Culture

In addition, the review found no consistent evidence that cannabidiol (CBD) moderates the effects of tetrahydrocannabinol (THC - the psychoactive component of cannabis) in healthy volunteers

Single dose of THC, roughly equivalent to smoking one joint, may induce a variety of psychiatric symptoms associated with schizophrenia and other psychiatric disorders. These effects are larger with intravenous administration than with inhaled administration, while tobacco smokers have fewer symptoms - though the authors stress that further work is needed to test this, and this finding should not be taken as a recommendation to use tobacco to counter the effects of THC.

These findings highlight the risks of cannabis use, which are highly relevant as medical, societal, and political interest in cannabinoids continues to grow.

A single dose of the main psychoactive component in cannabis, tetrahydrocannabinol (THC), can induce a range of psychiatric symptoms, according to results of a systematic review and meta-analysis of 15 studies including 331 people with no history of psychotic or other major psychiatric disorders, published in The Lancet Psychiatry journal.

At the same time, the results from an analysis of four studies found no consistent evidence that cannabidiol (CBD) induces psychiatric symptoms itself or that it moderates THC's effects in healthy volunteers. On the other hand, the review and analysis suggest that smokers are less sensitive to the effects of THC, but this finding is preliminary, and the authors do not recommend using tobacco for this purpose.

"As the THC-to-CBD ratio of street cannabis continues to increase, it is important to clarify whether these compounds can cause psychotic symptoms. Our finding that THC can temporarily induce psychiatric symptoms in healthy volunteers highlights the risks associated with the use of THC-containing cannabis products. This potential risk should be considered in discussions between patients and medical practitioners thinking about using cannabis products with THC. This work will also inform regulators, public health initiatives, and policy makers considering the medical use of THC-containing cannabis products or their legalisation for recreational use," says Professor Oliver Howes from King's College London, UK. [1]

Cannabis is one of the most widely used psychoactive substances worldwide, with 6-7% of the population in Europe using it every year, over 15% in the USA, and around 188 million people globally. The drug has been legalised in 11 US states, Canada, and Uruguay, and policymakers elsewhere are deliberating whether to allow the medicinal use of cannabis products.

Over 150 years ago, a first study found an association between cannabis use and psychotic symptoms, such as paranoia and hallucinations, and the effects were subsequently linked to THC. Many studies support the original findings, but there have been discrepancies, and the contribution made by factors such as dose, prior cannabis use, and the method of administration (inhaling, oral capsules, or intravenous injections) has not been systematically evaluated.

For the current review, researchers identified 15 studies that studied participants' psychiatric symptoms following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants. The studies included scores for an increase in severity of positive psychotic symptoms (including delusions and hallucinations), negative psychotic symptoms (such as blunted affect and amotivation), and general symptoms (including depression and anxiety), which were compared after THC administration versus placebo. A change in symptoms with an effect size of 0.4 or more was considered clinically important, and an effect size of more than 0.70 was considered a large effect.

The doses of THC in the meta-analysis ranged from 1.25mg to 10mg, leading to peak THC blood levels of 4.56 to 5.1 ng/ml when orally administered and 110-397 ng/ml when injected or inhaled. These blood levels are comparable to those seen shortly after smoking a single typical cannabis joint containing 16-34mg of THC.

Compared to placebo, THC was found to induce significantly more severe positive psychotic symptoms (average effect size of 0.91), negative symptoms (average effect size 0.78), general symptoms (average effect size 1.01) and total symptoms (average effect size 1.10). The effect sizes remained significant for all types of symptom regardless of sex, age, dose, route of administration, prior cannabis use and tobacco use. However, intravenous administration had more pronounced effects than inhaled THC on psychotic and negative symptoms, while there were insufficient studies to assess the effect of oral THC. [2] Greater induction of psychotic symptoms by THC was associated with lower rates of tobacco use, [3] and greater induction of negative symptoms was associated with a higher age [4].

Dr Faith Borgan from King's College London says: "Our finding that schizophrenia-like symptoms can be induced using a compound that activates the receptor to which THC binds in the brain adds to recent work showing that cannabinoid 1 receptor proteins are altered in people with schizophrenia. As our results were in healthy people, the implications for clinical patients will need further work," [1]

The authors speculate that the finding that the induction of psychotic symptoms was lower in people with higher tobacco use suggests tobacco smokers are less sensitive to the effects of THC. However, further work is needed to test causality and the authors do not recommend the use of tobacco to counter THC. They say that smokers could be less sensitive to the effects of THC due to an association between tobacco smoking and lower brain cannabinoid 1 receptor levels.

The authors also reviewed four studies that examined the effects of CBD on the development of the same psychiatric symptoms, compared to placebo, and no significant differences were found. In studies that focused on whether CBD counters THC-induced symptoms, one study identified reduced symptoms, using a modest sample, but three larger studies failed to replicate this finding.

The authors highlight several limitations to their study. Their finding that psychotic symptoms were not moderated by dose or by prior cannabis use contrasts with results from several studies and may reflect limited power in the analysis. They suggest that further work is needed to clarify the effects, particularly at the level of individual symptoms. The authors identified potential publication bias, where significant findings are more likely to be published than lower effect sizes. However, they found that the better the quality of the study, the greater the effect size, suggesting that their results - which also included lower quality studies - may in fact underestimate the size of the effect of THC on inducing symptoms.

Writing in a linked Comment, lead author Dr Carsten Hjorthøj (who was not involved in the study) from Copenhagen University Hospital, Denmark, says: "Finally, although THC, alone or in combination with, for example, CBD might have a role in treating certain symptoms, caution should not be thrown to the wind. As Hindley and colleagues have clearly demonstrated, there are at least transient psychiatric symptoms associated with even relatively low doses of THC. Of course, this result should not be extrapolated as meaning that single doses of THC will eventually lead to schizophrenia or other severe disorders. However, it might be prudent to extrapolate and paraphrase the words of Moore and colleagues from their 2007 meta-analysis to apply to both recreational and medicinal use of THC-containing cannabis: 'there is sufficient evidence to warn people that using THC could increase their risk of developing psychiatric symptoms or even a psychotic illness'."

