In Your Gut: How Bacteria Survive Low Oxygen Environments (Biology)

ITQB NOVA researchers have uncovered the mechanisms that allow the survival of the anaerobic pathogen Clostridioides difficile in the gut.

Researchers from ITQB NOVA, in collaboration with the Institut Pasteur in Paris, have shed light on the mechanisms that allow Clostridioides difficile, a pathogen that can only grow in oxygen-free environments, to be able to survive low oxygen levels. C. difficile is a major cause of intestinal problems associated with the use of antibiotics, causing an estimated number of 124k cases per year in the EU, costing on average 5k€ per patient, as a direct consequence of healthcare-associated contagion. Particularly pathogenic varieties of C. difficile are an important cause of high prevalence infections in health care environments and will keep hindering the ideal use of antimicrobial therapy unless these mechanisms are understood more rapidly than these organisms evolve.

Figure: “Clostridioides difficile’s tools to tolerate low oxygen tensions”

A healthy human gut is generally regarded as mainly free of oxygen but, in reality, there are varying levels of oxygen along the gastrointestinal tract, which poses a challenge to anaerobic organisms of the human microbiome, such as C. difficile. In organisms similar to this bacterium, two families of enzymes, flavodiiron proteins and rubrerythrins, have been shown to play an important role in protection against oxidative stress.

“Little was known about the actual proteins involved in the ability of C. difficile to tolerate O2, and our studies have demonstrated a key role of flavodiiron proteins and rubrerythrins proteins in providing C. difficile with the ability to grow in conditions such as those encountered in the colon”, says Miguel Teixeira, head of the Functional Biochemistry of Metalloenzymes Lab.

This finding led the ITQB NOVA team, along with the I. Martin- Verstreaet Lab at Institut Pasteur, to develop a comprehensive study on four of these types of proteins. It had been previously established that a flavodiiron protein is able to reduce both oxygen and hydrogen peroxide, and this study confirmed the same for two types of rubrerythrins proteins. In a particular mutant strain of C. difficile, inactivation of both rubrerythrins led to the bacteria not growing at an oxygen level above 0.1%, a significant difference from the bacteria’s usual resistance, of up to 0.4% O2.

By demonstrating that flavodiiron and reverse rubrerythrin proteins are essential in C. difficile’s ability to tolerate damage to its cells in the presence of oxygen, the two teams of researchers have managed a significant step towards better understanding its mechanisms of resistance. The researchers will now move on to explore other survival mechanisms of these bacteria.

References: Nicolas Kint, Carolina Alves Feliciano, Maria C. Martins, Claire Morvan, Susana F. Fernandes, Filipe Folgosa, Bruno Dupuy, Miguel Teixeira, Isabelle Martin-Verstraete, “How the Anaerobic Enteropathogen Clostridioides difficile Tolerates Low O2 Tensions”, American Society for Microbiology, 2020 | https://mbio.asm.org/content/11/5/e01559-20 Data references: https://www.ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/healthcare-associated-infections-antimicrobial-use-PPS.pdf

Provided by ITQB

Immunotherapy Side Effect Could Be A Positive Sign For Kidney Cancer Patients (Medicine)

Patients who developed acute interstitial nephritis, an autoimmune reaction, respond to immune checkpoint inhibitor drugs.

An autoimmune side effect of immune checkpoint inhibitor (ICI) drugs could signal improved control of kidney cancer, according to a new study by researchers in UT Southwestern’s Kidney Cancer Program (KCP).

Microscopic image of kidney tubules (yellow arrows) under an immune attack (green arrows) characteristic of acute interstitial nephritis (AIN). Micrograph taken from a biopsy of a kidney cancer patient treated with immunotherapy who had a good response against the cancer. ©UT Southwestern Medical Center.

The study, published today in the Journal for ImmunoTherapy of Cancer, may have broad implications for patients being treated with ICIs, a type of immunotherapy that is used against a large number of cancers, including lung, breast, liver, and cervical.

Renal cell carcinoma, the most common type of kidney cancer, is the ninth leading cause of cancer in the U.S. Once the cancer has spread to other organs, or metastasized, the survival rate averages 12 percent at five years.

With the advent of ICIs, kidney cancer survival rates are improving. However, only a fraction of patients respond to ICIs – and who will respond is unpredictable. ICIs disable cloaking mechanisms put in place by tumors to evade killing by immune cells. But taking down these cloaking mechanisms also increases the chances that the immune system will turn against the body, causing autoimmune side effects.

KCP investigators hypothesize that kidney cancer patients whose immune system attacked their kidneys may be more likely to benefit from ICIs. Using Kidney Cancer Explorer, a proprietary tool that extracts information from electronic health records, investigators identified metastatic kidney cancer patients treated with ICIs between 2014 and 2018. Using this tool, they analyzed thousands of laboratory test results to identify patients whose kidney function became impaired. Out of 177 patients, they found 36 such patients.

