.

Using its award-winning model, FIRETEC, on high-performance computers at Los Alamos, the team ran 101 simulations with U.S. Forest Service data for Arizona pine forests to realistically represent the variability of forests. The simulations coupled fire and atmospheric factors--such as wind moving through trees--at fine scales to provide a 3D view of how fire, wind, and vegetation interact.

To understand how the forest structure affects fire behavior, Atchley and colleagues repeated simulations with minor changes in the forest structure, which they made by moving trees and randomizing tree shapes. Small changes had monumental impact in fire behavior. However, despite highly variable fire behavior, observable forest characteristics, such as tree diversity and the size of a stand of trees or a clearing, also substantially control how fire spreads.

Results show that the more detailed and varied simulated forest decreases the forward spread of fire spread due to a combination of fuel discontinuities and increases fine-scale turbulent wind structures. On the other hand, large clearings can increase fire spread.

Imagine a 7-year-old and a college student both take a break from their virtual classes to get a drink of water. When they return, the 7-year-old has difficulty restarting the assignment, while the college student resumes working as if the break never occurred. Nelson Cowan, an expert in working memory at the University of Missouri, believes understanding this developmental age difference can help younger children and their parents to better adjust to a virtual learning environment during the COVID-19 pandemic.

"By understanding this developmental difference, then we can work to provide a little more structure for younger children in online settings, such as helping them organize their homework," said Cowan, a Curators Distinguished Professor in the Department of Psychological Sciences. "At school, teachers can provide more of that structure, but in a virtual environment, parents may also have to take on more of that responsibility. For parents who have younger children that are somewhat resistant to their actions, this might be difficult to do, however it needs to be made clear to children that their parents are assisting their teacher, rather than being the primary educational figure."

Kendall Holzum can relate. During the COVID-19 pandemic, the 7-year-old girl has been going to school online instead of in person.

"Sometimes it's hard to remember to go back and do your homework after you get off your Zoom call," Holzum said. "My parents have to help me a lot to remember to do my assignments. Homework is the hardest to follow directions on because your teacher isn't there to always help you."

Cowan, who has been interested in how the human brain works since he was a young child, suggests this insight can be a first step toward helping educators determine how to tailor a child's individual learning experience to their appropriate developmental level.

"Now, the challenge will be to understand how to adapt educational materials and work materials to be appropriate for each individual's developmental level in an online setting and perhaps try to teach children to be more proactive in their thinking," Cowan said. "I'm hoping this is a first step toward that notion and encourages people who do research in the classroom, or now in the virtual classroom, to consider the role of proactive behavior as an overall life skill and how to accommodate various levels of learning to meet that life goal."

A total of 180 people participated in the study by Cowan and his colleagues. Participants were split among three different age groups -- children ages 6-8, ages 10-14 and college students. Each age group was asked to remember a display of colored spots. Then, they were interrupted by a second, unexpected and more urgent task -- quickly pressing a button when a signal is heard or seen. Upon completion of the second task, they were asked to return to the first task and decide if a color came from the display. Cowan said more often, the younger children simply forgot to remember the colors they were supposed to recall after working on the second task. He said this study provides a clear example of the limits of working memory in younger children.

"In general, working memory is limited," Cowan said. "As the amount of things a person is trying to remember at one time increases, less memory is available to help remember a task, or what a person is supposed to be doing. An example of the difference between an adult and a child is when both try to catch a ball while carrying dishes. The child would be more likely to drop the dishes, while the adult remembers to also hold onto the dishes at the same time. Virtual school has created a whole new environment, and this study provides us with a first step in how we must help children adjust as some parts of virtual schooling are very likely to be here for a long time."

WASHINGTON, DC - Investigators leading the Lung Cancer Master Protocol, or Lung-MAP trial, will present findings from three translational medicine studies at the 2020 World Conference on Lung Cancer, to be held online January 28-31, 2021.

The presentations will mark the first time that investigators share translational medicine insights from Lung-MAP, the first large-scale precision medicine trial in lung cancer backed by the National Cancer Institute (NCI), part of the National Institutes of Health, and the first major NCI trial to test multiple treatments, simultaneously, under one "umbrella" design. Since it launched in June 2014, the trial has tested 12 new lung cancer drugs. Lung-MAP has also amassed a scientifically valuable cache of data and biospecimens from 3,021 patients.

"Lung-MAP now has one of the largest collections of data and biospecimens ever gathered for lung cancer," said Roy Herbst, MD, PhD, a Yale University professor and the Lung-MAP study chair. "It's gratifying to see this asset put to use to improve our understanding of lung cancer - and find better ways to treat it."

Results from the Lung-MAP studies will be shared at the 2020 World Conference on Lung Cancer, or WCLC. Organized annually by the International Association for the Study of Lung Cancer, the conference was planned for Singapore but will be held virtually due to the COVID-19 pandemic. The WCLC is the world's largest international gathering of clinicians, researchers, and scientists in the field of lung cancer and thoracic oncology.

