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Tag: Nature (journal)

  • The cause of recent cold waves over East Asia and North America was in the mid-latitude ocean fronts

    The cause of recent cold waves over East Asia and North America was in the mid-latitude ocean fronts

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    Newswise — If the world is warming, why are our winters getting colder? Indeed, East Asia and North America have experienced frequent extreme weather events since the 2000s that defy average climate change projections. Many experts have blamed Arctic warming and a weakening jet stream due to declining Arctic sea ice, but climate model experiments have not adequately demonstrated their validity. The massive power outage in Texas in February 2021 was caused by an unusual cold snap, and climate models are needed to accurately predict the risk of extreme weather events in order to prevent massive socioeconomic damage. In particular, climate technology leaders have recently set the ability to predict the climate of the next decade or so as an important goal.

    The Korea Institute of Science and Technology (KIST) announced that senior researcher Mi-Kyung Sung of the Sustainable Environment Research Center and professor Soon-Il An of the Center for Irreversible Climate Change at Yonsei University (President Seung-hwan Seo) have jointly discovered the role of mid-latitude oceans as a source of anomalous waves that are particularly frequent in East Asia and North America, paving the way for a mid- to long-term response to winter climate change.

    Ocean currents have a major impact on the weather and climate of neighboring countries as they transport not only suspended and dissolved matter but also heat energy. In particular, regions where temperatures change rapidly in a narrow latitudinal band, such as the Gulf Stream in the Atlantic Ocean and the downstream region of the Kuroshio Current in the Pacific Ocean, are called “ocean fronts,” and the KIST-Yonsei joint research team attributes the atmospheric wave response to the excessive accumulation of heat in these ocean fronts as the cause of the increase in extreme cold waves. From the early 2000s until recently, anomalous cold trend in East Asia coincided with the accumulation of heat near the Gulf Stream in the North Atlantic, and that in North America coincided with the intensification of heat accumulation near the Kuroshio Current. The oceanic frontal region acts as a thermostat to control the frequency of winter cold waves and anomalous high temperatures.

    The process of heat accumulation in oceanic frontal regions lasts from years to decades. During this time, a warming hiatus can occur in the continental regions that bucks the global warming trend. Conversely, during decades of ocean frontal cooling, continental regions appear to experience a sharp acceleration of warming. This suggests that the recent decadal cooling trend is essentially reinforced by temporary natural variability in the global climate system, and that we can expect unseasonably warm winter weather to become more prevalent as the heat buildup in the ocean front is relieved. These results are also evident in climate model experiments that vary the amount of heat accumulation near ocean fronts, showing that observations and climate model experiments are consistent in their conclusions, in contrast to conventional sea ice theory. This highlights the importance of accurately simulating ocean front variability in climate models to improve our ability to predict medium- and long-term climate change over the next decade.

    As global warming intensifies in the future and changes the structure of the ocean, these regional climate variations could change dramatically. Climate model experiments with increased greenhouse gases have shown that North America is likely to experience shorter and fewer warming hiatus, while East Asia is likely to experience more frequent intersections between warming hiatus and acceleration. These different continental responses are driven by the different oceanic responses of the Kuroshio Current and the Gulf Stream to global warming.

    “Applying the effects of ocean fronts revealed in this research to global warming climate models can improve climate change forecasts for the near future,” said Dr. Mi-Kyung Sung of KIST. “It will provide important references for long-term forecasts of winter energy demand and the construction of climate change response infrastructure to prevent climate disasters such as the 2021 Texas power outage.”

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    KIST was established in 1966 as the first government-funded research institute in Korea. KIST now strives to solve national and social challenges and secure growth engines through leading and innovative research. For more information, please visit KIST’s website at https://eng.kist.re.kr/

    The research, which was funded by the Ministry of Science and ICT (Minister Jong-ho Lee) through the Mid-Career Researcher Support Project (2021R1A2C1003934), the Leading Research Center Support Project (2018R1A5A1024958), and the Ultra-High Performance Computing Utilization Advancement Project (2022M3K3A1094114), was published on November 27 in the international journal Nature Communications

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    National Research Council of Science and Technology

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  • Research sheds new light on Moon rock formation, solving major puzzle in lunar geology

    Research sheds new light on Moon rock formation, solving major puzzle in lunar geology

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    Newswise — The study, published today in Nature Geoscience, reveals a key step in the genesis of these distinctive magmas.  A combination of high temperature laboratory experiments using molten rocks, together with sophisticated isotopic analyses of lunar samples, identify a critical reaction that controls their composition.

