Human cells harness power of detergents to wipe out bacteria

HOWARD HUGHES MEDICAL INSTITUTE

 VIDEO: WHEN SALMONELLA (RED) INVADES A CELL, APOL3 (GREEN) GLOMS ON TO THE BACTERIUM'S SURFACE AND BREAKS IT APART. view more 

CREDIT: R. GAUDET ET AL./SCIENCE 2021

Cells, like many of us, fend off germs with cleaning products.

Researchers have discovered that a molecule made throughout much of the body wipes out invading bacteria like a detergent attacking an oily stain.

This killer cleaner, a protein known as APOL3, thwarts infections by dissolving bacterial membranes, Howard Hughes Medical Institute Investigator John MacMicking and his colleagues report in the journal Science on July 15, 2021. His team tested the protein on the food-poisoning bacteria Salmonella and other similar microbes.

The work offers new insight into how human cells defend themselves against infection, a process termed cell-autonomous immunity. While scientists knew that cells could attack bacterial membranes, this study uncovers what appears to be the first example of a protective intracellular protein with detergent-like action.

MacMicking hopes the findings could one day aid efforts to develop new treatments for infections. "This is a case where humans make their own antibiotic in the form a protein that acts like a detergent," says MacMicking, an immunologist at Yale University. "We can learn from that."

CAPTION

When microbes like Salmonella (green) infect human cells, they overrun the cells' liquid interiors. Researchers have discovered how cells fight back: with a detergent-like molecule, called APOL3, that kills the bacteria by breaking up their membranes.

CREDIT

R. Gaudet et al./Science 2021

Breaching barriers

When it comes to defending the human body, the specialized cells of the immune system act as a crew of cellular bodyguards. But the same alarm signals that mobilize these cells can also activate average citizens. A signal called interferon gamma, for instance, cranks up protein production in non-immune cells that compose our tissues and organs. But scientists know little about how such proteins help cells fight pathogens.

The researchers infected some of these non-immune cells with a strain of Salmonella, which invades cells' watery interiors. Salmonella belongs to a class of bacteria bounded by two membranes. The outer bacterial membrane acts like armor, protecting the inner bacterial membrane from threats like antibiotics.

The team found that the interferon gamma alarm signal could prevent Salmonella from taking over human cells, but the researchers didn't know which proteins came to the rescue. MacMicking's team screened more than 19,000 of the human cells' genes, looking for ones that might encode protective proteins. That work led the researchers to discover APOL3, which receives assistance from a second molecule, GBP1, and probably others. Using high-resolution microscopy and other techniques, the team pieced together the mechanism: GBP1 damages a bacterium's outer membrane, allowing APOL3 through so it can break apart the inner membrane -- the "coup de grace" that kills the bacterium, MacMicking says.

Like a laundry detergent, APOL3 possesses parts attracted to water and parts drawn to grease. Instead of removing dirt from fabric, these components remove chunks of the bacterial inner membrane, which is composed of greasy molecules called lipids.

This process must be highly selective, MacMicking says, since APOL3 needs to avoid attacking membranes of the human cell itself. The team found that APOL3 avoids cholesterol, a major constituent of cell membranes, and instead targets distinctive lipids favored by bacteria.

CAPTION

Before killing Salmonella, the detergent-like protein APOL3 (green) must get through the bacteria's protective outer membrane (red), as shown in the cross sections above.

CREDIT

R. Gaudet et al./Science 2021

A new defender

APOL3 appears likely to be in the toolbox of many cells. MacMicking's team showed it defends cells within the blood vessels and gut. Because APOL3 appears in a variety of body tissues, the scientists believe it offers wide protection.

The discovery of this detergent-like molecule within non-immune cells "adds more evidence to the view that any cell in the body can be part of the immune system," says Carl Nathan, who studies host-pathogen interactions at Weill Cornell Medical College, and who was not involved in this research. "It also adds a new example of one of the limited ways living things kill each other," he notes.

Whether perforating, poisoning, or starving a pathogen, the immune system has developed several methods for killing threatening cells. APOL3 joins the group of mechanisms already known to fatally break down membranes, Nathan says.

Researchers are still a long way from being able to apply this discovery to therapies for infections. But deciphering the body's defenses could give humanity new tools against microbes that are increasingly evolving ways to thwart conventional antibiotics. Dialing up cellular detergents and other devices the body uses to kill bacteria, for instance, could help supplement the natural immune response, MacMicking says.

