Culture

Newly updated evidence published in the Cochrane Library today compares Alcoholics Anonymous (AA) and clinically-related Twelve-Step Facilitation (TSF) programs with other treatments, such as cognitive behavioural therapy, to see if they help people who suffer from alcohol use disorders achieve sobriety or reduce the amount of alcohol that they consume.

Alcohol use disorder (AUD) is a prevalent, world-wide problem, and in some countries it is accelerating. 'Alcoholics Anonymous' (or AA for short) has been a popular treatment for alcohol use disorder for decades, but much debate has persisted on whether AA - and related 12-step clinical treatments designed to increase AA participation are effective.

AA are peer-led mutual-help groups. Twelve-step facilitation programs adopt some of the principles and techniques of AA and are delivered by clinicians. They are aimed at engaging people within AA during and after treatment for alcohol use disorder. Some of these programs follow a manual, so that the same treatment can be delivered at different times and places.

This Cochrane review looks at the effects of these programs on reducing alcohol consumption and the effects of heavy drinking (such as physical health, family, or employment problems), and enhancing long-term abstinence. The authors of the review also examined whether AA and TSF programs reduce healthcare costs compared to other treatments.

The previous Cochrane review published in 2006 was based on the eight available studies including a few thousand participants. The quantity and quality of the research has increased substantially since then. Twenty-seven studies are now included in this updated Cochrane review, comprising 10,565 people. The studies included in this update examined a range of programs that differed in their approach and intensity, and these were compared against other programs and different treatments for alcohol use disorder.

The authors found high certainty evidence that clinically delivered and manualized TSF programs designed to increase AA participation can lead to higher rates of continuous abstinence over months and years, when compared to other active treatment approaches such as cognitive behavioural therapy. The evidence suggests that 42 % of participants participating in AA would remain completely abstinent one year later, compared to 35% of participants receiving other treatments including CBT. This effect is achieved largely by fostering increased AA participation beyond the end of the TSF program.

When compared to the other treatment approaches Alcoholics Anonymous (AA)-based programs may perform just as well at reducing drinking intensity, negative alcohol-related consequences and addiction severity.

Dr. John Kelly, Elizabeth R. Spallin Professor of Psychiatry at Harvard Medical School and Director of the Massachusetts General Hospital Recovery Research Institute said, "Alcohol use disorder can be devastating for individuals and their families and it presents a significant, worldwide, costly public health problem. Alcoholics Anonymous is a well-known, free, mutual-help fellowship that helps people recover and improve their quality of life. One important finding from this review was that it does matter what type of TSF intervention people receive - better organized and well-articulated clinical treatments have the best result. In other words, it is important for clinical programs and clinicians to use one of the proven manualized programs to maximize the benefits from AA participation."

"In terms of healthcare costs, policy makers will be interested that four of the five economics studies we identified showed considerable cost-saving benefits for AA and related 12-step clinical programs designed to increase AA participation, indicating these programs could reduce healthcare costs substantially."

The News in Brief:

Researchers visualized the first structure of a lipin enzyme - which helps make triglycerides - a first after 20 years of research.

Creating the structure enabled researchers to see how two regions (N-lip and C-lip) come together to form a functional enzyme and better understand how lipins regulate triglyceride production.

The structure is helping the team to understand how mutations in lipins lead to abnormal production of triglycerides central to diseases such as heart disease, obesity and diabetes.

STONY BROOK, NY, March 10, 2020 - The first structure of a lipin enzyme, which carries out an important step in the production of triglycerides, the main reservoir for long-term energy storage, will help scientists to better understand how lipins regulate the production of triglycerides. Led by Mike Airola, PhD, of the Department of Biochemistry and Cell Biology in the College of Arts and Sciences and Renaissance School of Medicine at Stony Brook University, the structure also provides scientists with insights as to why mutations in the enzyme cause a loss of activity that leads to abnormal production of triglycerides implicated in heart disease, obesity and diabetes. The study will published in Nature Communications.

Lipins complete the second to last step of triglyceride production. But when mutations interrupt lipin functions, the body loses its ability to store fat properly, thus potentially triggering a wide variety of metabolic-related conditions. Scientists have unsuccessfully tried to create the first visual structure a lipin enzyme since these enzymes were identified in 2001. Now Airola and colleagues successfully explain in the paper their first crystal structure of a specific enzyme called lipin PAP.

"This structure answers a long-standing question for how two essential regions, N-lip and C-lip, which are located on opposite ends of this protein in humans, come together to form a function enzyme to help make triglycerides," explains Airola, Assistant Professor in the Department of Biochemistry & Cell Biology and director of the Airola Lab. "Using this structure also helps us understand how the protein interacts with membranes, which is key to regulating its activity and the production of triglycerides."

The team used X-ray crystallography, mass spectrometry and biochemistry to visualize the structure, which represents the active state of a lipin enzyme during the production of triglycerides, as well as its other functions namely lipoprotein assembly and cellular signaling.

Valerie Khayyo, a Stony Brook graduate student in the Biochemistry & Structural Biology Program and first author of the study, added that the structure enables researchers to understand and see specific mutational changes in the amino acid building blocks of lipins that result in disease.

Khayyo noted that mutations in lipins are increasingly being identified in patients with muscle disorders as well, such as statin-induced myopathy and extreme cases in childhood rhabdomyolysis.

Overall, Airola says that the structure and study consolidates many previous observations into a unifying framework and sets the stage for scientists to resolve several remaining important questions concerning how lipins are regulated.

An international team of researchers, affiliated with UNIST has for the first time succeeded in demonstrating the ionization cooling of muons. Regarded as a major step in being able to create the world's most powerful particle accelerator, this new muon accelerator is expected to provide a better understanding of the fundamental constituents of matter.