In three of the 36 patients, the impairment was due to an immune-mediated attack. A fourth more recent patient was also identified. All four patients developed acute interstitial nephritis (AIN), an autoimmune condition in which immune cells attack kidney cells, causing inflammation and swelling. While ICIs induce responses in the cancer in up to 40 percent of patients, in this case all four patients with AIN had a response.

“For 100 percent of patients to respond is quite significant,” says Roy Elias, M.D., assistant instructor of internal medicine and co-first author of the study. “If a patient develops AIN, it is a sign that the treatment may be working.”

This is not the first time that a particular autoimmune effect has been linked to increased response rates to ICIs, says James Brugarolas, M.D., Ph.D., professor of internal medicine and director of the Kidney Cancer Program. In fact, patients with melanoma who developed vitiligo, a condition in which skin pigment cells are killed by immune cells, also had higher chances of response.

Upon identifying a second example of an immune attack to the tissue of origin associated with a favorable cancer response, KCP investigators propose that this finding may be generalizable to other tumor types.

“All cancer cells start out as normal cells,” says Brugarolas. “Even after turning malignant, they retain some of their original traits. Thus, an attack against the tissue of origin may signal a higher chance that the immune system will also recognize and attack the cancer.”

Further study will be needed to determine whether positive outcomes could be generalizable to patients with other cancers who are experiencing similar immune attacks against the cell of origin of the cancer.

References: http://dx.doi.org/10.1136/jitc-2020-001198

Provided by UT Southwestern Medical Center

An Underwater Navigation System Powered By Sound (Engineering)

New approach could spark an era of battery-free ocean exploration, with applications ranging from marine conservation to aquaculture.

GPS isn’t waterproof. The navigation system depends on radio waves, which break down rapidly in liquids, including seawater. To track undersea objects like drones or whales, researchers rely on acoustic signaling. But devices that generate and send sound usually require batteries — bulky, short-lived batteries that need regular changing. Could we do without them?

MIT researchers think so. They’ve built a battery-free pinpointing system dubbed Underwater Backscatter Localization (UBL). Rather than emitting its own acoustic signals, UBL reflects modulated signals from its environment. That provides researchers with positioning information, at net-zero energy. Though the technology is still developing, UBL could someday become a key tool for marine conservationists, climate scientists, and the U.S. Navy.

These advances are described in a paper being presented this week at the Association for Computing Machinery’s Hot Topics in Networks workshop, by members of the Media Lab’s Signal Kinetics group. Research Scientist Reza Ghaffarivardavagh led the paper, along with co-authors Sayed Saad Afzal, Osvy Rodriguez, and Fadel Adib, who leads the group and is the Doherty Chair of Ocean Utilization as well as an associate professor in the MIT Media Lab and the MIT Department of Electrical Engineering and Computer Science.

“Power-hungry”

It’s nearly impossible to escape GPS’ grasp on modern life. The technology, which relies on satellite-transmitted radio signals, is used in shipping, navigation, targeted advertising, and more. Since its introduction in the 1970s and ’80s, GPS has changed the world. But it hasn’t changed the ocean. If you had to hide from GPS, your best bet would be underwater.

Because radio waves quickly deteriorate as they move through water, subsea communications often depend on acoustic signals instead. Sound waves travel faster and further underwater than through air, making them an efficient way to send data. But there’s a drawback.

“Sound is power-hungry,” says Adib. For tracking devices that produce acoustic signals, “their batteries can drain very quickly.” That makes it hard to precisely track objects or animals for a long time-span — changing a battery is no simple task when it’s attached to a migrating whale. So, the team sought a battery-free way to use sound.

Good vibrations

Adib’s group turned to a unique resource they’d previously used for low-power acoustic signaling: piezoelectric materials. These materials generate their own electric charge in response to mechanical stress, like getting pinged by vibrating soundwaves. Piezoelectric sensors can then use that charge to selectively reflect some soundwaves back into their environment. A receiver translates that sequence of reflections, called backscatter, into a pattern of 1s (for soundwaves reflected) and 0s (for soundwaves not reflected). The resulting binary code can carry information about ocean temperature or salinity.

In principle, the same technology could provide location information. An observation unit could emit a soundwave, then clock how long it takes that soundwave to reflect off the piezoelectric sensor and return to the observation unit. The elapsed time could be used to calculate the distance between the observer and the piezoelectric sensor. But in practice, timing such backscatter is complicated, because the ocean can be an echo chamber.