WHAT:
The virus that causes coronavirus disease 2019 (COVID-19) is stable for several hours to days in aerosols and on surfaces, according to a new study from National Institutes of Health, CDC, UCLA and Princeton University scientists The New England Journal of Medicine. The scientists found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detectable in aerosols for up to three hours, up to four hours on copper, up to 24 hours on cardboard and up to two to three days on plastic and stainless steel. The results provide key information about the stability of SARS-CoV-2, which causes COVID-19 disease, and suggests that people may acquire the virus through the air and after touching contaminated objects. The study information was widely shared during the past two weeks after the researchers placed the contents on a preprint server to quickly share their data with colleagues.

The NIH scientists, from the National Institute of Allergy and Infectious Diseases' Montana facility at Rocky Mountain Laboratories, compared how the environment affects SARS-CoV-2 and SARS-CoV-1, which causes SARS. SARS-CoV-1, like its successor now circulating across the globe, emerged from China and infected more than 8,000 people in 2002 and 2003. SARS-CoV-1 was eradicated by intensive contact tracing and case isolation measures and no cases have been detected since 2004. SARS-CoV-1 is the human coronavirus most closely related to SARS-CoV-2. In the stability study the two viruses behaved similarly, which unfortunately fails to explain why COVID-19 has become a much larger outbreak.

The NIH study attempted to mimic virus being deposited from an infected person onto everyday surfaces in a household or hospital setting, such as through coughing or touching objects. The scientists then investigated how long the virus remained infectious on these surfaces.

The scientists highlighted additional observations from their study:

If the viability of the two coronaviruses is similar, why is SARS-CoV-2 resulting in more cases? Emerging evidence suggests that people infected with SARS-CoV-2 might be spreading virus without recognizing, or prior to recognizing, symptoms. This would make disease control measures that were effective against SARS-CoV-1 less effective against its successor.
In contrast to SARS-CoV-1, most secondary cases of virus transmission of SARS-CoV-2 appear to be occurring in community settings rather than healthcare settings. However, healthcare settings are also vulnerable to the introduction and spread of SARS-CoV-2, and the stability of SARS-CoV-2 in aerosols and on surfaces likely contributes to transmission of the virus in healthcare settings.

The findings affirm the guidance from public health professionals to use precautions similar to those for influenza and other respiratory viruses to prevent the spread of SARS-CoV-2:

Avoid close contact with people who are sick.
Avoid touching your eyes, nose, and mouth.
Stay home when you are sick.
Cover your cough or sneeze with a tissue, then throw the tissue in the trash.
Clean and disinfect frequently touched objects and surfaces using a regular household cleaning spray or wipe.

The signaling molecule interleukin-2 (IL-2) has long been known to have powerful effects on the immune system, but efforts to harness it for therapeutic purposes have been hampered by serious side effects. Now researchers have worked out the details of IL-2's complex interactions with receptor molecules on immune cells, providing a blueprint for the development of more targeted therapies for treating cancer or autoimmune diseases.

IL-2 acts as a growth factor to stimulate the expansion of T cell populations during an immune response. Different types of T cells play different roles, and IL-2 can stimulate both effector T cells, which lead the immune system's attack on specific antigens, and regulatory T cells, which serve to rein in the immune system after the threat is gone.

"IL-2 can act as either a throttle or a brake on the immune response in different contexts," said Nikolaos Sgourakis, assistant professor of chemistry and biochemistry at UC Santa Cruz. "Our investigation used detailed biophysical methods to show how it does this."

Sgourakis is a corresponding author of the new study, published March 17 in Proceedings of the National Academy of Sciences. First author Viviane De Paula, a visiting scientist in his lab from the Federal University of Rio de Janeiro, used nuclear magnetic resonance spectroscopy (NMR) to observe IL-2's structural dynamics. The study was done in close collaboration with corresponding author Christopher Garcia's group at Stanford University.

The researchers were able to show that IL-2 adopts two different structural forms (termed conformations) that affect how it interacts with the receptors on different types of T cells. In solution, IL-2 naturally shifts back and forth between a minor conformation and a major conformation. The study also showed how certain mutations or interactions with other molecules can bias IL-2 toward adopting one conformation or the other.

"We have now come one step closer to a detailed understanding of how the IL-2 cytokine works," de Paula said. "It is the first time that anyone has managed to observe a transient state of IL-2 directly. With the use of NMR, we were able to describe the structure, dynamics, and function of IL-2 in its two conformations."

The study opens up numerous possibilities for designing drugs to stabilize IL-2 in a particular conformation for therapeutic applications.

"We can use this information to tweak the balance, depending on what we want to achieve in a clinical setting," Sgourakis said. "To target regulatory T cells, we would want to stabilize the minor conformation, and to target effector T cells, we would want to stabilize the major conformation."

Previous efforts by other researchers had already shown that different monoclonal antibodies targeting IL-2 could promote the expansion of different T cell populations in mice. One of these antibodies in complex with IL-2 was effective in treating mouse models of autoimmune disease and inflammation. And a similar human monoclonal antibody is currently heading toward clinical trials for the treatment of autoimmune diseases.

The new study provides a mechanistic explanation for these effects that can guide further drug discovery efforts.

"The details of the mechanism we present offer a direct blueprint for drug discovery," said Garcia. "Every drug company wants to know how to engineer this cytokine, and this paper provides some of the first really bona fide structural clarity on the fascinating topic of IL-2 dynamics."