This breakthrough has been carried out by the Muon Ionization Cooling Experiment (MICE) collaboration, which includes many UK scientists, as well as Professor Moses Chung and his research team in the School of Natural Sciences at UNIST. Their findings have been published in the online version of Nature on February 5, 2020.

"We have succeeded in realizing muon ionization cooling, one of our greatest challenges associated with developing muon accelerators," says Professor Chung. "Achievement of this is considered especially important, as it could change the paradigm of developing the Lepton Collider that could replace the Neutrino Factory or the Large Hadron Collider (LHC)."

Muons are naturally occurring particles that are generated in the Earth's upper atmosphere by cosmic rays collisions, thus are regarded as a follow-on particle accelerator to replace the LHC. Protons, a type of hardon, are primarily used by the LHC and they partake in strong interactions. Leptons, like the electron and the muon, are not subject to the strong interaction, rather they interact via the weak force.

Muons have an extremely brief lifespan of two millionths of a second. They are produced by smashing a beam of protons into a target. These muons form a diffuse cloud, meaning that they are difficult to accelerate and there is a low chance of them colliding and producing useful interesting physical phenomena. To make the cloud less diffuse, a process known as 'Beam cooling' was suggested. This involves getting the muons closer together and moving in the same direction. However, due to the ultra-short lifespan of muons, it has been impossible to cool the beam with the traditional methods.

To tackle this challenge, the MICE collaboration team succeeded in channelling muons into a small enough volume to be able to study physics in new systems via a method, known as Ionization Cooling, which was previously suggested and developed into theoretically operable schemes in the 1980s.

The results of the experiment, carried out using the MICE muon beam-line at the Science and Technology Facilities Council (STFC) ISIS Neutron and Muon Beam facility on the Harwell Campus in the UK, clearly shows that the phase-space volume occupied by the muon beam can be controlled via the ionization cooling, as predicted by the theory.

Under our feet, in the soil, is a wealth of microbial activity. Just like humans have different metabolisms and food choices, so do those microbes. In fact, microbes play an important role in making nutrients available to plants.

A recent review paper from Xinda Lu and his team looks at different roles that various soil microbes have in soil's nitrogen cycle. Lu is a researcher at Massachusetts Institute of Technology.

According to Lu, "Soil microbes catalyze most of the transformations of soil nitrogen into plant-usable forms. Diverse microbes use different processes - and sometimes work together. Knowing the various styles of soil microbes, and linking microbes to specific soil processes, can be important knowledge for farmers."

Modern nitrogen fertilizers are applied in the form of ammonium. Through a biological process called nitrification, soil microbes convert ammonium to nitrates that plants can absorb. In order to be efficient at this process, microbes need oxygen. Researchers are studying nitrification because it can be linked to greenhouse gases and loss of fertilizer.

Although microbiologists have been studying the nitrogen cycle for over a century, not all steps were well understood. New microorganisms have recently been identified. A type of prokaryote (single-celled organism) called archaea has also been playing a role in nitrification.

Archaea are not technically soil bacteria, due to their structure. There are many more archaea that contribute to nitrification in some soils than there are bacteria responsible for the same activity. Including the role of archaea in nitrification has broadened the understanding of scientists and researchers.

Researchers reviewed various studies of soil nitrification. This included the abundance of microbes in soil in relation to various environmental factors. Soil pH, temperature and the ratio of soil carbon to soil nitrogen were all compared to the number of microbes in each soil sample. Soil depth and other factors also influence microbe abundance.

Previous studies have shown, for example, that nitrification archaea are more abundant than bacteria in warmer temperatures. Other microbes thrive in lower temperatures.

Soil pH also influences how active soil microbes are in the nitrification process. Soil bacteria Nitrospira were more dominant in acidic soils, including forests and farm fields.

Researchers have also studied how various microbes "talk" to each other. This keeps the nitrification process running smoothly. Various mechanisms have been proposed, including cell signaling. The presence of nitric oxide in soils may enhance interactions between microbes.

Soil scientists are sure they have not found all the microbes that contribute to the vast array of services soils provide. Just as astronomers discover new stars in the sky as tools advance, so will soil microbiologists find new soil microbes. Some may be involved in nitrification.

Collecting and cataloging the type, abundance and location of soil microbes will continue to advance the knowledge we have about the soil nitrogen cycle.

WHAT: Scientists at the National Institutes of Health and other institutions have devised a new strategy to stop tumors from developing the new blood vessels they need to grow. Once thought to be extremely promising for the treatment of cancer, blocking molecules that stimulate new blood vessel growth (angiogenesis) has proven ineffective because tumor cells respond by producing more stimulatory molecules. The new strategy involves disabling key enzymes that replenish the molecule that cells need for the reactions that sustain new vessel growth. The research team was led by Brant M. Weinstein, Ph.D., chief of the Section on Vertebrate Organogenesis at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The study appears in Nature Communications.

Among the angiogenesis factors that stimulate new vessel growth is vascular endothelial growth factor (VEGF), which binds to a receptor on cell surfaces. This binding sets off a sequence of chemical reactions inside the cells lining the inside of blood vessels, culminating in new vessel growth. Previous attempts have sought to prevent this binding by targeting VEGF with antibodies or drugs, or by blocking the receptor so VEGF can't bind to it. However, tumors respond by producing more VEGF, overwhelming such efforts.

After binding occurs, an enzyme that converts the compound phosphatidylinositol-(4,5)-bisphosphate (PIP2) into inositol triphosphate, which is needed for the reactions that fuel new blood vessel growth, and diacylglycerol (DAG). Through a series of enzyme-assisted steps, DAG is converted back into PIP2, allowing it to be recycled, as needed.