The sound waves don’t just travel directly between the observation unit and sensor. They also careen between the surface and seabed, returning to the unit at different times. “You start running into all of these reflections,” says Adib. “That makes it complicated to compute the location.” Accounting for reflections is an even greater challenge in shallow water — the short distance between seabed and surface means the confounding rebound signals are stronger.

The researchers overcame the reflection issue with “frequency hopping.” Rather than sending acoustic signals at a single frequency, the observation unit sends a sequence of signals across a range of frequencies. Each frequency has a different wavelength, so the reflected sound waves return to the observation unit at different phases. By combining information about timing and phase, the observer can pinpoint the distance to the tracking device. Frequency hopping was successful in the researchers’ deep-water simulations, but they needed an additional safeguard to cut through the reverberating noise of shallow water.

Where echoes run rampant between the surface and seabed, the researchers had to slow the flow of information. They reduced the bitrate, essentially waiting longer between each signal sent out by the observation unit. That allowed the echoes of each bit to die down before potentially interfering with the next bit. Whereas a bitrate of 2,000 bits/second sufficed in simulations of deep water, the researchers had to dial it down to 100 bits/second in shallow water to obtain a clear signal reflection from the tracker. But a slow bitrate didn’t solve everything.

To track moving objects, the researchers actually had to boost the bitrate. One thousand bits/second was too slow to pinpoint a simulated object moving through deep water at 30 centimeters/second. “By the time you get enough information to localize the object, it has already moved from its position,” explains Afzal. At a speedy 10,000 bits/second, they were able to track the object through deep water.

Efficient exploration

Adib’s team is working to improve the UBL technology, in part by solving challenges like the conflict between low bitrate required in shallow water and the high bitrate needed to track movement. They’re working out the kinks through tests in the Charles River. “We did most of the experiments last winter,” says Rodriguez. That included some days with ice on the river. “It was not very pleasant.”

Conditions aside, the tests provided a proof-of-concept in a challenging shallow-water environment. UBL estimated the distance between a transmitter and backscatter node at various distances up to nearly half a meter. The team is working to increase UBL’s range in the field, and they hope to test the system with their collaborators at the Wood Hole Oceanographic Institution on Cape Cod.

They hope UBL can help fuel a boom in ocean exploration. Ghaffarivardavagh notes that scientists have better maps of the moon’s surface than of the ocean floor. “Why can’t we send out unmanned underwater vehicles on a mission to explore the ocean? The answer is: We will lose them,” he says.

UBL could one day help autonomous vehicles stay found underwater, without spending precious battery power. The technology could also help subsea robots work more precisely, and provide information about climate change impacts in the ocean. “There are so many applications,” says Adib. “We’re hoping to understand the ocean at scale. It’s a long-term vision, but that’s what we’re working toward and what we’re excited about.”

This work was supported, in part, by the Office of Naval Research.

References: Dan Ackerman, “Underwater Backscatter Localization: Toward a Battery-Free Underwater GPS”, 2020.
http://www.mit.edu/~fadel/papers/UBL-paper.pdf

Provided by MIT

Devil In The Defect Detail Of Quantum Emissions Unravelled (Quantum)

Study helps unlock chemical structure in defects that emit single photons.

Systems which can emit a stream of single photons, referred to as quantum light sources, are critical hardware components for emerging technologies such as quantum computing, the quantum internet, and quantum communications.

An artist’s impression showing the incorporation of single photon emitters during hBN growth. ©Trong Toan Tran.

In many cases the ability to generate quantum light on-demand requires the manipulation and control of single atoms or molecules, pushing the limit of modern fabrication techniques, and making the development of these systems a cross-disciplinary challenge.

In new research, published in Nature Materials, an international multidisciplinary collaboration led by the University of Technology Sydney (UTS), has uncovered the chemical structure behind defects in white graphene (hexagonal boron nitride, hBN), a two dimensional nanomaterial that shows great promise as a platform for generating quantum light.

The defects, or crystal imperfections, can act as single photon sources and an understanding of their chemical structure is critical to being able to fabricate them in a controlled way.

“hBN single photon emitters display outstanding optical properties, among the best from any solid state material system, however, to make practical use of them we need to understand the nature of the defect and we have finally started to unravel this riddle,” says UTS PhD candidate Noah Mendelson and first author of the study.

“Unfortunately, we cannot simply combine powerful techniques to visualize single atoms directly with quantum optics measurements, so obtaining this structural information is very challenging. Instead we attacked this problem from a different angle, by controlling the incorporation of dopants, like carbon, into hBN during growth and then directly comparing the optical properties for each, ” he said.