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Citation

Ryan Gaudet et al. "A human apolipoprotein L with detergent-like activity kills intracellular pathogens." Science. Published online July 15, 2021. doi: 10.1126/science.abf8113

 

For people with kidney disease, there is no safe amount of lead in drinking water

Study reveals that even low levels allowed by the Environmental Protection Agency can impact health.

AMERICAN SOCIETY OF NEPHROLOGY

Research News

 

Washington, DC (July 15, 2021) -- Lead levels in drinking water that are permissible by the Environmental Protection Agency have detrimental health effects in individuals with kidney disease, according to a new study. The findings appear in an upcoming issue of JASN.

Despite advances in reducing the amount of lead in drinking water, low levels of contamination remain widespread throughout the United States. This may be especially dangerous for the 30-40 million Americans living with chronic kidney disease, who have heightened susceptibility to the toxic effects of lead.

To examine the effects of low levels of lead contamination on individuals with advanced kidney disease, investigators analyzed health information for 597,968 patients initiating dialysis in the United States between 2005 and 2017. The team also assessed lead concentrations in community water systems in the 5-year period prior to dialysis initiation, relying on city-level data from the Environmental Protection Agency's Safe Drinking Water Information System.

The investigators focused on the potential effects of lead on levels of hemoglobin, the oxygen carrying protein in red blood cells known to be effected by lead poisoning.

Individuals living in cities with detectable levels of lead in their community's water had significantly lower hemoglobin concentrations before starting dialysis and during the first month of dialysis therapy. They also were prescribed higher doses of medications to treat anemia, which occurs when red blood cell counts or hemoglobin levels are lower than normal. These associations were observed at lead levels below the Environmental Protection Agency's threshold (0.015 mg/L) that mandates regulatory action.

The findings suggest that for patients with poor kidney function, there is no safe amount of lead in drinking water. "While drinking water may seem uniformly healthy, low levels of lead contamination found in the majority of drinking water systems in the United States may have toxic effects for those with chronic kidney disease," said lead author John Danziger, MD, MPhil, of Beth Israel Deaconess Medical Center. "More rigorous efforts to improve the water system infrastructure may be needed to protect individuals from unrecognized hazard."

Importantly, the study also revealed concerning inequities, with higher water lead levels observed for Black compared with white patients. "Combined with the increased susceptibility to kidney disease among Blacks, this represents an important environmental injustice," said Dr. Danziger.

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Study co-authors include Eric Weinhandl PhD, MS and Kenneth J. Mukamal, MD, MPH.

Disclosures: The authors reported no financial disclosures.

The article, titled "Associations of Lead Concentrations in Drinking Water with Hemoglobin Concentrations and Erythropoietin Stimulating Agent Use Among Patients with Advanced Chronic Kidney Disease," will appear online at http://jasn.asnjournals.org/ on July 15, 2021, doi: 10.1681/ASN.2020091281.

The content of this article does not reflect the views or opinions of The American Society of Nephrology (ASN). Responsibility for the information and views expressed therein lies entirely with the author(s). ASN does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies.

Since 1966, ASN has been leading the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients. ASN has more than 21,000 members representing 131 countries. For more information, visit http://www.asn-online.org.

 

Glaucoma test 'best yet'

15-times more likely to detect high risk patients

FLINDERS UNIVERSITY

Research News

 

IMAGE: ASSOCIATE PROFESSOR OWEN SIGGS, FLINDERS UNIVERSITY AND GARVAN INSTITUTE OF MEDICAL RESEARCH GLAUCOMA RESEARCHER. view more 

CREDIT: FLINDERS FOUNDATION

The latest investigations into a promising new genetic test for glaucoma - the leading cause of blindness worldwide - has found it has the ability to identify 15 times more people at high risk of glaucoma than an existing genetic test.

The study, just published in JAMA Ophthalmology, builds on a long-running international collaboration between Flinders University and the QIMR Berghofer Medical Research Institute and other research partners around the world to identify genetic risk factors for glaucoma. "Early diagnosis of glaucoma can lead to vision-saving treatment, and genetic information can potentially give us an edge in making early diagnoses, and better treatment decisions," says lead researcher Associate Professor Owen Siggs, from Flinders University in South Australia and the Garvan Institute of Medical Research in Sydney, NSW.

Senior author, Flinders University Professor Jamie Craig, says the latest research highlights the potential of the test in glaucoma screening and management.

"Genetic testing is not currently a routine part of glaucoma diagnosis and care, but this test has the potential to change that. We're now in a strong position to start testing this in clinical trials," says Professor Craig, a consulting ophthalmologist who also runs a in world-leading glaucoma research program at Flinders University, funded by Australia's NHMRC.