Thriving bacteria employ some of the strategies of a good rummy player, says Bert Ely, a University of South Carolina biologist.

Ely recently discovered that when bacteria add new DNA to their genome, they release another group of genes that had not proven useful. Much like a rummy player who draws a card and then discards it later if it doesn't help complete the hand.

"That's what I see these bacteria doing," Ely said. "They take some random piece of DNA and incorporate it into the genome, and it doesn't do them a bit of good. So when the next one comes, they replace one that they don't need."

His discovery, recently published in the science journal PLOS ONE, details how bacteria gain new DNA without overloading their genomes.

Bacteria take in DNA from the environment around them through a process called horizontal gene transfer. It can result in the microorganisms gaining new biochemical abilities, which can help them outgrow other bacteria and possibly infect other organisms, like humans, more easily.

But if their genomes become too large, the cells would have to spend more time and energy replicating their DNA, giving them an evolutionary disadvantage, Ely says. The way bacteria kept their genome sizes under control was a mystery until recently, when Ely was studying related strains of bacteria in a lab.

A biologist friend had asked Ely to sequence a strain of bacteria to confirm that it had a particular mutation. "Instead, what I found out is that the strain is a hybrid of two strains that were in the lab," Ely says. "In this case, I knew where the new segments in the genome came from -- from the other strains in the lab."

Because he had sequenced the DNA for the strain he was examining as well as two closely related strains, Ely was able to compare the genomes. He noticed that the bacteria were not only adding genes, but they were shedding some, too.

"What this study showed was that they don't just take up and add genes to the chromosomes that they have, but they take up and swap out," Ely says. "Every time they add something, they remove something."

What's more, Ely says, the portions of DNA that were removed tended to be genes that were already different from their parent cells. In other words, they were genes that had been taken on through an earlier instance of horizontal gene transfer. Because most new pieces of DNA would not be helpful for survival, there is an evolutionary preference for deleting those portions, Ely says.

But if the DNA is helpful, it is more likely to stay. "Any bacterium with a new gene that is beneficial will outgrow its neighbors," Ely says. "The gene addition/deletion occurs about once per 20,000 generations a beneficial gene is unlikely to be lost."

One draw every 20,000 generations? That's a very slow game of rummy.

"But you might draw the right card after only 20,000 generations," Ely says. "Optimism is important."

A new laboratory method allows researchers to create compartments within a liquid that, like drops of oil in water, are separate but have no physical barrier between them. The method could help researchers understand how human cells use similar "membraneless compartments" to segregate and concentrate components for important cellular processes, chemical reactions, or other biological functions.

Researchers at Penn State developed and used the method to create complex multi-sectioned compartments and compartments within compartments, all without any physical dividers or membranes. Their results are published in a paper that appears online in the journal Biomacromolecules.

"A cell has a variety of compartments or containers, like the nucleus and mitochondria, with membranes that separate their contents from the rest of the cell," said Gregory Mountain, graduate student at Penn State and an author of the study. "These compartments help the cell perform different tasks in different locations. But researchers are continuing to discover compartments within the cell that lack physical outer membranes and that can form and then dissolve as needed. Disruption of these membraneless compartments has been implicated in diseases such as ALS, Alzheimer's, and Type II Diabetes."

Membraneless compartments within cells result from the separation of molecules like proteins and RNA into different liquid phases. To create membraneless compartments in the lab, the researchers combined simplified charged polymers of repeating amino acids and/or nucleic acids in water. The polymers were fluorescently labeled, which allowed the researchers to monitor the resulting interactions.

As the charged polymers interacted, with opposite charges attracting, separate compartments formed in the liquid with no physical dividers. Combining four polymers allowed the researchers to produce droplets with two compartments as well as compartments-within-compartments. Combining six polymers produced droplets with three compartments.

"This straightforward method allows us to understand the basic chemistry of how multi-phase compartments could form and dissolve within a cell," said Mountain. "Then we can build up the complexity. Factors like temperature, salt concentration, acidity, and charge strength of the polymers can affect how these compartments behave, so it is important to first understand the common conditions under which their formation is possible."

To understand how molecules might accumulate within compartments, the researchers added macromolecule probes. They found that the probes tended to accumulate within compartments that contained polymers having the strongest charge-based interactions with the probes.

"Membraneless compartments might form within a cell to perform a specific task using specific components," said Mountain. "But it's unclear how the cell controls what components go where and why some molecules end up in one compartment versus another. By identifying the properties that determine where probe molecules end up within multi-phase compartments, we can start to understand how cells might prepare for chemical reactions."

Next, the researchers are exploring how to selectively dissolve and reform individual compartments using a variety of control mechanisms. For example, manipulating one of the charged polymers within a compartment to make it neutral could cause that compartment to selectively dissolve within a multi-compartment system.

"Eventually we hope to control when compartments appear and what types of molecules they contain." said Mountain. "We also hope to create systems with multiple kinds of membraneless compartments that can be individually controlled. Our work provides the groundwork for an experimental model of multi-compartment membraneless organelles within living cells and may one day also allow us to create artificial cells with multi-phase compartments."

Botulinum toxins -- a.k.a. botox -- have a variety of uses in medicine: to treat muscle overactivity in overactive bladder, to correct misalignment of the eyes in strabismus, for neck spasms in cervical dystonia, and more. Two botulinum toxins, types A and B, are FDA-approved and widely used. Although they are safe and effective, the toxins can drift away from the site of injection, reducing efficacy and causing side effects.

New research at Boston Children's Hospital finds that some small engineering tweaks to botox B could make it more effective and longer-lasting with fewer side effects. The findings were reported today in PLOS Biology.