To realise this comprehensive study, the team, led by Professor Igor Aharonovich, chief investigator of the UTS node of the ARC Centre of Excellence for Transformative Meta-Optical Materials (TMOS), turned to collaborators in Australia and around the world to provide the array of samples needed.

The researchers were able to observe, for the first time, a direct link between carbon incorporation into the hBN lattice and quantum emission.

“Determining the structure of material defects is an incredibly challenging problem and requires experts from many disciplines. This is not something we could have done within our group alone. Only by teaming up with collaborators from across the world whose expertise lies in different materials growth techniques could we study this issue comprehensively. Working together were we finally able to provide the clarity needed for the research community as a whole,” said Professor Aharonovich.

“It was particularly exciting as this study was enabled by the new collaborative efforts with collaborators Dipankar Chugh, Hark Hoe Tan and Chennupati Jagadish from the TMOS node at the Australian National University, ” he said.

The scientists also identified another intriguing feature in their study, that the defects carry spin, a fundamental quantum mechanical property, and a key element to encode and retrieve quantum information stored on single photons.

“Confirming these defects carry spin opens up exciting possibilities for future quantum sensing applications, specifically with atomically thin materials.” Professor Aharonovich said.

The work brings to the forefront a novel research field, 2D quantum spintronics, and lays the groundwork for further studies into quantum light emission from hBN. The authors anticipate their work will stimulate increased interest in the field and facilitate a range of follow up experiments such as the generation of entangled photon pairs from hBN, detailed studies of the spin properties of the system, and theoretical confirmation of the defect structure.

“This is just the beginning, and we anticipate our findings will accelerate the deployment of hBN quantum emitters for a range of emerging technologies,” concludes Mr. Mendelson.

References: Mendelson, N., Chugh, D., Reimers, J.R. et al. Identifying carbon as the source of visible single-photon emission from hexagonal boron nitride. Nat. Mater. (2020). https://doi.org/10.1038/s41563-020-00850-y http://dx.doi.org/10.1038/s41563-020-00850-y

Provided By University Of Sydney

Room Temperature Conversion Of CO2 to CO: A New Way To Synthesize Hydrocarbons (Chemistry)

Researchers at the National Institute of Standards and Technology (NIST) and their colleagues have demonstrated a room-temperature method that could significantly reduce carbon dioxide levels in fossil-fuel power plant exhaust, one of the main sources of carbon emissions in the atmosphere.

Illustration of a novel room-temperature process to remove carbon dioxide (CO2) by converting the molecule into carbon monoxide (CO). Instead of using heat, the nanoscale method relies on the energy from surface plasmons (violet hue) that are excited when a beam of electrons (vertical beam) strikes aluminum nanoparticles resting on graphite, a crystalline form of carbon. In the presence of the graphite, aided by the energy derived from the plasmons, carbon dioxide molecules (black dot bonded to two red dots) are converted to carbon monoxide (black dot bonded to one red dot. The hole under the violet sphere represents the graphite etched away during the chemical reaction CO2 + C = 2CO. ©NIST.

Although the researchers demonstrated this method in a small-scale, highly controlled environment with dimensions of just nanometers (billionths of a meter), they have already come up with concepts for scaling up the method and making it practical for real-world applications.

In addition to offering a potential new way of mitigating the effects of climate change, the chemical process employed by the scientists also could reduce costs and energy requirements for producing liquid hydrocarbons and other chemicals used by industry. That’s because the method’s byproducts include the building blocks for synthesizing methane, ethanol and other carbon-based compounds used in industrial processing.

The team tapped a novel energy source from the nanoworld to trigger a run-of-the-mill chemical reaction that eliminates carbon dioxide. In this reaction, solid carbon latches onto one of the oxygen atoms in carbon dioxide gas, reducing it to carbon monoxide. The conversion normally requires significant amounts of energy in the form of high heat — a temperature of at least 700 degrees Celsius, hot enough to melt aluminum at normal atmospheric pressure.

Instead of heat, the team relied on the energy harvested from traveling waves of electrons, known as localized surface plasmons (LSPs), which surf on individual aluminum nanoparticles. The team triggered the LSP oscillations by exciting the nanoparticles with an electron beam that had an adjustable diameter. A narrow beam, about a nanometer in diameter, bombarded individual aluminum nanoparticles while a beam about a thousand times wider generated LSPs among a large set of the nanoparticles.

In the team’s experiment, the aluminum nanoparticles were deposited on a layer of graphite, a form of carbon. This allowed the nanoparticles to transfer the LSP energy to the graphite. In the presence of carbon dioxide gas, which the team injected into the system, the graphite served the role of plucking individual oxygen atoms from carbon dioxide, reducing it to carbon monoxide. The aluminum nanoparticles were kept at room temperature. In this way, the team accomplished a major feat: getting rid of the carbon dioxide without the need for a source of high heat.