The latest results benchmarked the performance of genetic testing on 2507 Australian individuals with glaucoma, and 411,337 individuals with or without glaucoma in the UK.

One in 30 Australians will ultimately develop glaucoma, many of whom are diagnosed late due to lack of symptoms.

Once diagnosed, several treatment options can slow or halt the progression of glaucoma vision loss.

The new test, performed on a blood or saliva sample, has the potential to identify high-risk individuals before irreversible vision loss occurs.

Members of the research team are also launching a spin-out company to develop an accredited test for use in clinical trials, with recruitment expected to begin in 2022.

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The paper, Association of monogenic and polygenic risk with the prevalence of open-angle glaucoma (2021) by OM Siggs, X Han, A Qassim, E Souzeau, S Kuruvilla, HN Marshall, S Mullany, DA Mackey, AW Hewitt, P Gharahkhani, S MacGregor and JE Craig, has been published in JAMA Ophthalmology DOI:

Acknowledgements: The research was funded by the National Health and Medical Research Council (NHMRC), and the Rebecca L Cooper Medical Research Foundation.

Declaration: Conflict of interest declaration is that some of the authors have filed a patent related to this test (JEC, AWH, SM), and/or are cofounders in a company formed to commercialise the test (OMS, JEC, AWH, SM).

Extraordinary carbon emissions from El Nino-induced biomass burning estimated using Japanese aircraft and shipboard observations in Equatorial Asia

NATIONAL INSTITUTE FOR ENVIRONMENTAL STUDIES

 VIDEO: A MOVIE TO DEMONSTRATE THE AIRCRAFT AND SHIP OBSERVATIONS AND OVERVIEW THE RESULTS. view more 

CREDIT: NIES

Equatorial Asia, which includes Indonesia, Malaysia, Papua New Guinea, and surrounding areas, experienced devastating biomass burning in 2015 due to the severe drought condition induced by the extreme El Niño and a positive anomaly of the Indian Ocean dipole. This biomass burning emitted a significant amount of carbon, mainly in the form of carbon dioxide (CO2), into the atmosphere.

Equatorial Asia has very few ground-based stations that observe CO2 and other related atmospheric constitutents. Meanwhile, a few satellites could observe atmospheric CO2; however, their observations were less available and subject to errors due to cumulus cloulds typical in the tropics and smokes from the biomass burning.

To estimate the fire-induced carbon emissions from Equatorial Asia for 2015, the research team of the National Institute for Envrionmental Studies (NIES), Japan, and Meteorological Research Institute (MRI), Japan, expoloited high-precision observations onboard commercial passenger aircraft and a cargo ship that traveled in Equatorial Asia. These observations are unique because measurements are made on a moving platform, enabling to capture three-dimensional gradients of atmospheric CO2 concentrations. The aircraft observations are conducted by the NIES-MRI collaborative research project named CONTRAIL. The shipboard observations are operated by NIES as a part of the Global Environmental Monitoring project.

Using these aircraft and ship observations, the team performed an inverse analysis, which is based on numerical simulations of atmospheric transport, and estimated that the amount of carbon emitted from Equatorial Asia in September - October 2015 was 273 Tg C. The validity of the simulation-based analysis was carefully evaluated by comparing the simulated atomospheric concentrations with those of the observations, not only for CO2, but also for carbon monoxide, which was used as a proxy for combustion sources. In fact, this estimate is slightly smaller than the estimates of previous studies. However, nearly 300 Tg C emissions for only two months are extraordinary because they are comparable to the annual CO2 emissions from Japan.

"Our analysis is the first study that used in-situ high-precision observations for estimating the fire-induced emissions from Equatorial Asia for 2015, which contributes to improving our understanding of biomass burning in this region. It is considered that biomass burning here is dominated by fires in peatland, which has a remarkably high carbon density. Because Equatorial Asia has a significant amount of peatland, the region has a distinct role in the global carbon cycle despite its small terrestrial coverage", Yosuke Niwa (NIES & MRI), the leading author of the study, said. "Peatland forms over thousands of years. Therefore, it is difficult to restore carbon in burnt peatland. Meanwhile, forests could recover by taking CO2 from the atmosphere. However, such CO2 uptake by forest regrowth would not be large enough if the burnt land was converted to a crop field or fires frequently occurred at the same place", said Akihiko Ito (NIES), a coauthor of the study who works on terrestrial biosphere simulations. "It is important to keep on monitoring atmospheric CO2 concentrations. Despite difficult circumstances due to the COVID-19 pandemic, these observations are ongoing thanks to great efforts of the commercial companies that operate the aircraft and the ship. To provide useful information for mitigating climate change, we will continue these observations for many years to come", Toshinobu Machida (NIES), the leader of the CONTRAIL project, said.