A third way for botox B to bind to nerves

Botox works by attaching to nerves near their junction with muscles, using two cell receptors. Once docked, it blocks release of neurotransmitter, paralyzing the muscle.

Min Dong, PhD, at Boston Children's, with lab members Linxiang Yin, PhD, Sicai Zhang, PhD, and Jie Zhang, PhD, had been looking for ways to get botox B to bind to nerve cells more strongly, to keep it in place and avoid side effects. In another member of the botox family, type DC, they identified a potential third means of attachment: a lipid-binding loop capable of penetrating lipid membranes. Through structural modeling studies, they discovered that when particular amino acids are at the tip of the loop, the toxin can indeed use the loop to attach to the nerve-cell surface, in addition to binding to toxin receptors.

They further found that although botox B contains this same lipid-binding loop, it lacks these key amino acids at its tip. So Dong and colleagues added them in through genetic engineering.

As hoped, the introduced changes enhanced the toxin's ability to bind to nerve cells. In a mouse model, the engineered toxin was absorbed by local neurons around the injection site more efficiently than the FDA-approved form of botox B, with less diffusion away from the injection site. This led to more effective local muscle paralysis, longer-lasting local paralysis, and reduced systemic toxicity.

"Based on our mechanistic insight, we created an improved toxin that showed higher therapeutic efficacy, better safety range, and much longer duration," says Dong. "The type A toxin does not have the lipid-binding loop, so we are still working on engineering this lipid-binding capability into type A."

Researchers at Baylor College of Medicine have identified a genetic signature combining certain maternal and fetal gene variants that are associated with a higher risk of preeclampsia. Preeclampsia is a pregnancy complication resulting from sudden elevation in blood pressure that may lead to maternal organ dysfunction and fetal growth restriction. If the condition is not controlled, eclampsia, a serious disorder that causes life-threatening seizures, may follow. Ten to 15 percent of maternal mortality is associated with preeclampsia and eclampsia.

What causes preeclampsia is not known, and the condition is difficult to predict, but in this new study published in Scientific Reports, Drs. Manu Banadakoppa, Meena Balakrishnan and Chandra Yallampalli in the Department of Obstetrics & Gynecology at Baylor discovered that a particular combination of two maternal and one fetal gene variants seems to predispose women to preeclampsia. The genes are linked to the complement system, an important part of the body's immune defense against infection that also can drive inflammation. This genetic signature of the condition could be used in the future to identify women at risk and prepare in advance to manage their condition.

A University of Massachusetts Amherst biostatistician who directs the UMass-based Flu Forecasting Center of Excellence was invited by the White House Coronavirus Task Force to participate Wednesday morning in a coronavirus modeling webinar.

The four-hour, virtual gathering will include 20 of the world's leading infectious disease and pandemic forecasting modelers, from researchers at Harvard, Johns Hopkins and the Centers for Disease Control and Prevention (CDC) in the U.S. to those based at institutions in England, Hong Kong, South Africa and the Netherlands.

According to the White House Coronavirus Task Force coordinator Dr. Charles Vitek, "This webinar is designed to highlight for the Task Force what modeling can tell us regarding the potential effects of mitigation measures on the coronavirus outbreak. The unprecedented speed and impact of the nCoV-19 epidemic requires the best-informed public health decision-making we can produce."

Nicholas Reich, associate professor in the School of Public Health and Health Sciences, heads a flu forecasting collaborative that has produced some of the world's most accurate models in recent years. He and postdoctoral researcher Thomas McAndrew have been conducting weekly surveys of more than 20 infectious disease modeling researchers to assess their collective expert opinion on the trajectory of the COVID-19 outbreak in the U.S. The researchers and modeling experts design, build and interpret models to explain and understand infectious disease dynamics and the associated policy implications in human populations.

Reich is co-author of a new study in the Annals of Internal Medicine that calculates that the median incubation period for COVID-19 is just over five days and that 97.5 percent of people who develop symptoms will do so within 11.5 days of infection. The incubation period refers to the time between exposure to the virus and the appearance of the first symptoms.

The study's lead author is UMass Amherst biostatistics doctoral alumnus Stephen Lauer, a former member of the Reich Lab and current postdoctoral researcher at the Johns Hopkins Bloomberg School of Public Health.

The researchers examined 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. They conclude that "the current period of active monitoring recommended by the U.S. Centers for Disease Control and Prevention [14 days] is well supported by the evidence."

Everyday life without artificial intelligence is barely conceivable in today's world. Countless applications in areas such as autonomous driving, foreign language translations or medical diagnostics have found their way into our lives. In chemical research, too, great efforts are being made to apply artificial intelligence (AI), also known as machine learning, effectively. These technologies have already been used to predict the properties of individual molecules, making it easier for researchers to select the compound to be produced.

This production, known as synthesis, usually involves considerable effort as there are many possible synthesis routes to producing a target molecule. Since the success of each individual reaction depends on numerous parameters, it is not always possible, even for experienced chemists, to predict whether a reaction will take place - and even less how well it will work. In order to remedy this situation, a team of chemists and computer scientists from the University of Münster (Germany) has joined forces and developed an AI tool which has now been published in the journal "Chem".

Background and method:

"A chemical reaction is a highly complex system", explains Frederik Sandfort, PhD student at the Institute of Organic Chemistry and one of the lead authors of the publication. "In contrast to the prediction of properties of individual compounds, a reaction is the interaction of many molecules and thus a multidimensional problem," he adds. Moreover, there are no clearly defined "rules of the game" which, as in the case of modern chess computers, simplify the development of AI models. For this reason, previous approaches to accurately predicting reaction results such as yields or products are mostly based on a previously gained understanding of molecular properties. "The development of such models involves a great deal of effort. Moreover, the majority of them are highly specialized and cannot be transferred to other problems," Frederik Sandfort adds.