Previous methods of removing carbon dioxide have had limited success because the techniques have required high temperature or pressure, employed costly precious metals, or had poor efficiency. In contrast, the LSP method not only saves energy but uses aluminum, a cheap and abundant metal.

Although the LSP reaction generates a poisonous gas — carbon monoxide — the gas readily combines with hydrogen to produce essential hydrocarbon compounds, such as methane and ethanol, that are often used in industry, said NIST researcher Renu Sharma.

She and her colleagues, including scientists from the University of Maryland in College Park and DENSsolutions, in Delft, the Netherlands, reported their findings in Nature Materials.

“We showed for the first time that this carbon dioxide reaction, which otherwise will only happen at 700 degrees C or higher, can be triggered using LSPs at room temperature,” said researcher Canhui Wang of NIST and the University of Maryland.

The researchers chose an electron beam to excite the LSPs because the beam can also be used to image structures in the system as small as a few billionths of a meter. This enabled the team to estimate how much carbon dioxide had been removed. They studied the system using a transmission electron microscope (TEM).

Because both the concentration of carbon dioxide and the reaction volume of the experiment were so small, the team had to take special steps to directly measure the amount of carbon monoxide generated. They did so by coupling a specially modified gas cell holder from the TEM to a gas chromatograph mass spectrometer, allowing the team to measure parts-per-millions concentrations of carbon dioxide.

Sharma and her colleagues also used the images produced by the electron beam to measure the amount of graphite that was etched away during the experiment, a proxy for how much carbon dioxide had been taken away. They found that the ratio of carbon monoxide to carbon dioxide measured at the outlet of the gas cell holder increased linearly with the amount of carbon removed by etching.

Imaging with the electron beam also confirmed that most of the carbon etching — a proxy for carbon dioxide reduction — occurred near the aluminum nanoparticles. Additional studies revealed that when the aluminum nanoparticles were absent from the experiment, only about one-seventh as much carbon was etched.

Limited by the size of the electron beam, the team’s experimental system was small, only about 15 to 20 nanometers across (the size of a small virus).

To scale up the system so that it could remove carbon dioxide from the exhaust of a commercial power plant, a light beam may be a better choice than an electron beam to excite the LSPs, Wang said. Sharma proposes that a transparent enclosure containing loosely packed carbon and aluminum nanoparticles could be placed over the smokestack of a power plant. An array of light beams impinging upon the grid would activate the LSPs. When the exhaust passes through the device, the light-activated LSPs in the nanoparticles would provide the energy to remove carbon dioxide.

The aluminum nanoparticles, which are commercially available, should be evenly distributed to maximize contact with the carbon source and the incoming carbon dioxide, the team noted.

The new work also suggests that LSPs offer a way for a slew of other chemical reactions that now require a large infusion of energy to proceed at ordinary temperatures and pressures using plasmonic nanoparticles.

“Carbon dioxide reduction is a big deal, but it would be an even bigger deal, saving enormous amounts of energy, if we can start to do many chemical reactions at room temperature that now require heating,” Sharma said.

References: Canhui Wang, Wei-Chang D. Yang, David Raciti, Alina Bruma, Ronald Marx, Amit Agrawal, and Renu Sharma. Endothermic Reaction at Room Temperature enabled by Deep-Ultraviolet Plasmons. Nature Materials. Nov. 2, 2020. DOI: 10.1038/s41563-020-00851-x link: http://dx.doi.org/10.1038/s41563-020-00851-x

Provided by NIST

Hungry Plants Rely On Their Associated Bacteria To Mobilize Unavailable Iron (Botany)

In nature, healthy plants are awash with bacteria and other microbes, mostly deriving from the soil they grow in. This community of microbes, termed the plant microbiota, is essential for optimal plant growth and protects plants from the harmful effects of pathogenic microorganisms and insects. The plant root microbiota is also thought to improve plant performance when nutrient levels are low, but concrete examples of such beneficial interactions remain scarce. Iron is one of the most important micronutrients for plant growth and productivity. Although abundant in most soils, iron’s poor availability often limits plant growth, as it is found in forms that cannot be taken up by plants. Thus, adequate crop yields often necessitate the use of chemical fertilizers, which can be ecologically harmful in excessive application. Now, MPIPZ researchers led by Paul Schulze-Lefert have uncovered a novel strategy employed by plants to overcome this problem: they release substances from their roots that direct plant-associated bacteria to mobilise soil iron so that plants can easily take it up.

In iron-limiting soils, plants activate an iron-deficiency response that includes production and secretion of coumarins. These compounds alter the composition of the root microbiota and elicit a microbial activity that rescues plant iron nutrition, improving plant growth. ©Christopher J. Harbort.