The researchers showed that they could stop angiogenesis by blocking any of the enzymes in this PIP2 recycling series. They first halted angiogenesis in human cell cultures and zebrafish embryos by disabling the genes for one or more of the enzymes. They then targeted tumors in mice with drugs that block the recycling enzymes. Compared to normal mice, the treated mice had less tumor and tumor blood vessel growth. Moreover, adding more VEGF depleted any remaining PIP2, further reducing blood vessel growth.

You're at the office. You've typed up a report and press print. Walk over to the printer and retrieve the fresh, inkjet-printed paper. As you admire your work, were you aware that scientists consider the charge of the particles in the liquid ink for improved print quality? Were you aware that understanding charges of particles allows for engineers to make the paints aggregate (gather together) or disperse according to such particle interactions?

A surfactant is something that is added to a liquid (in this study), to make it act with other surfaces. People use surfactants daily at home with soaps, detergents and shampoos to aid in lifting grime off of surfaces. Surfactants also have important industrial uses such as in the lining of pipelines to reduce drag. As one can imagine, understanding how the effect of charges of particles in liquid can have significant impact on how well surfactants work and systems run efficiently. Until now, there was an absence of exploration into how the flow of liquids effect the charges of the particles in the liquid, surfaces and surfactants.

To investigate flow, Cathy McNamee and Hayato Kawakami of Shinshu University built an apparatus where they combined an Atomic Force Microscope, peristaltic pump and camera to visually capture the liquid in the process of flow. They used silica particles and silicon wafers, both with negatively charged surfaces in the presence of ionic surfactants. An ionic surfactant has a "head" that attracts water and a "tail" that repels water. A negative and positive surfactant of the same chain length was used to determine the effect of the charge on the forces, sodium dodecyl sulfate (anionic surfactant) and dodecyl trimethylammonium bromide (cationic surfactant).

McNamee and Kawakami were able to determine that:

* The adsorption of the surfactants to the particles can change when the liquid flow changes the forces between charged particles.

* When the charge of the surfactant was the same as the surface, liquid flow did not increase the adsorption of the surfactants to the particle surfaces, but increased the number of ions near the surfaces. The inter-particle repulsive forces slightly decreased.

* When the charge of the surfactant was opposite to the particles, a low concentration of surfactant flow increased the adsorption of the surfactants to the particle surfaces. This changed the inter-particle forces and could change attractions to repulsions if the appropriate surfactant concentration was used. With high surfactant concentrations where the charge of the surfaces change in the absence of flow, flow tended to increase the stiffness of the film of the adsorbed surfactants.

* It might be possible to control the aggregating ability of charged particles with the flow rate if the appropriate surfactant type and concentration is used.

Professor McNamee found that the flow rate can possibly be used to control the aggregation and dispersion of charged particles, allowing for less surfactant use. During real world uses such as water treatment, it is possible to remove impurities and harmful substances by using charges to gather or repel certain substances. Even our bodies cleverly use surfactants, too. Bile salts, (a surfactant!) aids in digestion. The potential applications of this research range from medicine, such as flow cytometer to all aspects of industry.

Researchers have explained how visual cortexes develop uniquely across the brains of different mammalian species. A KAIST research team led by Professor Se-Bum Paik from the Department of Bio and Brain Engineering has identified a single biological factor, the retino-cortical mapping ratio, that predicts distinct cortical organizations across mammalian species.

This new finding has resolved a long-standing puzzle in understanding visual neuroscience regarding the origin of functional architectures in the visual cortex. The study published in Cell Reports on March 10 demonstrates that the evolutionary variation of biological parameters may induce the development of distinct functional circuits in the visual cortex, even without species-specific developmental mechanisms.

In the primary visual cortex (V1) of mammals, neural tuning to visual stimulus orientation is organized into one of two distinct topographic patterns across species. While primates have columnar orientation maps, a salt-and-pepper type organization is observed in rodents.

For decades, this sharp contrast between cortical organizations has spawned fundamental questions about the origin of functional architectures in the V1. However, it remained unknown whether these patterns reflect disparate developmental mechanisms across mammalian taxa, or simply originate from variations in biological parameters under a universal development process.

To identify a determinant predicting distinct cortical organizations, Professor Paik and his researchers Jaeson Jang and Min Song examined the exact condition that generates columnar and salt-and-pepper organizations, respectively. Next, they applied a mathematical model to investigate how the topographic information of the underlying retinal mosaics pattern could be differently mapped onto a cortical space, depending on the mapping condition.

The research team proved that the retino-cortical feedforwarding mapping ratio appeared to be correlated to the cortical organization of each species. In the model simulations, the team found that distinct cortical circuitries can arise from different V1 areas and retinal ganglion cell (RGC) mosaic sizes. The team's mathematical sampling model shows that retino-cortical mapping is a prime determinant in the topography of cortical organization, and this prediction was confirmed by neural parameter analysis of the data from eight phylogenetically distinct mammalian species.

Furthermore, the researchers proved that the Nyquist sampling theorem explains this parametric division of cortical organization with high accuracy. They showed that a mathematical model predicts that the organization of cortical orientation tuning makes a sharp transition around the Nyquist sampling frequency, explaining why cortical organizations can be observed in either columnar or salt-and-pepper organizations, but not in intermediates between these two stages.

Professor Paik said, "Our findings make a significant impact for understanding the origin of functional architectures in the visual cortex of the brain, and will provide a broad conceptual advancement as well as advanced insights into the mechanism underlying neural development in evolutionarily divergent species."

He continued, "We believe that our findings will be of great interest to scientists working in a wide range of fields such as neuroscience, vision science, and developmental biology."

Transformative actions implemented by cities to address and mitigate the impacts of climate change may be hindered by political struggles for municipal power. This is clear from a study developed by researchers from the Institute of Environmental Science and Technology of the Universitat Autònoma de Barcelona (ICTA-UAB) and the Pompeu Fabra University (UPF), published in the journal Cities, which analyses the complexity of the processes of implementation of urban measures against climate change, with the example of Barcelona's "Superblocks" as a case study.