The focus of the work presented was therefore on a general applicability of the programme, so that other chemists can easily use it for their own work. To ensure this, the model is based directly on molecular structures. "Every organic compound can be represented as a graph, in principle as an image," explains Marius Kühnemund, another author, from the field of computer science. "On such graphs, simple structural queries - comparable to the question of colours or shapes in photo - can be made in order to capture the so-called chemical environment as accurately as possible."

The combination of many such successive queries results in a so-called molecular fingerprint. These simple number sequences have long been used in chemoinformatics to find structural similarities and are well suited for computer-aided applications. In their approach, the authors use a large number of such fingerprints to represent the chemical structure of each molecule as accurately as possible. "In this way, we have been able to develop a robust system that can be used to predict completely different reaction results," adds Marius Kühnemund, "The same model can be used to predict both yields and stereoselectivities, which is unique".

The authors demonstrated that their programme can be applied easily and allows accurate predictions, especially in combination with modern robotics, by using a data set that was not originally created for machine learning. "This data set contains only relative sales of the starting materials and no exact yields," Frederik Sandfort explains. "For exact yields, calibrations have to be created. However, due to the high effort involved, this is rarely done in reality".

The team will continue to develop their programme further and equip it with new functions in the future. Prof. Frank Glorius is confident: "When it comes to evaluating large amounts of complex data, computers are fundamentally superior to us. However, our goal is not to replace synthetic chemists with machines, but to support them as effectively as possible. Models based on artificial intelligence can significantly change the way we approach chemical syntheses. But we are still at the very beginning."

A majestic ponderosa pine, standing tall in what is widely thought to have been the "center of the world" for the Ancestral Puebloan people, may have more mundane origins than previously believed, according to research led by tree-ring experts at the University of Arizona.

A study published in the journal American Antiquity provides new data that calls into question the long-held view of the Plaza Tree of Pueblo Bonito as the sole living tree in an otherwise treeless landscape, around which a regional metropolis in New Mexico's Chaco Canyon was built.

Combining various lines of evidence, the study is the first to apply a technique called dendroprovenance to a sample of the plaza tree that uses tree-ring growth patterns to trace the tree's origin. The data revealed that the tree did not grow where it was found, and is therefore unlikely to have played a role as significant as various authors have ascribed to it ever since it was discovered in 1924.

According to the study's first author, Christopher Guiterman, who is an assistant research scientist at the University of Arizona's Laboratory of Tree-Ring Research, "the tree goes back all the way to the birth of tree-ring science - a supposedly living tree growing in 'downtown Chaco' during the height of its occupancy - which would make it the only tree of its kind that we know of in southwestern archaeology."

The largest of the buildings known as great houses in Chaco Canyon, Pueblo Bonito is considered widely as the center of the Chaco world, which spanned the four corners region all the way to the edge of the Colorado Plateau. Pueblo Bonito's significance has been likened to Stonehenge in Great Britain and Machu Picchu in Peru. According to the National Park Service, the cultural thriving of the Chacoan people began in the mid 800s and lasted more than 300 years.

During that time, the occupants constructed massive stone buildings, or great houses, consisting of multiple stories that accommodated hundreds of rooms. By 1050, Chaco had become the ceremonial, administrative and economic center of the San Juan Basin and is thought to have served as a major hub connecting trading routes. Pueblo descendants consider Chaco a special gathering place where people shared ceremonies, traditions and knowledge.

During a 1924 dig at Pueblo Bonito, archeologists of the National Geographic Society excavated a 20-foot long pine log in the west courtyard of the monumental great house. The discovery itself was a sensation, Guiterman said.

"The likelihood of finding such a tree after lying undisturbed for 800-plus years seems unbelievable, but we know that is what happened because tree rings don't lie," he said.

The tree was reportedly found just beneath the present-day soil surface, lying on the last utilized pavement. Its "great, snag-like roots precluded the possibility of it ever having been moved," according to the description of expedition leader Neil Judd of the Smithsonian Institution.

"It's important to recognize that these are only the stubs of roots, not the entire root system," said co-author Jeffrey Dean, UArizona professor emeritus of anthropology. "Lacking the root system, combined with the fact that the log was lying flat on top of the latest plaza surface, means that the plaza tree did not grow in the Pueblo Bonito Plaza."

Dendrochronological analyses initiated in 1928 by Andrew Ellicott Douglass, the founder of the University of Arizona Laboratory of Tree-Ring Research, confirmed that the tree lived between 732 and 981, and likely longer, since its outermost wood had eroded away over time.

Guiterman said he had been vexed by the tree's origin story for a long time. Was it the lone remnant of a pine forest growing in Chaco Canyon, the only tree that didn't get cut down for some unknown reason? Or had it been lying there undisturbed all along, even during the peak of the Chacoan culture?

"You don't just find a 1,000-year-old piece of wood on the ground like that," said Guiterman, whose earlier research in the School of Natural Resources and the Environment revealed that the 25,000 trees used to build Pueblo Bonito did not grow nearby, but were transported from distant mountain ranges.

To find out where the plaza tree had come from, Guiterman and his co-authors assembled three lines of evidence, "not unlike building a legal case," as he put it. They scrutinized documentary records, including unpublished correspondence and reports from the early archeological expeditions, strontium isotope signatures from pine trees living in the Chaco Canyon area today and tree-ring patterns that allow scientists to pinpoint the source of the wood in question.

While winter precipitation patterns are fairly uniform across Arizona, New Mexico and Colorado, the summer rainstorms known as monsoons are much more local, Guiterman explained, and the resulting variation in tree-ring patterns allows researchers to match a wood sample to the area where it grew.