CAPTION

Locations of the observations obtained by aircraft (magenta) and ship (blue) for Nov 2014 - Jan 2016. The orange region indicates Equatorial Asia, the target region of this study.

CREDIT

NIES

Mammalian-like hippocampal activity in a food-caching songbird

AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE

Research News

Tufted titmice - tiny songbirds with exceptional memories - process spatial memory using mammalian-like neural mechanisms, researchers report. Food-caching birds like the tufted titmouse are extreme memory specialists and can remember the precise locations of thousands of hidden food stores in the environment. Because of this, they are often regarded as a textbook model of spatial memory and an iconic example of higher cognition in animals. Although spatial memory is observed widely among vertebrates, the hippocampus-like brain regions responsible for it are anatomically distinct between vertebrate clades. As a result, it's been widely assumed that non-mammals use fundamentally different neural mechanisms for memory. Using electrophysical recordings from freely behaving birds, Hannah Payne and colleagues analyzed neuronal activity in the hippocampus homolog of the tufted titmouse and zebra finch - bird species that do, and do not display food-caching behavior, respectively. Payne et al. found mammalian-like neural activity in the titmouse hippocampus, including sharp-wave ripples and anatomically organized place cells. However, compared to titmice, spatial activity was weaker and less abundant in the non-food-caching zebra finches. The findings suggest that neural mechanisms underlying spatial memory are similar between birds and mammals and conserved across widely divergent hippocampal brain circuits.

 

Stakeholders' sentiment can make or break a new CEO

New study finds that stakeholders' sentiment toward a new CEO has a stronger effect on post succession performance than the CEO's previous experience and fit and this is more critical for new external CEOs

BOCCONI UNIVERSITY

Research News

IMAGE: DOVEV LAVIE, BOCCONI UNIVERSITY view more 

CREDIT: PAOLO TONATO

When a CEO steps down or is dismissed, the attention of the board is on how to choose the right executive to succeed that CEO. However, Bocconi University professor Dovev Lavie claims that managing the process of introducing the new CEO and choking the negative sentiment that can arise among stakeholders in a moment of uncertainty could be a more critical task, especially when the new CEO comes from outside the firm.

The effect of such a negative sentiment, which is a form of psychological bias, on a firm's performance is stronger than the implications of the new CEO's previous experience and fit between the CEO's corporate background and the appointing firm's characteristics.

Professor Lavie and co-authors Thomas Keil (University of Zurich) and Stevo Pavi?evi? (Frankfurt School of Finance and Management), in a paper in-press on the Academy of Management Journal, investigate the link between the appointment of an outside CEO and a firm's performance. The appointment of outside CEOs has become increasingly common in recent years, with about a third of appointed CEOs originating from outside the firm. Yet most studies report that they underperform compared to inside CEOs and exhibit greater performance variability.

Analyzing 1,275 appointments in 882 publicly listed US firms during 2001-2014, the study refines existing CEO-centric theories on the effect of a CEO's previous experience and fit, while introducing a novel stakeholder-centric perspective, which relates post-succession performance to the sentiment of stakeholders toward CEO appointments.

"Our findings reveal that, counter to expectations, the length and breadth of a CEO's executive experience do not enhance firm performance, nor explain the performance differences between inside and outside CEOs," Professor Lavie says. "Rather, the misfit between the CEO's corporate background and the appointing firm's characteristics, in terms of industry, firm size and firm age, undermines firm performance, especially following outside CEO appointments."

More importantly, the authors contend that negative sentiment originating from the firm's stakeholders toward the appointment of the CEO may hamper a new CEO's effectiveness, and hence firm performance.

They capture stakeholder sentiment using textual analysis of 27,092 press items around the announcement of CEO successions and further study the reactions of relevant stakeholders, such as analysts' buy/sell recommendations, executives' sales of their firm's stocks, and employees' ratings of their new CEOs.

Negative sentiment turns out to undermine post-succession performance and this effect is more significant than that of corporate misfit. Negative sentiment, if left unattended, can escalate, leading to increased scrutiny, deprived support, organizational resistance, and reputational damage.

Both inside and outside CEOs can suffer negative sentiment, but the effects are stronger for outside CEOs because they are less familiar with the hiring firm and cannot readily use workplace politics and personal networks to muffle them. The study finds that outside CEOs have an advantage so long as their corporate background makes a good fit with the hiring firm and the negative sentiment is effectively dealt with.