When confronted with iron in unavailable forms, plants mount a compensatory response to avoid iron deficiency. This starvation response involves extensive reprogramming of gene expression and the production and secretion of coumarins, aromatic compounds that are discharged from plant roots and which themselves can improve iron solubility. Interestingly, it was recently shown that coumarins are a selective force, shaping the composition of plant-associated bacterial communities. Now, it emerges that some coumarins also act as an “SOS” signal that prompts the root microbiota to support plant iron nutrition.

To first assess the contribution of the root microbiota to iron-limiting plant performance, first-author Christopher Harbort and colleagues used a controlled system which allowed them to regulate the availability of iron as well as the presence of root-associated bacteria. Using the laboratory model thale cress, they compared plants completely lacking bacteria and ones with an added synthetic community (SynCom) of bacterial commensals which reflects the root bacterial diversity observed in nature. The authors found that addition of this bacterial SynCom strongly improved the performance of plants grown on unavailable iron but not those grown with iron that was readily available. Growing plants in associations with single bacterial strains allowed them to determine that this iron-rescuing capacity is widespread among bacteria from different bacterial lineages of the root microbiota. When the researchers performed the same experiments with plants compromised in the production or secretion of coumarins, the community of bacteria provided no benefits. Thus, they could show that plant-secreted coumarins are responsible for eliciting nutritional assistance from bacterial commensals under iron limitation.

The authors’ findings strongly suggest that the root microbiota is an integral part of how plants adapt to growth in iron-limiting soil. Furthermore, by identifying the plant-to-microbe signal for assistance, this research brings us one step closer to harnessing naturally present soil bacteria as a substitute for synthetic fertilizers. Improving plant iron nutrition could not only improve agricultural yields, but also increase the nutrient content of staple food crops, a potential strategy for tackling iron deficiency in humans as well.

References: Christopher J. Harbort, Masayoshi Hashimoto, Haruhiko Inoue, Yulong Niu, Rui Guan, Adamo D. Rombol, Stanislav Kopriva, Mathias J.E.E.E. Voges, Elizabeth S. Sattely, Ruben Garrido-Oter, Paul Schulze-Lefert, “Root-Secreted Coumarins and the Microbiota Interact to Improve Iron Nutrition in Arabidopsis”, Cell Host & Microbe, 2020, ISSN 1931-3128, doi:
https://doi.org/10.1016/j.chom.2020.09.006 link:
http://www.sciencedirect.com/science/article/pii/S1931312820305072

Provided by Max Planck Institute For Plant Breeding Research

New Insight Into How Brain Neurons Influence Choices (Neuroscience)

When you are faced with a choice — say, whether to have ice cream or chocolate cake for dessert — sets of brain cells just above your eyes fire as you weigh your options. Animal studies have shown that each option activates a distinct set of neurons in the brain. The more enticing the offer, the faster the corresponding neurons fire.

By studying animals choosing between two drink options, researchers at Washington University School of Medicine in St. Louis have discovered that the activity of certain neurons in the brain leads directly to the choice of one option over another. The findings could lead to better understanding of how decision-making goes wrong in conditions such as addiction and depression. ©Mike Worful.

Now, a study in monkeys by researchers at Washington University School of Medicine in St. Louis has shown that the activity of these neurons encodes the value of the options and determines the final decision. In the experiments, researchers let animals choose between different juice flavors. By changing the neurons’ activity, the researchers changed how appealing the monkeys found each option, leading the animals to make different choices. The study is published Nov. 2 in the journal Nature.

A detailed understanding of how options are valued and choices are made in the brain will help us understand how decision-making goes wrong in people with conditions such as addiction, eating disorders, depression and schizophrenia.

“In a number of mental and neuropsychiatric disorders, patients consistently make poor choices, but we don’t understand exactly why,” said senior author Camillo Padoa-Schioppa, PhD, a professor of neuroscience, of economics and of biomedical engineering. “Now we have located one critical piece of this puzzle. As we shed light on the neural mechanisms underlying choices, we’ll gain a deeper understanding of these disorders.”

In the 18th century, economists Daniel Bernoulli, Adam Smith and Jeremy Bentham suggested that people choose among options by computing the subjective value of each offer, taking into consideration factors such as quantity, quality, cost and the probability of actually receiving the promised offer. Once computed, values would be compared to make a decision. It took nearly three centuries to find the first concrete evidence of such calculations and comparisons in the brain. In 2006, Padoa-Schioppa and John Assad, PhD, a professor of neurobiology at Harvard Medical School, published a groundbreaking paper in Nature describing the discovery of neurons that encode the subjective value offered and chosen goods. The neurons were found in the orbitofrontal cortex, an area of the brain just above the eyes involved in goal-directed behavior.