"We have this incredible database from 100-plus years of tree-ring science," said Guiterman, who has dated hundreds of trees. "Trees from the San Juan Mountains, the Jemez Mountains or the Chuska Mountains - they all have their own kind of flavor, their own peculiar signature."

Based on the combined analyses of the available evidence, Guiterman and his co-authors conclude that the Plaza Tree of Pueblo Bonito did not grow in Pueblo Bonito or Chaco Canyon. Instead, it most likely was hauled in from the Chuska Mountain range 50 miles west of Chaco Canyon, probably along with many other ponderosa pine beams used in construction. The tree lived in the Chuska Mountains for more than 250 years.

"We will never know exactly when it died because its outer sapwood rings were lost to decay," the authors wrote, "but we estimate that it was living until the early 1100s. Following its death, by either natural causes or cutting, it was transported to Pueblo Bonito in the 12th century, where it was either abandoned or employed for some purpose (possibly as a standing pole). It could have toppled or been left standing to eventually collapse onto the plaza. Finally, it was buried by windblown sand over the centuries."

Yet, even knowing the likely birthplace of Pueblo Bonito's Plaza Tree, the mystery of its purpose remains, Guiterman said.

"Why did the ancient Chacoans carry this tree there, and how?" he said. "We don't see any drag marks, so they must have treated these heavy beams with great care. How they did that is up for debate."

Various roles for the plaza tree of Pueblo Bonito have been brought forth. For example, it could have been used as a ceremonial pole or as a gnomon -- the part of a sundial that casts a shadow. Or perhaps it was simply leftover lumber or cast aside as firewood.

According to Barbara Mills, a Regents Professor in the UArizona School of Anthropology who was not involved in the study, it is unlikely a conclusive answer will ever be found.

"Nobody knows what the tree was used for, and unless there were any further clues waiting to be uncovered, such as traces of pollen left behind on the log, we have no way of knowing," Mills said.

Pine trees are known to play roles in present-day Puebloan life. During the San Geronimo Festival held in Taos, New Mexico, for example, pine trees are brought in and used for ceremonial pole climbing or to hang bags with offerings.

"It is not uncommon to bring a pine tree into the plaza during ceremonies, and certain kinds of dancers or kachinas hold boughs of pine in their hands during their dances," Mills said, "but we don't know how far back those practices go. We rely on descendant oral tradition as much as we can, but we have to be careful to not over-extend our interpretations and use as many lines of evidence as we can."

For months in 2019, Chidiogo Anyigbo, M.D., MPH, had been consumed by the need to learn more and read more about the upcoming 2020 Census. Dr. Anyigbo realized that in asking peers to underscore the importance of the Census with patients and families, the pediatrician hadn't yet put herself in their shoes.

In late-December 2019, she decided it was time act. She fastened a big yellow pin provided by the DC Mayor's Census Complete Count Committee that stated "Ask me about the 2020 Census" and that day strove to weave her brief spiel into patients' clinical visits.

"To my surprise, I was able to have a meaningful exchange in two minutes. I discovered ways to
work the topic into conversation while gathering the social history, finishing the physical exam
or when providing anticipatory guidance. While some parents met my question with a quizzical
look, others were excited to share their positive and negative thoughts about the Census," Dr. Anyigbo writes in "In the Moment," the latest installment in a narrative series published by Academic Pediatrics.

Dr. Anyigbo's research focuses on the relationship between stress, health and social determinants of health. She aims to develop family-centered interventions that can support parents in minimizing the toxic effects of adversity on children. For her, an accurate Census count can play a critical role since the data drives funding for key resources such as health care, schools, grocery stores and nutrition programs that are critical to disrupting the negative effects of poverty and other adverse experiences.

One of her encounters that clinic day was with a mother and her 11-year-old son who had not participated in the 2010 Census. Dr. Anyigbo's narrative describes how she was able to learn why and discuss with the family the importance of completing this year's Census.

"The exchange with this mother and son put a face to the statistic of the 1 million children not
counted in the 2010 Census," Dr. Anyigbo writes in the narrative. "Thinking about my patient, I realize that for a majority of his childhood, he was invisible and not counted in the planning and allocation of resources for programs such as Medicaid, Women, Infants and Children (WIC) and funding for Title I schools for his community. His complex housing situation put him, along with children who live with grandparents or households with low English proficiency, at the greatest risk of being missed in the Census."

Because of her passion for her patients and the community she serves, Dr. Anyigbo plans to bring up the importance of the Census again and again, well beyond the April 1, 2020, official Census Day.

"Few other two-minute investments of my time can have such a profound and lasting impact," Dr. Anyigbo writes. "My message to families is simple: Please complete the Census, include all children who live in your home, and know that your responses are safe and secure."

Melbourne researchers have mapped immune responses from one of Australia's first novel coronavirus (COVID-19) patients, showing the body's ability to fight the virus and recover from the infection.

Researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) - a joint venture between the University of Melbourne and the Royal Melbourne hospital - were able to test blood samples at four different time points in an otherwise healthy woman in her 40s, who presented with COVID-19 and had mild-to-moderate symptoms requiring hospital admission.

Published today in Nature Medicine is a detailed report of how the patient's immune system responded to the virus. One of the authors on the paper, research fellow Dr Oanh Nguyen said this was the first time that broad immune responses to COVID-19 have been reported.

"We looked at the whole breadth of the immune response in this patient using the knowledge we have built over many years of looking at immune responses in patients hospitalised with influenza," Dr Nguyen said.

"Three days after the patient was admitted, we saw large populations of several immune cells, which are often a tell-tale sign of recovery during seasonal influenza infection, so we predicted that the patient would recover in three days, which is what happened."

The research team was able to do this research so rapidly thanks to SETREP-ID (Sentinel Travellers and Research Preparedness for Emerging Infectious Disease), led by Royal Melbourne Hospital Infectious Diseases Physician Dr Irani Thevarajan at the Doherty Institute.