"Boards should develop practices that enable outside CEOs to quickly integrate into the firm and its social networks, while carefully and promptly managing the reactions of all stakeholders. For their part, newly appointed CEOs should consider tactics for offsetting negative sentiment before it escalates, e.g., by restructuring the top management team, leveraging public relations, or building social ties in the firm prior to taking office," the authors suggest.

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Guiding principles for work shift duration published by AASM and SRS

Key factors for determining shift length will help manage fatigue-related risks while meeting operational demands

AMERICAN ACADEMY OF SLEEP MEDICINE

Research News

DARIEN, Ill. -- The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) have published evidence-based guiding principles to help employers determine optimal work shift durations for their workplace. With a process that assesses risks, considers countermeasures, and institutes an informed approach to determine and evaluate shift durations, employers can make shift duration decisions that manage fatigue-related risks while also maintaining high productivity and safety.

"Historically, shift duration guidance has set maximum shift durations in a one-size-fits-all approach that focused primarily on physical fatigue," said Dr. Indira Gurubhagavatula, corresponding author for the paper and a physician in the division of sleep medicine of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. "Rather than providing a single, generic recommendation, these new guiding principles involve taking a more holistic view when setting customized shift durations for each individual workplace, considering not just physical fatigue, but mental fatigue, time of day, job requirements, safety risks, lifestyle factors, and health."

Determining optimal work shift durations is an important issue that affects performance and safety - both at work and in the community. Organizations, communities, workers, and regulatory agencies struggle with how to best manage shift durations. Scientific evidence that is essential for designing effective solutions has grown substantially in recent years, providing a foundation for making informed decisions about shift durations while preserving the integrity and feasibility of workplace operations.

When establishing work shift durations, the guiding principles recommend an approach that includes three strategies: (1) assess risk factors, (2) consider countermeasures, and (3) institute an informed approach.

Assess Risk Factors

The duration of work shifts is linked to adverse performance, safety, and health outcomes, especially when shifts are misaligned with a worker's biological clock. Work shift timing, workload factors, commute time, other demands on people's time, and individual biological factors all contribute to the impact of shift durations.

"An overall assessment of the risk factors associated with work shifts in a particular setting is key to making informed decisions about optimal shift durations in that setting," said senior author Hans Van Dongen, director of the Sleep and Performance Research Center at Washington State University in Spokane.

Consider Countermeasures

Countermeasure tools and strategies can be deployed in the workplace to reduce or manage risks associated with extended work shifts. Some are aimed at increasing sleep through nap opportunities or improving alertness with strategic caffeine consumption, for instance. Other countermeasures target operational risk outcomes; examples include quality control checks, warning systems, and team-based work strategies.

The choice of countermeasures should be based on assessment of the risks to be managed. After implementation, both positive and negative effects should be monitored to identify any unintended consequences and evaluate opportunities for improvement.

Institute an Informed Approach

Determining appropriate shift durations often involves finding an optimal compromise between competing goals. To ensure everyone understands the trade-offs, the decision-making process about shift durations should be fully informed, transparent, and based on scientific evidence. It should incorporate representatives of all stakeholders, and those whose lives and livelihoods would be directly impacted by changes to shift durations should be encouraged to participate in the decision-making process.

Any changes made to shift duration work policies should be monitored and evaluated, with corrective action taken in the event of unintended consequences.

The paper providing the recommendations and the supporting scientific evidence, "Guiding Principles for Determining Work Shift Duration and Addressing the Effects of Work Shift Duration on Performance, Safety, and Health," will be co-published July 15, 2021, in the peer-reviewed scientific publications the Journal of Clinical Sleep Medicine and SLEEP. Links to the paper will be active when the embargo lifts.

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About the American Academy of Sleep Medicine

Established in 1975, the AASM advances sleep care and enhances sleep health to improve lives. The AASM has a combined membership of 11,000 accredited member sleep centers and individual members, including physicians, scientists, and other health care professionals (aasm.org). The monthly, peer-reviewed Journal of Clinical Sleep Medicine is the official publication of the AASM.

About the Sleep Research Society

The Sleep Research Society (SRS) is a professional membership society that advances sleep and circadian science. The SRS provides forums for the exchange of information, establishes and maintains standards of reporting and classifies data in the field of sleep research, and collaborates with other organizations to foster scientific investigation on sleep and its disorders. The SRS also publishes the peer-reviewed, scientific journals SLEEP and SLEEP Advances.