Cities are high producers of greenhouse gas emissions and urban residents are under high risk of negative climate impacts. However, there are strong untapped opportunities for climate change mitigation and adaptation. These projects promote shifts in the urbanization of cities, which are meant to challenge current unsustainable forms of development. In this regard, the study, led by Christos Zografos researcher from the Department of Political and Social Sciences at Pompeu Fabra University, and co-signed by ICTA-UAB researchers Kai Klause, Isabelle Anguelovski, and James O'Connolly, analyses the process of implementing the "Superblocks" in the Poblenou neighbourhood of Barcelona.

Recent studies determine that Barcelona is particularly vulnerable to climate change-related threats, specifically sea level rise and floods, increasing temperature including urban heat waves, the loss of biodiversity and more frequent and intense drought periods. Within the framework of the Climate Plan (2018-2030), Barcelona launched the "Superblocks" program, which aims to drastically reorganize urban mobility and land use. A superblock is a group of city blocks delimited in a perimeter that can only be accessed by vehicles that have their origin or destination there. Traffic runs outside while the interior is reserved for pedestrians and cyclists.

So far superblocks have been implemented in two areas (Poblenou in 2016 and Sant Antoni in 2018), but the City Council plans to remodel the city in 503 superblocks thereby reducing car traffic by 21% while restructuring the public transit and cycling system and infrastructure. In this way, CO2 emissions will be reduced by 40%, as well as the 3,500 premature deaths per year associated with air pollution, converting 60% of the space occupied by car use into public pedestrian and neighbourhood leisure spaces.

Political and neighbourhood forces for and against its implementation became mobilized. "The study analyses these resistances in Barcelona as an extrapolated example of the difficulties of urban transformational adaptation of cities in the face of climate change," explains Christos Zografos.

The results of the study show that the everyday political struggle for municipal authority that is behind much of the opposition to superblocks has been scarcely highlighted in the international literature. This fight is materialized in clashing visions for the future city, and who has the political influence to define them. The difficulties are also related to discontent over the public participation aspects of project implementation and a perceived imposition of authority. "The civic and political contestation over the authority of 'climate champions' (or climate policy drivers) can jeopardize not only the achievements of transformational adaptation to climate change, but also the political survival of those who drive them", the authors of the article add.

According to ICTA-UAB researcher Isabelle Anguelovski, these actions "can be obstructed not only out of fear of the material and political effects of the transformation measures, but also because of the message it conveys as concerns who is entitled to decide for the common good". Therefore, she indicates, "brave politicians that take on struggles for authority in the short-term are needed to achieve mid- to long-term transformational goals".

New study from Eleanor Coffey's lab at Turku Bioscience Centre in Finland identifies that the JNK protein triggers nerve cells to withdraw their synapses when stressed.

Synapses are tiny cell protrusions where electrochemical impulses pass between nerves. Prolonged stress in the brain causes synapse withdrawal and maladaptive changes to circuits that are linked to the development of major depressive disorder.

Postdoctoral Researcher Patrik Hollós and colleagues used a light-activated optogenetic tool to switch off the activity of a protein called JNK specifically in synapses.

- Using a light beam to inhibit the JNK protein prevented synapses from shrinking in response to stress. Specifically the internalisation of a receptor called "AMPAR", an early event in synapse disassembly, was blocked, explains Hollós.

JNK Is a Stress Sensor in Synapses and May Elicit the Effects of Ketamine

Researchers also found that the novel, fast-acting anti-depressant ketamine inhibited the JNK protein while preventing synapse retraction.

- These results show that the JNK protein is a stress sensor in synapses. When activated, it triggers the disassembly of synapse machinery followed by rapid synapse regression. Conversely, inhibiting the JNK protein makes synapses able to withstand chronic endocrine stress. This may be relevant for conditions where hormonal stress leads to synapse elimination but also to control synapse number under normal homeostatic conditions, says team leader Eleanor Coffey.

These findings help us to understand how stress dismantles synapses, and provides clues for novel targeted therapies.

DURHAM, N.C. - Tanker traffic through the Strait of Hormuz can decline for up to two years after a piracy attack, a new Duke University study finds, but the adverse effects of the slowdown are far greater on some Persian Gulf countries than others.

"Large exporters of crude oil, such as Saudi Arabia, see little significant long-term impact. But for smaller countries such as Bahrain or Kuwait that rely on exports of refined petroleum products in addition to crude oil, it's a different story," said Lincoln F. Pratson, Gendell Family Professor of Energy and Environment at Duke's Nicholas School of the Environment.

These countries export much less energy than their larger neighbors, so their exports - though smaller in magnitude - make up a proportionally larger share of their gross domestic product, Pratson explained. "Even a marginal slowdown in energy shipping will therefore be more significant to them," he said.

If outgoing tanker traffic from Bahrain drops by just one vessel a year following a piracy attack, that country may experience a 1.6% reduction in its gross domestic product (GDP), the new study suggests. Kuwait may see a .67% drop in its GDP if its annual export traffic drops by one vessel.

Their reliance on exports of gasoline, diesel fuel and other refined petroleum products adds to the countries' vulnerability.

"Crude oil is a more resilient export commodity because only a few regions produce it. If prices rise because of security concerns, demand remains strong. But there are nearly 700 refineries worldwide, so when costs for refined petroleum products from the Persian Gulf rise due to piracy, importers can turn to other sources or opt to increase their own domestic production," said Jun U. Shepard, a PhD student in Earth and Ocean Sciences at the Nicholas School and an Energy Data Analytics Fellow at the Duke University Energy Initiative.

"In either case, Bahrain and Kuwait risk losing market share that may not be recovered for years," Shepard said.