SETREP-ID is a platform that enables a broad range of biological sampling to take place in returned travellers in the event of a new and unexpected infectious disease outbreak, which is exactly how COVID-19 started in Australia.

"When COVID-19 emerged, we already had ethics and protocols in place so we could rapidly start looking at the virus and immune system in great detail," Dr Thevarajan said.

"Already established at a number of Melbourne hospitals, we now plan to roll out SETREP-ID as a national study."

Working together with University of Melbourne Professor Katherine Kedzierska, a laboratory head at the Doherty Institute and a world-leading influenza immunology researcher, the team were able to dissect the immune response leading to successful recovery from COVID-19, which might be the secret to finding an effective vaccine.

"We showed that even though COVID-19 is caused by a new virus, in an otherwise healthy person, a robust immune response across different cell types was associated with clinical recovery, similar to what we see in influenza," Professor Kedzierska said.

"This is an incredible step forward in understanding what drives recovery of COVID-19. People can use our methods to understand the immune responses in larger COVID-19 cohorts, and also understand what's lacking in those who have fatal outcomes."

Dr Thevarajan said that current estimates show more than 80 per cent of COVID-19 cases are mild-to-moderate, and understanding the immune response in these mild cases is very important research.

"We hope to now expand our work nationally and internationally to understand why some people die from COVID-19, and build further knowledge to assist in the rapid response of COVID-19 and future emerging viruses," she said.

High-resolution micro-CT scanning of the skull of the fossil specimen known as "Little Foot" has revealed some aspects of how this Australopithecus species used to live more than 3 million years ago.

The meticulous excavation, cleaning and scanning of the skull of the ~3.67 million-year-old fossil specimen has revealed the most complete Australopithecus adult first cervical vertebra yet found. A description of the vertebra by Wits University researchers Dr Amélie Beaudet and the Sterkfontein team was published in the Scientific Reports. This research program is supported by the the Centre of Excellence in Palaeosciences, Scientific Palaeontological Trust, National Research Foundation, University of the Witwatersrand and the French National Centre for Scientific Research through the French Institute of South Africa.

The first cervical vertebra (or atlas) plays a crucial role in vertebrate biology. Besides acting as the connection between the head and the neck, the atlas also plays a role in how blood is supplied to the brain via the vertebral arteries.

By comparing the atlas of "Little Foot" with other fossils from South and East Africa as well as living humans and chimpanzees, the Wits University team shows that Australopithecus was capable of head movements that differ from modern humans.

"The morphology of the first cervical vertebra, or atlas, reflects multiple aspects of an organism's life," says Beaudet, the lead author of the study. "In particular, the nearly complete atlas of 'Little Foot' has the potential to provide new insights into the evolution of head mobility and the arterial supply to the brain in the human lineage."

The shape of the atlas determines the range of head motions while the size of the arteries passing through the vertebrae to the skull is useful for estimating blood flow supplying the brain.

"Our study shows that Australopithecus was capable of head movements that differ from us. This could be explained by the greater ability of Australopithecus to climb and move in the trees. However, a southern African Australopithecus specimen younger than 'Little Foot' (probably younger by about 1 million years) may have partially lost this capacity and spent more time on the ground, like us today."

The overall dimensions and shape of the atlas of "Little Foot" are similar to living chimpanzees. More specifically, the ligament insertions (that could be inferred from the presence and configuration of bony tubercles) and the morphology of the facet joints linking the head and the neck all suggest that "Little Foot" was moving regularly in trees.

Because "Little Foot" is so well-preserved, blood flow supply to the brain could also be estimated for the first time, using evidence from the skull and vertebrae. These estimations demonstrate that blood flow, and thus the utilisation of glucose by the brain, was about three times lower than in living humans, and closer to the those of living chimpanzees.

"The low investment of energy into the brain of Australopithecus could be tentatively explained by a relatively small brain of the specimen (around 408cm3), a low quality diet (low proportion of animal products) or high costs of other aspects of the biology of Australopithecus (such as upright walking). In any case, this might suggest that the human brain's vascular system emerged much later in our history."

Currently we are facing a dementia epidemic, with estimations showing that by 2050 approximately 131 million people will be affected. Every 7 seconds a patient is diagnosed worldwide. Because the common forms of dementia occur in the elderly, delaying the onset or worsening of the cognitive impairment could translate into a significant reduction of the incidence of the disease. Estimations have shown that of the huge number of cases expected by 2050, roughly 23 million could be avoided if the onset of the disease could be delayed by 2 years. Despite the ambition to identify a disease modifying therapy or a cure for dementia by 2025 set by the G8 dementia summit in 2013, the findings so far are not very encouraging.

To date there is growing evidence of the association of vascular risk factors like hypertension, high cholesterol levels or diabetes mellitus with cognitive impairment and Alzheimer's disease. Unfortunately, simply managing these risk factors had little effect in reducing the incidence of dementia. These factors, however, strongly increase the risk of a patient to suffer an ischemic stroke and incident stroke approximately doubles the risk of dementia. From the study of Saver published in 2006 we know that "each hour in which treatment fails to occur the brain loses as many neurons as it does in 3.6 years of normal aging".

These neuronal losses occur through ischemic necrosis in the core of the infarction, but may be prolonged up to 2 weeks after the ischemic insult in the penumbral area surrounding the ischemic core through another type of cell loss, namely apoptosis. In initiating apoptosis oxidative species have a major role. Several authors have shown consistent increases in oxidative stress after an ischemic stroke. As the authors pointed out in a previous study, oxidative stress increases mainly after cardioembolic stroke, followed by lacunar stroke, with a less prolonged burst of generation of oxidative species following thrombotic stroke.