Thinking without a brain

Studies in brainless slime molds reveal that they use physical cues to decide where to grow

WYSS INSTITUTE FOR BIOLOGICALLY INSPIRED ENGINEERING AT HARVARD

Research News

If you didn't have a brain, could you still figure out where you were and navigate your surroundings? Thanks to new research on slime molds, the answer may be "yes." Scientists from the Wyss Institute at Harvard University and the Allen Discovery Center at Tufts University have discovered that a brainless slime mold called Physarum polycephalum uses its body to sense mechanical cues in its surrounding environment, and performs computations similar to what we call "thinking" to decide in which direction to grow based on that information. Unlike previous studies with Physarum, these results were obtained without giving the organism any food or chemical signals to influence its behavior. The study is published in Advanced Materials.

"People are becoming more interested in Physarum because it doesn't have a brain but it can still perform a lot of the behaviors that we associate with thinking, like solving mazes, learning new things, and predicting events," said first author Nirosha Murugan, a former member of the Allen Discovery Center who is now an Assistant Professor at Algoma University in Ontario, Canada. "Figuring out how proto-intelligent life manages to do this type of computation gives us more insight into the underpinnings of animal cognition and behavior, including our own."

Slimy action at a distance

Slime molds are amoeba-like organisms that can grow to be up to several feet long, and help break down decomposing matter in the environment like rotting logs, mulch, and dead leaves. A single Physarum creature consists of a membrane containing many cellular nuclei floating within a shared cytoplasm, creating a structure called a syncytium. Physarum moves by shuttling its watery cytoplasm back and forth throughout the entire length of its body in regular waves, a unique process known as shuttle streaming.

"With most animals, we can't see what's changing inside the brain as the animal makes decisions. Physarum offers a really exciting scientific opportunity because we can observe its decisions about where to move in real-time by watching how its shuttle streaming behavior changes," said Murugan. While previous studies have shown that Physarum moves in response to chemicals and light, Murugan and her team wanted to know if it could make decisions about where to move based on physical cues in its environment alone.

The researchers placed Physarum specimens in the center of petri dishes coated with a semi-flexible agar gel and placed either one or three small glass discs next to each other atop the gel on opposite sides of each dish. They then allowed the organisms to grow freely in the dark over the course of 24 hours, and tracked their growth patterns. For the first 12 to 14 hours, the Physarum grew outwards evenly in all directions; after that, however, the specimens extended a long branch that grew directly over the surface of the gel toward the three-disc region 70% of the time. Remarkably, the Physarum chose to grow toward the greater mass without first physically exploring the area to confirm that it did indeed contain the larger object.

How did it accomplish this exploration of its surroundings before physically going there? The scientists were determined to find out.

It's all relative

The researchers experimented with several variables to see how they impacted Physarum's growth decisions, and noticed something unusual: when they stacked the same three discs on top of each other, the organism seemed to lose its ability to distinguish between the three discs and the single disc. It grew toward both sides of the dish at roughly equal rates, despite the fact that the three stacked discs still had greater mass. Clearly, Physarum was using another factor beyond mass to decide where to grow.

To figure out the missing piece of the puzzle, the scientists used computer modeling to create a simulation of their experiment to explore how changing the mass of the discs would impact the amount of stress (force) and strain (deformation) applied to the semi-flexible gel and the attached growing Physarum. As they expected, larger masses increased the amount of strain, but the simulation revealed that the strain patterns the masses produced changed, depending on the arrangement of the discs.

"Imagine that you are driving on the highway at night and looking for a town to stop at. You see two different arrangements of light on the horizon: a single bright point, and a cluster of less-bright points. While the single point is brighter, the cluster of points lights up a wider area that is more likely to indicate a town, and so you head there," said co-author Richard Novak, Ph.D., a Lead Staff Engineer at the Wyss Institute. "The patterns of light in this example are analogous to the patterns of mechanical strain produced by different arrangements of mass in our model. Our experiments confirmed that Physarum can physically sense them and make decisions based on patterns rather than simply on signal intensity."

The team's research demonstrated that this brainless creature was not simply growing toward the heaviest thing it could sense - it was making a calculated decision about where to grow based on the relative patterns of strain it detected in its environment.

But how was it detecting these strain patterns? The scientists suspected it had to do with Physarum's ability to rhythmically contract and tug on its substrate, because the pulsing and sensing of the resultant changes in substrate deformation allows the organism to gain information about its surroundings. Other animals have special channel proteins in their cell membranes called TRP-like proteins that detect stretching, and co-author and Wyss Institute Founding Director Donald Ingber, M.D., Ph.D had previously shown that one of these TRP proteins mediates mechanosensing in human cells. When the team created a potent TRP channel-blocking drug and applied it to Physarum, the organism lost its ability to distinguish between high and low masses, only selecting the high-mass region in 11% of the trials and selecting both high- and low-mass regions in 71% of trials.