At the time, though, they were unable to demonstrate that the values encoded in the brain led directly to choosing one option over another.

“We found neurons encoding subjective values, but value signals can guide all sorts of behaviors, not just choice,” Padoa-Schioppa said. “They can guide learning, emotion, perceptual attention, and aspects of motor control. We needed to show that value signals in a particular brain region guide choices.”

To examine the connection between values encoded by neurons and choice behavior, researchers performed two experiments. The study was conducted by first authors Sébastien Ballesta, PhD, then a postdoctoral researcher, and Weikang Shi, a graduate student, with the help of Katherine Conen, PhD, then a graduate student, who designed one of the experiments. Ballesta is now an associate professor at the University of Strasbourg in Strasbourg, France; Conen is now at Brown University.

In one experiment, the researchers repeatedly presented monkeys with two drinks and recorded the animals’ selections. The drinks were offered in varying amounts and included lemonade, grape juice, cherry juice, peach juice, fruit punch, apple juice, cranberry juice, peppermint tea, kiwi punch, watermelon juice and salted water. The monkeys often preferred one flavor over another, but they also liked to get more rather than less, so their decisions were not always easy. Each monkey indicated its choice by glancing toward it, and the chosen drink was delivered.

Then, the researchers placed tiny electrodes in each monkey’s orbitofrontal cortex. The electrodes painlessly stimulate the neurons that represent the value of each option. When the researchers delivered a low current through the electrodes while a monkey was offered two drinks, neurons dedicated to both options began to fire faster. From the perspective of the monkey, this meant that both options became more appealing but, because of the way values are encoded in the brain, the appeal of one option increased more than that of the other. The upshot is that low-level stimulation made the animal more likely to choose one particular option, in a predictable way.

In another experiment, the monkeys saw first one option, then the other, before they made a choice. Delivering a higher current while the monkey was considering one option disrupted the computation of value taking place at that time, making the monkey more likely to choose whichever option was not disrupted. This result indicates that values computed in the orbitofrontal cortex are a necessary part of making a choice.

“When it comes to this kind of choices, the monkey brain and the human brain appear very similar,” Padoa-Schioppa said. “We think that this same neural circuit underlies all sorts of choices people make, such as between different dishes on a restaurant menu, financial investments, or candidates in an election. Even major life decisions like which career to choose or whom to marry probably utilize this circuit. Every time a choice is based on subjective preferences, this neural circuit is responsible for it.”

References: Ballesta, S., Shi, W., Conen, K.E. et al. Values encoded in orbitofrontal cortex are causally related to economic choices. Nature (2020). https://doi.org/10.1038/s41586-020-2880-x link: https://www.nature.com/articles/s41586-020-2880-x

Provided by Washington University School Of Medicine

New Study Finds Earliest Evidence For Mammal Social Behavior (Paleontology)

A new study led by paleontologists at the University of Washington and its Burke Museum of Natural History & Culture indicates that the earliest evidence of mammal social behavior goes back to the Age of Dinosaurs.

A life-like reconstruction along with identified fossilized bones found of Filikomys primaevus. Its powerful shoulders and elbows suggest it was a burrowing mammal. ©Misaki Ouchida.

The evidence, published Nov. 2 in the journal Nature Ecology & Evolution, lies in the fossil record of a new genus of multituberculate — a small, rodent-like mammal that lived during the Late Cretaceous of the dinosaur era — called Filikomys primaevus, which translates to “youthful, friendly mouse.” The fossils are the most complete mammal fossils ever found from the Mesozoic in North America. They indicate that F. primaevus engaged in multi-generational, group-nesting and burrowing behavior, and possibly lived in colonies. Study co-authors — including lead author Luke Weaver, a UW graduate student in biology, and senior author Gregory Wilson Mantilla, a UW professor of biology and curator of vertebrate paleontology at the Burke Museum — analyzed several fossils, all about 75.5 millioin years old, and extracted from a well-known dinosaur nesting site called Egg Mountain in western Montana.

Fossil skulls and skeletons of at least 22 individuals of F. primaevus were discovered at Egg Mountain, typically clustered together in groups of two to five, with at least 13 individuals found within a 30 square-meter area in the same rock layer. Based on how well preserved the fossils are, the type of rock they’re preserved in, and F. primaevus’ powerful shoulders and elbows — which are similar to today’s living burrowing animals — Weaver, Wilson Mantilla and co-authors hypothesize these animals lived in burrows and were nesting together. Furthermore, the animals found were a mixture of multiple mature adults and young adults, suggesting these were truly social groups as opposed to just parents raising their young.