Reducing the impacts of piracy on Bahrain and Kuwait's energy exports is important, she added, "not only because we still very much rely on these products, but because the Persian Gulf countries are petrostates that rely on their energy exports as a source of revenue to buy food and other goods that they can't produce on their own."

"If Bahrain and Kuwait can't continue doing this, it could trigger geopolitical instability and civil unrest in the region, which we want to avoid," Shepard said. "It could also increase the volatility of the global transition from fossil fuels to alternative energy sources."

She and Pratson published their peer-reviewed paper March 3 in the journal Energy Policy. They based their findings on a statistical analysis of seven years of data, from 2010 to 2017, on energy exports transported from Persian Gulf countries through the Strait of Hormuz.

Roughly a third of the world's annual supply of energy exports flows through the Strait of Hormuz, which provides the only passage from the Persian Gulf to the open ocean. Bordered by Iran to the north and the United Arab Emirates to the south, the 22-mile-wide strait is a flashpoint for geopolitical conflict and a hotbed of maritime piracy.

More than 750 hijacking attempts occurred in and around the strait from 2010 to 2017, the new study shows. Shipping traffic through the strait declined by 7.5 vessels a year, on average, for up to two years following each incident.

"Maritime piracy in the strait is a kind of low-grade chronic impact on the flow of energy sources to the rest of the world. Past studies have looked at its effect on trade, but this is the first study to examine its impacts on the Persian Gulf countries themselves," Pratson said. "And what we find is that its impact is selective."

Brazilian researchers have just reported proving the potential of zika virus to combat advanced-stage central nervous system tumors in dogs. The study was published on Tuesday, March 10, in the journal Molecular Therapy.

Three elderly dogs with spontaneous brain tumors were treated with injections of zika virus by scientists affiliated with the Human Genome and Stem Cell Research Center (HUG-CELL) supported by São Paulo Research Foundation - FAPESP and hosted by the University of São Paulo (USP).

"We observed a surprising reversal of the clinical symptoms of the disease, as well as tumor reduction and longer survival with quality, which matters most. Moreover, the treatment was well tolerated and there were no adverse side-effects. We're genuinely excited by the results," Mayana Zatz, a professor at USP's Institute of Biosciences (IB) and HUG-CELL's principal investigator told.

The group had already demonstrated zika's capacity to infect and destroy central nervous system tumor cells in mice (read more at: agencia.fapesp.br/27677). In this model, the formation of human tumors is induced in the laboratory, a procedure that can be performed only using immunosuppressed animals. One of the key advantages of the new study, according to the authors, was the possibility of evaluating the effects of the therapy in animals with an active immune system.

"The findings confirm that the therapy acts via two mechanisms. On one hand, the virus infects tumor cells, starts to replicate in them, and eventually kills them. On the other, it alerts the immune system to the presence of the tumor. The infection triggers an inflammatory reaction, and defense cells migrate to the site," said Carolini Kaid, who has a postdoctoral scholarship from FAPESP and is first author of the article.

According to Kaid, central nervous system tumors respond poorly to immunotherapy because the blood-brain barrier that protects the brain from potentially toxic substances present in the blood hinders migration of defense cells to the site.

However, post-mortem analysis of the dogs' brain tissue showed that T lymphocytes, macrophages and monocytes had infiltrated the tumor mass.

"The analysis also showed that zika was present only at the edges of the tumor. No other brain cells were affected. This is a most important finding, enhancing our confidence that the treatment is safe," Kaid said.

Treatment protocol

Three dogs were treated by the HUG-CELL team, all of them patients of Raquel Azevedo dos Santos Madi, a veterinary physician at a private hospital in Granja Vianna, a district of metropolitan São Paulo. All three were diagnosed by MRI scans with advanced-stage cancer, when the clinical signs of the disease are evident. Without treatment, such patients survive for 20-30 days on average.

The virus was inserted into the dogs' cerebrospinal fluid by means of an injection in the region of the spine just below the base of the skull. The virus derived from a strain isolated from a Brazilian patient (ZIKVBR). It was purified and gifted to the group by partners at the São Paulo-based Butantan Institute.

The treatment was conducted at the hospital. The animals were allowed to go home only after three negative tests for the presence of the virus in their blood and urine. "We followed a very strict protocol to avoid contaminating anyone," Zatz said.

The first dog to receive the therapy was Pirata, a 13-year-old pit bull weighing 26 kilograms (kg). "He came to us in a pre-coma. He was unable to stand up and his only source of nutrients was an IV drip. Three days after the injection, he was able to eat again, stand up and even take a few steps. He survived for 14 days but was already very weak and suffered a cardiac arrest. His owners had to put him down," Zatz said.

The longest survival time was observed in Matheus, an eight-year-old boxer weighing 32 kg. This dog survived for 150 days after the therapy. An MRI scan showed 35.5% tumor reduction.

The third patient treated was Nina, a 12-year-old dachshund weighing 6.4 kg. This animal survived for 80 days, with 37.92% tumor reduction.

"In contrast with the effects of chemotherapy, the animals displayed no negative reactions to the treatment. We began with a small dose, which was well tolerated, so we injected a second dose that was ten times larger," Zatz said.

Versatile therapy

The type of tumor was confirmed in each dog by post-mortem histopathology. The boxer had an oligodendroglioma, and the dachshund an intracranial meningioma. "We were unable to identify the pit bull's tumor as we found no tumor cells. The tumor was small and seems to have been eliminated," Kaid said.

In the group's prior experiments with mice, zika destroyed tumor cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor (AT/TR), central nervous system cancers of embryonic origin that usually manifest in children. The researchers also conducted in vitro tests in which they observed zika's potential to infect and destroy glioblastoma and ependymoma cells.