"Our discovery of this slime mold's use of biomechanics to probe and react to its surrounding environment underscores how early this ability evolved in living organisms, and how closely related intelligence, behavior, and morphogenesis are. In this organism, which grows out to interact with the world, its shape change is its behavior. Other research has shown that similar strategies are used by cells in more complex animals, including neurons, stem cells, and cancer cells. This work in Physarum offers a new model in which to explore the ways in which evolution uses physics to implement primitive cognition that drives form and function," said corresponding author Mike Levin, Ph.D., a Wyss Associate Faculty member who is also the Vannevar Bush Chair and serves and Director of the Allen Discovery Center at Tufts University.

The research team is continuing its work on Physarum, including investigating at what point in time it makes the decision to switch its growth pattern from generalized sampling of its environment to directed growth toward a target. They are also exploring how other physical factors like acceleration and nutrient transport could affect Physarum's growth and behavior.

"This study confirms once again that mechanical forces play as important a role in the control of cell behavior and development as chemicals and genes, and the process of mechanosensation uncovered in this simple brainless organism is amazingly similar to what is seen in all species, including humans," said Ingber. "Thus, a deeper understanding how organisms use biomechanical information to make decisions will help us to better understand our our own bodies and brains, and perhaps even provide insight into new bioinspired forms of computation." Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

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Additional authors of the paper include Daniel Kaltman, Paul Jin, Melanie Chien, and Cuong Nguyen from the Allen Center for Discovery at Tufts University, Ramses Flores from the Wyss Institute, and Anna Kane from both the Allen Center and the Wyss Institute.

This research was supported by the Allen Discovery Center program through The Paul G. Allen Frontiers Group, Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement Number HR0011-18-2-0022, Lifelong Learning Machines program from DARPA/MTO, and the Wyss Institute at Harvard University.

 

Nitrogen-producing process of anammox bacterium finally uncovered

RADBOUD UNIVERSITY NIJMEGEN

Research News

After years of research, the molecular structure of the enzyme responsible for a large part of the global nitrate and nitrogen production by bacteria has finally been uncovered. The anammox bacterium and other bacteria use this enzyme to convert toxic nitrite into nitrate. Now that the working of the enzyme has become clear, new possibilities have opened for the improved deployment of the anammox bacterium for power generation from wastewater and for the production of rocket fuel. Researchers from Radboud University and the Max Planck Institutes in Heidelberg and Frankfurt published a paper on the subject in Nature Microbiology today.

Nitrogen-consuming bacteria like the anammox bacterium require the nitrite oxidoreductase enzyme (NXR) to convert toxic nitrite into nitrate. The enzyme fulfils a central role in nature's nitrogen cycle. Significant amounts of ammonium end up in soil due to activities such as the use of fertilisers. The ammonium is subsequently converted into nitrate, which is water-soluble and therefore easily washes away into groundwater and surface water. This process forms an important part of the reason why too much nitrogen has such an environmental impact.

Complex molecule

"Despite the enzyme being such a vital part of the nitrogen cycle, we knew relatively little about how it worked", says Mike Jetten, professor of Ecological Microbiology at Radboud University. "It took us more than ten years to map the molecular structure of this enzyme in the anammox bacterium."

"NXR turns out to have a complex structure and contains unexpected parts", explains Thomas Barends of the Max Planck Institute for Medical Research in Heidelberg. "Together with our colleagues in Frankfurt, we found a building block that ensures the protein combines into long threads. We have also gained greater insight into the way proteins are able organise inside a cell in general."

Wastewater and rocket fuel

The knowledge of the inner working of NXR will help in the deployment of the anammox bacterium in interesting applications. Jetten: "Anammox requires this enzyme to grow, but it also grows slowly by nature. We might now be able to suppress the bottlenecks in the growing process, allowing for the application of the bacterium in smaller and faster installations."

Nijmegen microbiologists have long studied the properties of this unique anammox bacterium. It is the only known bacterium that is able to convert harmful ammonium into harmless nitrogen gas without requiring oxygen in the process. Since its discovery, anammox has been widely used for wastewater treatment.

A year ago, the microbiologists discovered that the bacterium can help to generate power from wastewater. "This - previously impossible - reaction was made possible by circumventing the NXR enzyme. Another point on our bucket list is to have anammox produce rocket fuel on a large scale. To achieve this, we will need to know how to circumvent the enzyme even more efficiently: this will cause the bacterium to focus less of growth and more on the synthesis of the by-product hydrazine, one of the compounds used in liquid rocket fuel."