Here are summaries of the Lung-MAP presentations to be delivered:

Fred Hirsch, MD, PhD (Tisch Cancer Institute, Mount Sinai) will give an oral presentation on work that examined tumor mutational burden - or TMB - and related biomarkers to evaluate whether there were any connections to clinical outcomes of immunotherapy. Using next-generation sequencing data on tissue from 320 patients enrolled in two sub-studies of patients receiving immunotherapy for the first time under the original Lung-MAP master protocol, Hirsch and colleagues evaluated associations between TMB and how long patients lived, and how long they remained cancer-free. They found that higher TMB was significantly associated with better survival rates, and longer periods of time before patients' lung cancer returned or spread. However, expression of the PD-L1 gene - a "brake" on the immune system that contributes to cancer growth - was not associated with better outcomes. "We found TMB to be a good predictor of outcomes to immunotherapy, which operates independently of PD-L1 expression," Hirsch said. "What was interesting in the findings is the emergence of the idea that when we look at TMB to predict outcomes, we should assess TMB as a continuous variable rather than using fixed cut-off values." Hirsch presents this work January 29 (Abstract OA01.04).

David Kozono, MD, PhD (Dana Farber Cancer Institute) will give a mini-oral presentation of an analysis of next-generation sequencing data gathered from the original Lung-MAP master protocol S1400. Patients on that study had tumor tissue samples genetically tested with Foundation Medicine's FoundationOne T5 assay, which sequences 313 cancer-related genes. Kozono and colleagues analyzed Lung-MAP data from 1,672 patients with squamous cell lung cancer and compared it with squamous lung cancer data from The Cancer Genome Atlas. A primary goal: spot novel pairs of genetic alterations in squamous cell lung cancers. These pairs are important because they provide clues about how mutations may contribute to the growth and spread of cancer - information that can be used to create more effective cancer drugs. In the Lung-MAP data, the team uncovered a set of three genes that have never before appeared together - PARP4, NFE2L2, and KEAP1. These findings suggest that all three genes may affect how lung cells respond to oxidative stress, and how treatment resistance may form, and, for the first time, suggest that PARP4 may play role in this key biological pathway. "With novel pairs of mutations, it's 'guilt by association,'" Kozono says. "When you find these, they can hold a real clue about what a gene does. And when you know what a gene does, you have a better understanding of how it might affect responses to a drug. Kozono presents this work January 31 (Abstract MA11.10).

Philip Mack, PhD (Tisch Cancer Institute, Mount Sinai) will give a mini-oral presentation on the feasibility of using plasma circulating tumor DNA (ctDNA) to detect key cancer mutations that can be used to guide therapy in lung cancer, such as alterations in the BRAF, RET, EGFR, KRAS and MET genes. In Lung-MAP, patients who submitted fresh tissue samples for genetic screening also provided plasma samples to measure ctDNA, an approach to cancer detection, characterization, and monitoring known as a "liquid biopsy." Mack and colleagues studied paired samples of both tissue and plasma from 129 Lung-MAP patients. Of those, 52 had critical driver mutations detected in their tissue biopsy samples. The analysis showed that 43 patients also had the same drivers detected in plasma - for an 83 percent sensitivity rate. Of the 77 patients with no drivers detected in their tissue, two patients had drivers detected in ctDNA - for a 97 percent specificity rate. While the ctDNA results were impressive, Mack said they don't yet support a plasma-only approach to genetic screening. While ctDNA testing is faster, cheaper, and much less invasive for patients, tissue samples are still the genetic screening gold standard. Mack said the results do support the use of ctDNA if patients can't - or won't - undergo a second tumor biopsy. "This would speed enrollment onto the trial, and spare patients time, money, and a painful procedure," Mack said. "That's good news." Mack delivers his presentation January 30 (Abstract MA08.10).

To see the full abstracts for these and all WCLC presentations, visit the conference website.

Lung-MAP is a groundbreaking public-private partnership, one that includes the NCI and its National Clinical Trials Network (NCTN) including SWOG Cancer Research Network, Friends of Cancer Research, the Foundation for the National Institutes of Health (FNIH), Foundation Medicine, pharmaceutical companies which provided their drugs for the study, and several lung cancer advocacy organizations.

Since the trial is offered at more than 700 U.S. medical centers and community hospitals under the NCTN and the NCI Community Oncology Research Program (NCORP), Lung-MAP makes it easier for patients to receive investigational treatments to fight their non-small cell lung cancer. Lung-MAP is more flexible, and faster, than traditional clinical trial models. Where typical trials require the development of individual studies for each new drug tested, Lung-MAP uses a single "master protocol," which is amended as drugs enter and exit the trial, preserving infrastructure and patient outreach efforts. This makes Lung-MAP more efficient and cost-effective, allowing researchers to quickly answer the critical question: Does this new drug work?