A block of Filikomys primaevus fossils analyzed from the Egg Mountain Formation in western Montana. This particular block includes skulls and skeletons of two adult and one subadult individuals. ©Luke Weaver.

“It was crazy finishing up this paper right as the stay-at-home orders were going into effect — here we all are trying our best to socially distance and isolate, and I’m writing about how mammals were socially interacting way back when dinosaurs were still roaming the Earth!” said Weaver. “It is really powerful, I think, to see just how deeply rooted social interactions are in mammals. Because humans are such social animals, we tend to think that sociality is somehow unique to us, or at least to our close evolutionary relatives, but now we can see that social behavior goes way further back in the mammalian family tree. Multituberculates are one of the most ancient mammal groups, and they’ve been extinct for 35 million years, yet in the Late Cretaceous they were apparently interacting in groups similar to what you would see in modern-day ground squirrels.”

Previously, scientists thought social behavior in mammals first emerged after the mass extinction that killed off the dinosaurs, and mostly in the Placentalia — the group of mammals humans belong to, which all carry the fetus in the mother’s uterus until a late stage of development. But these fossils show mammals were socializing during the Age of Dinosaurs, and in an entirely different and more ancient group of mammals — the multituberculates.

“These fossils are game changers,” said Wilson Mantilla. “As paleontologists working to reconstruct the biology of mammals from this time period, we’re usually stuck staring at individual teeth and maybe a jaw that rolled down a river, but here we have multiple, near complete skulls and skeletons preserved in the exact place where the animals lived. We can now credibly look at how mammals really interacted with dinosaurs and other animals that lived at this time.”

References: Weaver, L.N., Varricchio, D.J., Sargis, E.J. et al. Early mammalian social behaviour revealed by multituberculates from a dinosaur nesting site. Nat Ecol Evol (2020). https://doi.org/10.1038/s41559-020-01325-8 link: http://dx.doi.org/10.1038/s41559-020-01325-8

Provided by University of Washington

New Analysis Method Can Lead To Better Cancer Drugs (Medicine)

While proteins on the surface of cells are the targets for most drugs, refined methods are needed to analyse how these membrane proteins are organised. Researchers at Karolinska Institutet have developed a new DNA-based analytical method that could contribute to the development of future drugs for breast and other cancers. The study is published in Nature Nanotechnology.

(Left) Ana Teixeira, researcher, and Elena Ambrosetti, postdoctoral researcher, the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. ©Ulf Sirborn.

The efficacy of most drugs in clinical use is attributable to their interaction with proteins on cell membranes. It is therefore essential to understand how these proteins operate in health and disease.

Many of the proteins on the cell membrane are distributed into functional units, domains of nano-scale dimensions (i.e. 10-6 mm).

Membrane proteins are analysed using super-resolution microscopy, a technique limited by the fact that only a small number of membrane proteins – normally three – can be analysed at the same time.

Researchers at Karolinska Institutet have now developed a method that increases this number. This non-microscope-based method for analysing entire populations of cells is called NanoDeep (NANOscale DEciphEring of membrane Protein nanodomains).

The method is based on the use of DNA analysis to translate information on membrane-protein organisation. There are no limits to the number of such proteins that NanoDeep can analyse simultaneously. Their work has not only enabled the researchers to corroborate previous findings but also led to new discoveries.

“NanoDeep currently has a resolution in the 10 nanometre interval, that’s 10 billionths of a metre, which surpasses many other methods of super-resolution microscopy,” says the study’s last author Ana Teixeira, researcher at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. “NanoDeep has the potential to bring new insights into the regulation of membrane protein function.”

Using NanoDeep, the researchers have been able to describe protein environments surrounding the membrane receptor Her2, a membrane protein that transmits information to proteins inside the cell.

Her2 is over-represented in breast and other types of cancer. A better understanding of Her2 will improve the chances of developing new drugs that prevent most recurrences of such cancers.

The new method has been developed to be as simple as possible.

“Our method makes the use of information on the spatial organisations of proteins at a nano-scale more accessible as a diagnostic tool in clinical tests,” says the study’s first author, postdoctoral researcher Elena Ambrosetti. “It can also be used as a tool for developing new kinds of drug designed to affect the function of membrane proteins.”

References: “A DNA-nanoassembly-based approach to map membrane protein nanoenvironments”, Elena Ambrosetti, Giulio Bernardinelli, Ian Hoffecker, Leonard Hartmanis, Georges Kiriako, Ario de Marco, Rickard Sandberg, Bjorn Hogberg, Ana I. Teixeira. Nature Nanotechnology, online November 2 2020, doi: 10.1038/s41565-020-00785-0. Link: http://dx.doi.org/10.1038/s41565-020-00785-0

Provided by Karolinska Institute