According to Oswaldo Keith Okamoto, a professor at IB-USP and a member of HUG-CELL, the data suggests viral therapy may be applicable to several types of central nervous system cancer in both children and patients over the age of 60. "These two groups tend to suffer more often than not from aggressive types of tumor, for which there are no effective treatments at present," he said.

For over fifteen years, Okamoto has investigated strategies for destroying tumor cells with similar characteristics to stem cells. Although they cannot differentiate into any other type of cell, these "tumor stem cells" make the disease more aggressive and hard to treat (read more at: agencia.fapesp.br/21959/).

The in vitro studies performed by the HUG-CELL group compared the virus's interactions with "tumor stem cells" and healthy neural progenitor cells, a type of brain stem cell that gives rise to neurons, astrocytes and oligodendrocytes, among other nerve cells.

"When we infect the neural progenitor cells, zika interrupts their proliferation, and some of them die. But the spheres [formed when progenitor cells cluster together in 3D culture] remain relatively intact. In the case of tumor stem cells, the destruction is far more prominent. Our in vitro tests also showed that the virus doesn't infect mature nerve cells such as neurons. That's a very positive finding," Kaid said.

According to Okamoto, groups in the United Kingdom and Greece are interested in leading collaborative projects in search of a better understanding of zika's action mechanism in tumor stem cells.

In parallel, the HUG-CELL researchers are refurbishing the dog kennels at IB-USP in preparation for the installation of an intensive care unit for use in further studies. "We learned a great deal from the study with these three dogs, and we now plan to begin a new preclinical trial with a larger number of animals. One of our aims is to discover the ideal dose of the virus for the treatment. If it works, it will offer hope that both dogs and humans can be given the treatment, but we'll need more funding and we're looking for partners," Zatz said.

Breathing dirty air takes a heavy toll on gut bacteria, boosting risk of obesity, diabetes, gastrointestinal disorders and other chronic illnesses, new University of Colorado Boulder research suggests.

The study, published online in the journal Environment International, is the first to link air pollution to changes in the structure and function of the human gut microbiome - the collection of trillions of microorganisms residing within us.

The gaseous pollutant ozone, which helps make up Denver's infamous 'brown cloud' - is particularly hazardous, the study found, with young adults exposed to higher levels of ozone showing less microbial diversity and more of certain species associated with obesity and disease.

"We know from previous research that air pollutants can have a whole host of adverse health effects," said senior author Tanya Alderete, an assistant professor of integrative physiology, pointing to studies linking smog with Type 2 diabetes, weight gain and inflammatory bowel diseases. "The takeaway from this paper is that some of those effects might be due to changes in the gut."

The study comes at a time when air quality in many U.S. cities is worsening after decades of improvement. In December, the Environmental Protection Agency downgraded the Denver metro and north Front Range regions to "serious non-attainment" status for failing to meet national ozone standards.

Regions of eight other states, including some in California, Texas, Illinois, Connecticut, Indiana, New Jersey, New York and Wisconsin, were also penalized for high ozone. Worldwide, according to research published this month, air pollution kills 8.8 million people annually - more than smoking or war.

While much attention has been paid to respiratory health, Alderete's previous studies have shown pollution can also impair the body's ability to regulate blood sugar and influence risk for obesity. Other research has shown visits to emergency rooms for gastrointestinal problems spike on high pollution days, and youth with high exposure to traffic exhaust have greater risk of developing Crohn's disease.

To investigate just what might be going on inside the gut, Alderete's team used cutting-edge whole-genome sequencing to analyze fecal samples from 101 young adults in Southern California.

The researchers looked at data from air-monitoring stations near the subjects' addresses to calculate their previous-year exposure to ozone (which forms when emissions from vehicles are exposed to sunlight), particulate matter (hazardous particles suspended in the air), and nitrous oxide (a toxic byproduct of burning fossil fuel).

Of all the pollutants measured, ozone had the greatest impact on the gut by far, accounting for about 11% of the variation seen between study subjects - more of an impact than gender, ethnicity or even diet. Those with higher exposure to ozone also had less variety of bacteria living in their gut.

"This is important since lower (bacteria) diversity has been linked with obesity and Type 2 diabetes," noted Alderete.

Subjects with higher exposure to ozone also had a greater abundance of a specific species called Bacteroides caecimuris. That's important, because some studies have associated high levels of Bacteroides with obesty.

In all, the researchers identified 128 bacterial species influenced by increased ozone exposure. Some may impact the release of insulin, the hormone responsible for ushering sugar into the muscles for energy. Other species can produce metabolites, including fatty acids, which help maintain gut barrier integrity and ward off inflammation.

"Ozone is likely changing the environment of your gut to favor some bacteria over others, and that can have health consequences," said Alderete.

The study was relatively small and has some limitations, including the fact that stool samples were taken only once.

Alderete is now moving ahead with a larger, more expansive study of young adults in the Denver area. Thanks to a new grant from the nonprofit Health Effects Institute, she's also exploring how prenatal or early-life exposure to air pollution impacts the formation of the gut microbiome in 240 infants.

She said she hopes her work will ultimately influence policymakers to consider moving parks, playgrounds and housing developments away from busy roads and high pollution areas, and invest more in meeting or exceeding air quality standards.

"A lot of work still needs to be done, but this adds to a growing body of literature showing that human exposure to air pollution can have lasting, harmful effects on human health."

Life converts food into cells via dense networks involving thousands of reactions. New research uncovers insights as to how such networks could have arisen from scratch at life's origin. An international team of researchers in Germany, New Zealand and the U.S.A. has investigated metabolic networks of primitive microbes and identified autocatalytic sets (interconnected collections of self-reinforcing reactions) that are older than genes.