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Study shows strong association between perceived risk, availability and past-year cannabis use

Individuals who perceived cannabis as both low-risk and available were 22 times more likely to have used cannabis in the past year than those perceiving cannabis as both high-risk and unavailable

COLUMBIA UNIVERSITY'S MAILMAN SCHOOL OF PUBLIC HEALTH

Research News

Combined perceptions of the risk and availability of cannabis influence the risk of cannabis use more than perceived risk and perceived availability alone, according to a new study at Columbia University Mailman School of Public Health. Researchers observed that those who perceived cannabis as low-risk and available were more likely to report using the drug in the past year and almost daily compared to those individuals who perceived cannabis as high-risk and unavailable. This is the first study to consider the joint effects of perceived risk and perceived availability. The results are published in the journal Drug and Alcohol Dependence.

"Our study described the evolution of joint perceptions of cannabis risk and availability from 2002-2018 and estimated the relationship between combined perceptions and past-year cannabis use, frequent use, and cannabis use disorder," said Natalie Levy, MPH, doctoral student in the Department of Epidemiology at Columbia Mailman School, and first author. "Studying perceived risk and availability in conjunction revealed more nuanced patterns than considering each perception in isolation.."

Using data on 949,285 participants from the National Surveys on Drug Use and Health from 2002-2018, researchers observed that the prevalence of perceiving cannabis use as low-risk doubled over this period while the prevalence of perceiving cannabis as available increased only marginally. When looking at joint categories of perceived risk and perceived availability, they found that prevalence of perceiving cannabis as both low-risk and available increased, from 17 percent in 2002 to 36 percent in 2018 while the proportion of the population perceiving cannabis as high-risk and available or high-risk and unavailable declined. By 2018, a larger proportion of the population perceived marijuana as low-risk and available (36 percent) than both high-risk and available and high-risk and unavailable, at 26 percent and 27 percent, respectively.

Individuals who perceived cannabis as low-risk were six times more likely to have used cannabis in the past-year than individuals who perceived the drug as high-risk. Similarly, individuals who perceived cannabis as available were five times more likely to have used cannabis in the past year than individuals who perceived it as unavailable. However, individuals who perceived marijuana as both low-risk and available were 22 times more likely to have used the drug in the past year than those who perceived cannabis as high-risk and unavailable.

In 2018, most individuals who reported no past-year cannabis use perceived cannabis as high-risk, whether or not they distinguished between its availability or non-availability. In contrast, the majority of individuals who used cannabis in the past year perceived the drug as low-risk and available and this perception rose to even higher levels among those reporting frequent use.

Cannabis perceptions also differed by gender. Overall, a larger proportion of males viewed cannabis as lower risk and more available compared with females, but patterns differed by age. "We found minimal differences in perceptions by gender in the 12-17-year age group while among all those 18 years of age and older, the prevalence of perceiving cannabis as low-risk and available was higher for males than females; perceiving cannabis as high-risk and unavailable was more common among females in every year," noted Levy.

"Our results provide an important starting point for exploring specific hypotheses regarding the effects of perceptions on individual cannabis outcomes and highlight the importance of exploring perceived risk and availability together," said Silvia Martins, MD, PhD, Columbia Mailman School associate professor of Epidemiology, director of the Substance Use Epidemiology Unit of the Department of Epidemiology, and senior author. "For example, our findings suggest that prevention efforts that focus only on the risks of cannabis use may be less effective among individuals who perceive cannabis as easily available.

"Trends in perceptions - especially among younger age groups -- may also identify priority groups for intervention," observed Levy. "Further understanding of these relationships is particularly important in light of rapidly changing cannabis policies, a contextual factor that may influence perceptions of both risk and availability of cannabis and subsequent use."

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Co-authors are Pia Mauro, Christine Mauro, and Luis Segura, Columbia Mailman School of Public Health.

The study was supported by National Institutes of Health, grants R01DA037866 and K01DA045224.

Columbia University Mailman School of Public Health

Founded in 1922, the Columbia University Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Columbia Mailman School is the seventh largest recipient of NIH grants among schools of public health. Its nearly 300 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change and health, and public health preparedness. It is a leader in public health education with more than 1,300 graduate students from 55 nations pursuing a variety of master's and doctoral degree programs. The Columbia Mailman School is also home to numerous world-renowned research centers, including ICAP and the Center for Infection and Immunity. For more information, please visit http://www.mailman.columbia.edu.