Since its launch, Lung-MAP has registered more than 3,660 patients. Lung-MAP leaders have worked with 10 pharmaceutical partners, in coordination with the FNIH, to launch 13 studies, 12 of which are completed. The trial is addressing questions about the efficacy of immunotherapies and immunotherapy combinations and the validity of new biomarkers. The trial has also produced critical insights into the conduct of large-scale precision medicine trials, including tissue sampling and banking, genetic screening, and patient communication.

Plastic is ubiquitous in people's lives. Yet, when plastic-containing items have fulfilled their missions, only a small amount is recycled into new products, which are often of lower quality compared to the original material. And, transforming this waste into high-value chemicals requires substantial energy. Now, researchers reporting in ACS' JACS Au have combined a ruthenium-carbon catalyst and mild, lower-energy reaction conditions to convert plastics used in bottles and other packaging into fuels and chemical feedstock.

Global production of sturdy, single-use plastic for toys, sterile medical packaging, and food and beverage containers is increasing. Polyolefin polymers, such as polyethylene and polypropylene, are the most common plastics used in these products because the polymers' molecular structures -- long, straight chains of carbon and hydrogen atoms -- make materials very durable. It's difficult to degrade the carbon-to-carbon bonds in polyolefins, however, so energy-intensive procedures using high temperatures, from 800 to 1400 F, or strong chemicals are needed to break down and recycle them. Previous studies have shown that noble metals, such as zirconium, platinum and ruthenium, can catalyze the process of splitting apart short, simple hydrocarbon chains and complicated, plant-based lignin molecules at moderate reaction temperatures requiring less energy than other techniques. So, Yuriy Román-Leshkov and colleagues wanted to see if metal-based catalysts would have a similar effect on solid polyolefins with long hydrocarbon chains, disintegrating them into usable chemicals and natural gas.

The researchers developed a method to react simple hydrocarbon chains with hydrogen in the presence of noble- or transition-metal nanoparticles under mild conditions. In their experiments, ruthenium-carbon nanoparticles converted over 90% of the hydrocarbons into shorter compounds at 392 F. Then, the team tested the new method on more complex polyolefins, including a commercially available plastic bottle. Despite not pretreating the samples, as is necessary with current energy-intensive methods, they were completely broken down into gaseous and liquid products using this new method. In contrast to current degradation methods, the reaction could be tuned so that it yielded either natural gas or a combination of natural gas and liquid alkanes. The researchers say implementing their method could help reduce the volume of post-consumer waste in landfills by recycling plastics to desirable, highly valuable alkanes, though technology to purify the products is needed to make the process economically feasible.

What makes cancer cells different from ordinary cells in our bodies? Can these differences be used to strike at them and paralyze their activity? Cancer researchers have been debating this question since the mid-19th century.

A new study from Tel Aviv University (TAU) shows, for the first time, how an abnormal number of chromosomes (aneuploidy) -- a unique characteristic of cancer cells that researchers have known about for decades -- could become a weak point for these cells. The study could lead to the development of future drugs that will use this vulnerability to eliminate the cancer cells.

The study was conducted in the laboratory of Dr. Uri Ben-David of TAU's Sackler Faculty of Medicine, in collaboration with six laboratories from four other countries. It was published in the journal Nature on January 27, 2021.

Aneuploidy is a hallmark of cancer. Normal human cells contain two sets of 23 chromosomes each, one from the father and one from the mother. But aneuploid cells have a different number of chromosomes. When aneuploidy forms in cancer cells, the cells not only "tolerate" it, but it can even advance the progression of the disease. The relationship between aneuploidy and cancer was discovered over a century ago, long before it was known that cancer was a genetic disease and even before the discovery of DNA as hereditary material.

According to Dr. Ben-David, aneuploidy is the most common genetic change in cancer. Approximately 90% of solid tumors, such as breast cancer and colon cancer, and 75% of blood cancers are aneuploid in nature. But researchers' understanding of the how aneuploidy contributes to the development and spread of cancer has been limited.

In the study, the researchers used advanced bioinformatics methods to quantify aneuploidy in approximately 1,000 cancer cell cultures. They then compared the genetic dependency and drug sensitivity of the cells with a high level of aneuploidy to those of the cells with a low level of aneuploidy.

They found that aneuploid cancer cells demonstrate heightened sensitivity to damage to the mitotic checkpoint - a cellular checkpoint that ensures the proper separation of chromosomes during cell division. They also discovered the molecular basis for the heightened sensitivity of aneuploid cancer cells.

The study has important implications for the drug discovery process in personalized cancer medicine. Drugs that delay the separation of chromosomes are undergoing clinical trials, but it is not known which patients will respond to them and which will not. The results of this study suggest that it will be possible to use aneuploidy as a biological marker to identify patients who will respond better to these drugs.

"It should be emphasized that the study was done on cells in a culture and not on cancer patients. In order to translate it to treatment of cancer patients, many more follow-up studies must be performed. Still, even at this stage it is clear that the study could have a number of medical implications," Dr. Ben-David says.