Living cells are the end product of metabolic networks. Food molecules that enter the cell are converted to central intermediates that are then channeled into the pathways that produce the molecules of which cells are made. These networks typically entail more than 1000 reactions, almost all of which are performed by enzymes (proteins), which are encoded by genes (nucleic acids). The link between genes and proteins is, in turn, the universal genetic code that instructs ribosomes to make proteins according to the information stored in genes. These components are all interlinked: the ribosome is 50% protein and 50% RNA by weight, the proteins are made of amino acids, the RNA is made of nucleic acid bases, and the amino acids and bases are made by the roughly 1000 reactions in metabolism, which are catalyzed by the enzymes that the genes encode. With so many layers of mutual interdependence, it is no wonder that scientists have been flatly stumped for over a century when it comes to the question of how such a complex system of interactions could arise at the origin of life. As with the evolution of all complex systems, it had to start from something simpler. But what? New findings by Joana C. Xavier and colleagues reported in Proceedings of the Royal Society B in London provide new inroads into this longstanding question.

The new clues come from the least expected of all places: mathematics. Almost 50 years ago the American polymath Stuart Kauffman suggested that theoretical constructs called autocatalytic sets might have been intermediates in the origin of molecular complexity of the kind that we find in metabolism and cells. Such autocatalytic sets consist of elements (members of the set) that are both products and catalysts such that they can make more of themselves given suitable starting material. The analogy to metabolism and enzymes is evident. The existence and properties of such autocatalytic sets remained the subject of much speculation and decades of fierce debate until the mathematician Mike Steel from the University of Canterbury in New Zealand and Wim Hordijk, a computer scientist from The Netherlands, both coauthors on the study, found ways of harnessing them in the computer. They found that a particular class of autocatalytic sets called RAFs (for reflexively autocatalytic food generated networks), which are very similar in design to cellular metabolism, have the unexpected property of being downright likely to arise from scratch. "The surprise is that the elements only need to add a tiny amount of catalysis to the system before they start to make more of themselves" says Steel. "This is what physicists call self organization, a kind of holy grail in origin of life research" adds Hordijk.

With a background in the metabolic networks of real cells, Joana C. Xavier in the Institute for Molecular Evolution at the University of Düsseldorf asked whether RAFs could be detected in the metabolic networks of the most primitive microbes, strict anaerobes that live from H2 and CO2. Indeed, she found that RAFs were there in the metabolism of ancient anaerobes, but they were substantially smaller than the whole metabolic map, comprising only 394 reactions in the case of an ancient microbe that converts H2 and CO2 to acetate for a living and 209 reactions in the case of an ancient microbe that converts H2 and CO2 to methane. "This intermediate size is interesting" says Xavier, "because it points to an intermediate state in the evolution of metabolism, something more complex than individual reactions but less complex than a cell."

The two kinds of unicellular organisms at the focus of the study, called acetogens and methanogens, have long been in the sights of microbiologists interested in the origin of life. They have been linked to the last universal common ancestor, LUCA, and to geochemical reactions at hydrothermal vents. Xavier found that the acetogen and methanogen sets overlap to form an ancient core network of 172 reactions. This ancient conserved core predates the divergence of bacteria and archaea and has intriguing properties. It can generate amino acids and nucleic acid bases from a simple starting food set, but if provided only the bases as food, no network at all emerges. "Not only have autocatalytic networks left fossils in real metabolism, they preceded both RNA and protein polymers in evolution, that is a step forward in my book," says Kauffman, coauthor of the study and autocatalysis pioneer.

William Martin at the University of Düsseldorf and coauthor of the study says "The networks that trace to LUCA's metabolism are older than genes, they point to natural order in the chemical reactions of life." Acetogens and methanogens grow under the kinds of conditions that are encountered today at hydrothermal vents. Did life arise at hydrothermal vents? "The closer we look, the more signs keep pointing in that direction" says Xavier, "the idea keeps uncovering findings that converge. These vents were probably the first bioreactors on Earth." The identification of autocatalytic networks as components of modern metabolism takes them off the drawing board and into the real world of microbial life. That they uncover fossils from the earliest stages of chemical evolution was unexpected, and opens up new routes for the study of our deepest evolutionary past, probing the time 4 billion years ago, when life was just starting from a small set of naturally-occurring chemical reactions that took place somewhere, perhaps at a hydrothermal vent.

LA JOLLA, CA--Within two months, SARS-CoV-2, a previously unknown coronavirus, has raced around globe, infecting over a 100,000 people with numbers continuing to rise quickly. Effective countermeasures require helpful tools to monitor viral spread and understand how the immune system responds to the virus.

Publishing in the March 16, 2020, online issue of Cell, Host and Microbe, a team of researchers at La Jolla Institute for Immunology, in collaboration with researchers at the J. Craig Venter Institute, provides the first analysis of potential targets for effective immune responses against the novel coronavirus. The researchers used existing data from known coronaviruses to predict which parts of SARS-CoV-2 are capable of activating the human immune system.

When the immune system encounters a bacterium or a virus, it zeroes in on tiny molecular features, so called epitopes, which allow cells of the immune system to distinguish between closely related foreign invaders and focus their attack. Having a complete map of viral epitopes and their immunogenicity is critical to researchers attempting to design new or improved vaccines to protect against COVID-19, the disease caused by SARS-CoV-2.

"Right now, we have limited information about which pieces of the virus elicit a solid human response," says the study's lead author Alessandro Sette, Dr. Biol.Sci, a professor in the Center for Infectious Disease and Vaccine Research at LJI. "Knowing the immunogenicity of certain viral regions, or in other words, which parts of the virus the immune system reacts to and how strongly, is of immediate relevance for the design of promising vaccine candidates and their evaluation."

While scientists currently know very little about how the human immune system responds to SARS-CoV-2, the immune response to other coronaviruses has been studied and a significant amount of epitope data is available.