There is a considerable overlap between the oxidative stress-induced pathogenesis in ischemic stroke and Alzheimer's disease including mitochondrial dysfunction (the mitochondria being the main generators of energy in the cells), calcium overload of the cells, activation of different destructive enzymes by the excess intracellular calcium, aberrant gene transcription and expression, induction of autophagy (a process by which cells degrade their own cytoplasmic proteins and organelles) and activation of inflammatory responses.

Despite promising results of antioxidant molecules in animal models of ischemic stroke, human clinical trials were disappointing possibly due to late administration and incorrect selection of patients. However, in a study published in 2019, edaravone (an antioxidant molecule) given within 48 hours after endovascular revascularization in acute ischemic stroke was associated with greater functional independence at hospital discharge, lower in-hospital mortality and reduced intracranial hemorrhage after admission in a study which enrolled over 10,000 patients. More recently in a report presented at the International Stroke Conference 2020, nerinetide or NA1, a molecule which reduces endogenous nitric oxide (also an oxidative species) generated inside the cell during ischemia, improved the outcome of ischemic stroke patients who underwent endovascular thrombectomy. Unfortunately, NA1 interacted with alteplase, limiting its efficiency in patients who were also thrombolysed.

Antioxidants have been evaluated also in patients suffering from degenerative diseases, Alzheimer's disease included, with promising results in animal models but inconclusive results in clinical trials. Therapeutic strategies are hampered by the dual role of oxidative species in the organism. On one hand, increased ROS production contributes to age-related chronic conditions and on the other, oxidant species function as signaling molecules in pathways that are critical for cell survival. However, based on the compelling evidence of the implication of oxidative stress in AD pathogenesis and of the pivotal role of mitochondria, molecules acting as mitochondria-targeted antioxidants show promise in animal models of neurodegenerative diseases, improve mitochondrial function after coronary ischemia/reperfusion in rats, and some have already been developed into drugs used in clinical trials in type 2 diabetic patients.

In view of the implication of oxidative stress in the genesis of AD pathology, the authors hypothesize that with aging, in the presence of well-established vascular risk factors, and possibly with a genetic contribution, AD pathology develops slowly without clinically overt cognitive impairment. However, after a stroke there is a sudden burst in oxidative stress which accelerates the pathogenesis of dementia and leads to clinically obvious cognitive impairment. If this hypothesis would be proven the reason for reaching antioxidant treatment in acute ischemic stroke would be reinforced. Further studies in this direction with long follow-up periods would be needed. Nonetheless, in view of the high incidence and prevalence of the disease, the results could be rewarding.

Many foods - whether it's the mozzarella on your favorite pizza, the olive oil in salad dressing or hollandaise sauce during asparagus season - contain lots of fat. The fatty acids in these foods are among the essential nutrients that people need to survive. When someone eats more fatty acids than the body can immediately convert into energy, the extra amount is stored in tissues - often in the form of unwanted rolls of fat around the hips or stomach - and serves as a kind of reserve supply.

The quantity of fatty acids transported by blood to the tissues and deposited there is determined by a wide range of factors. Researchers at the Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC) have now identified one of these factors as the protein EHD2.

If this protein is missing completely, fat-storing cells take up significantly more fatty acids from the cellular environment. Dr. Claudia Matthaeus first observed this phenomenon in the brown adipose tissue of mice during her work at the MDC. She finds it particularly exciting that EHD2 apparently plays a key role in human fat metabolism, too. "We have discovered that overweight people produce less EHD2 than people with normal weight," Matthaeus says. It is not clear yet why this is the case. Based on these new insights, Matthaeus and her colleagues, including researchers from the MDC research group led by Professor Oliver Daumke, assume that EHD2 controls a metabolic pathway that regulates fatty acid uptake in fat cells. This pathway is modified in obesity, the researchers write in the journal PNAS.

Cellular uptake of fat occurs when portions of the cell membrane pinch off

Oliver Daumke is long acquainted with EHD2. The structural biologist has been characterizing the structure and mechanimsm of this protein for more than ten years. As a membrane protein, EHD2 resides inside muscle and fat cells. During the inward folding of the cell envelope, small flask-shaped membrane structures called caveolae are formed. These invaginations either remain on the surface of the cell membrane or they pinch off and carry foreign material - such as fatty acids - into the cell. This process is known as endocytosis, Daumke explains. The researcher assumes that the EHD2 protein assembles into ring-like structures around the neck of the membrane vessel and thus stymies the pinch-off process. Daumke is convinced that if EHD2 is not present as a stabilizer, caveolae pinch off more frequently and the cell takes up more fat.

This is precisely what Matthaeus and her colleagues examined. The researchers worked with mice in which the EHD2 gene had been switched off. Using an electron microscope, Matthaeus observed that compared to normal mice, many more caveolae had become detached from the plasma membrane. She was also able to determine that fatty acid uptake was greater in cells lacking EHD2 and that the lipid droplets, which are intracellular accumulations of fat, were larger in these cells.

Obesity influences EHD2 production

Matthaeus asked herself if she would also be able to observe an influence of EHD2 on fat metabolism in humans. So she, together with a colleague from Leipzig University, studied tissue samples from men and women with different body weight. She quickly discovered that in people who were overweight (body mass index of 25 or higher), cells produce less EHD2 than in slim people. The researcher presumes that there is a correlation between frequent membrane pinch-off and the formation of fat depots. "During obesity, we observed that the number of caveolae and their detachment from the membrane get out of sync," Matthaeus says.

In November, Matthaeus left the MDC to take a position at the National Institutes of Health in the United States. There she plans to continue her research into caveolae and fat metabolism. "There are still many unanswered questions," Matthaeus says. She is now especially interested in investigating the transport of fatty acids within the cell and the formation of lipid droplets.