Four other coronaviruses are currently circulating in the human population. They cause generally mild symptoms and together they are responsible for an estimated one quarter of all seasonal colds. But every few years, a new coronavirus emerges that causes severe disease as was the case with SARS-CoV in 2003 and MERS-CoV in 2008, and now SARS-CoV-2.

"SARS-CoV-2 is most closely related to SARS-CoV, which also happens to be the best characterized coronavirus in terms of epitopes," explains first author Alba Grifoni, Ph.D, a postdoctoral researcher in the Sette lab.

For their study, the authors used available data from the LJI-based Immune Epitope Database (IEDB), which contains over 600,000 known epitopes from some 3,600 different species, and the Virus Pathogen Resource (ViPR), a complementary repository of information about pathogenic viruses. The team compiled known epitopes from SARS-CoV and mapped the corresponding regions to SARS-CoV-2.

"We were able to map back 10 B cell epitopes to the new coronavirus and because of the overall high sequence similarity between SARS-CoV and SARS-CoV-2, there is a high likelihood that the same regions that are immunodominant in SARS-CoV are also dominant in SARS-CoV-2 is," says Grifoni.

Five of these regions were found in the spike glycoprotein, which forms the "crown" on the surface of the virus that gave coronaviruses their name; two in the membrane protein, which is embedded in the membrane that envelopes the protective protein shell around the viral genome and three in the nucleoprotein, which forms the shell.

In a similar analysis, T cell epitopes were also mostly associated with the spike glycoprotein and nucleoprotein.

In a completely different approach, Grifoni used the epitope prediction algorithm hosted by the IEDB to predict linear B cell epitopes. A recent study by scientists at the University of Texas Austin determined the three-dimensional structure of the spike proteins, which allowed the LJI team to take the protein's spatial architecture into account when predicting epitopes. This approach confirmed two of the likely epitope regions they had predicted earlier.

To substantiate the SARS-CoV-2 T cell epitopes identified based on their homology to SARS-CoV, Grifoni compared them with epitopes pinpointed by the Tepitool resource in the IEDB. Using this approach, she was able verify 12 out of 17 SARS-CoV-2 T cell epitopes identified based on sequence similarities to SARS-CoV.

"The fact that we found that many B and T cell epitopes are highly conserved between SARS-CoV and SARS-CoV-2 provides a great starting point for vaccine development," says Sette. "Vaccine strategies that specifically target these regions could generate immunity that's not only cross-protective but also relatively resistant to ongoing virus evolution."

Driven by the discovery of mechanisms associated with the microbiota (the set of microbes that make up the intestinal flora) and its impact on health, the two scientific articles now published are the result of work previously developed at IGC and which involves three Research Groups. In 2014, when researchers first realized that the bacterium E. coli, when introduced into the host, developed genetic mutations with a speed and frequency never before anticipated, new questions arose: What is the influence of the other species of bacteria in the intestine in this process? What influence does host aging have on the process? What impact does inflammation have on the evolution of the microbiota? What genetic mutations occur and how do they happen?

Using the mouse as an animal model (host) and the bacterium E. coli, a well-studied colonizer of the human intestine that is susceptible to mutations in the intestinal tract, the research groups have unveiled two new mechanisms in the microbiota.

The research group led by Isabel Gordo is interested in understanding how bacteria evolve. Knowing that old age leads to changes in the composition of gut bacteria, the study now published (1) looked at populations of young and old mice and how E. coli evolved in both communities.

Assuming that old age is associated with a progressive deterioration of the host functions, the surprising fact that resulted from this work shows that E. coli evolves in the elderly to cope with the stressful environment, becoming potentially pathogenic and potentially increasing the risk of disease.

The inflammation associated with the old age of the host gives an added stress factor to the bacterium in the gut, causing it to evolve into a version potentially more dangerous to the health of the host.

For Isabel Gordo, leader of the research group, "it was fascinating to observe that in just one month of colonization of the old mice, the evolution of E. coli revealed its versatility in acquiring mutations capable of adapting to the pressure imposed by the increased inflammation of the intestine".

The discoveries now made will allow the start of a new investigation focused on the study of these mechanisms in people with inflammatory bowel disease. In Portugal alone, inflammatory bowel disease (such as Ulcerative Colitis and Crohn's Disease) affects about 7000 to 15000 people and impacts their quality of life.

Knowing that E. coli evolves in young and elderly people differently, since in the intestine of the elderly the type of colonizing species differs from the type that colonizes the youngest, the researchers wanted to understand how this bacterium acts when alone or when accompanied.

The research group led by Karina Xavier, responsible for studying the signaling features of bacteria, found that the metabolism of E. coli differs if it is alone or in the company of other bacteria (2).

When introduced into the host alone, E. coli proved to be an excellent colonizer, gaining a lot of space in its environment and consuming amino acids. When it is introduced in the company of another bacteria from the microbiota, Blautia coccoides, the investigation revealed that the genetic changes of the bacterium happened faster and in a mora diversified way due to the interaction: there is competition for available nutrients and E. coli starts to consume other nutrients, only made available due to the presence of B. coccoides.

This work shows that the evolution of E. coli in the mouse gut is responding primarly to the interaction with other members of the microbiota. According to the leader of the research group, Karina Xavier, " our data demonstrates that the presence of a competing species in the host's intestine alters the metabolic environment of the gut, and the bacteria quickly adapt to the new metabolic environement by reshapping their metabolism ". When alone in the gut E. coli evolved to be more efficient in consuming aminoacids, as these were the most abundant nutrients in the intestines. In the presence of a member of the microbiota aminoacids become scarce and simple sugars released by the metabolism of the micobiota members become available and thus evolution favored selection for mutants that are better in consuming these compounds. In the future "we will study how the microbiota reacts and evolves in the presence of different host behaviors, such as the type of diet, and how this is reflected in health or pathogenicity."