    This reaction took place in the deep lunar interior some three and a half billion years ago, involving exchange of the element iron (Fe) in the magma with the element magnesium (Mg) in the surrounding rocks, modifying the chemical and physical properties of the melt.  

    Co-lead author Tim Elliott, Professor of Earth Sciences at the University of Bristol, said: “The origin of volcanic lunar rocks is a fascinating tale involving an ‘avalanche’ of an unstable, planetary-scale crystal pile created by the cooling of a primordial magma ocean. 

    “Central to constraining this epic history is the presence of a magma type unique to the Moon, but explaining how such magmas could even have got to the surface, to be sampled by Space missions, has been a troublesome problem. It is great to have resolved this dilemma.”

    Surprisingly high concentrations of the element titanium (Ti) in parts of the lunar surface have been known since the NASA Apollo missions, back in the 1960s and 1970s, which successfully returned solidified, ancient lava samples from the Moon’s crust. More recent mapping by orbiting satellite shows these magmas, known as ‘high-Ti basalts’, to be widespread on the Moon.

    “Until now models have been unable to recreate magma compositions that match essential chemical and physical characteristics of the high-Ti basalts. It has proven particularly hard to explain their low density, which allowed them to be erupted some three and a half billion years ago,” added co-lead author Dr Martijn Klaver, Research Fellow at the University of Münster Institute of Mineralogy.

    The international team of scientists, led by the Universities of Bristol in the UK and Münster in Germany managed to mimic the high-Ti basalts in the process in the lab using high-temperature experiments.  Measurements of the high-Ti basalts also revealed a distinctive isotopic composition that provides a fingerprint of the reactions reproduced by the experiments.

    Both results clearly demonstrate how the melt-solid reaction is integral in understanding the formation of these unique magmas. 

    Paper

    ‘Titanium-rich basaltic melts on the Moon modulated by reactive flow processes’ by Martijn Klaver et al in Nature Geoscience

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    University of Bristol

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  • Study: Reflective surfaces, tree irrigation cool hot city by 4.5°C.

    Study: Reflective surfaces, tree irrigation cool hot city by 4.5°C.

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    Newswise — It’s possible to significantly reduce the temperatures of a major city in a hot desert climate while reducing energy costs, a new study by UNSW Sydney shows.

    The findings, published today in Nature Cities, detail a multi-faceted strategy to cool Saudi Arabia’s capital city by up to 4.5°C, combining highly reflective ‘super cool’ building materials developed by the High-Performance Architecture Lab with irrigated greenery and energy retrofitting measures. The study, which was conducted in collaboration with the Royal Commission of Riyadh, is the first to investigate the large-scale energy benefits of modern heat mitigation technologies when implemented in a city.

    “The project demonstrates the tremendous impact advanced heat mitigation technologies and techniques can have to reduce urban overheating, decrease cooling needs, and improve lives,” says UNSW Scientia Professor Mattheos (Mat) Santamouris, Anita Lawrence Chair in High-Performance Architecture and senior author of the study.

    Prof. Santamouris specialises in developing heat mitigation technologies and strategies to decrease urban temperatures in cities. Extreme urban heat affects more than 450 cities worldwide, increasing energy consumption needs and adversely impacting health, including heat-related illness and death. 

    Riyadh, the capital of Saudi Arabia, is one such city. Situated in the centre of a desert, it is one of the hottest cities in the world, with temperatures that can exceed 50°C during summer. Furthermore, climate change and rapid urbanisation are increasing the magnitude of overheating.

    “Limited greenery and large artificial surfaces made of conventional building materials like asphalt and concrete trap heat, meaning the city continues to heat up,” says Prof. Santamouris. “Additional heat from car pollution and industrial activities also increases the city’s temperature.” 

    Simulating city-scale heat mitigation scenarios

    For the study, the team led by UNSW researchers ran large-scale cooling climatic and energy simulations of the Al Masiaf precinct of Riyadh, including the energy performance of 3323 urban buildings, under eight different heat mitigation scenarios to evaluate optimal strategies for lowering the temperature of the city and reducing cooling needs.

    The modelling, which considered different combinations of super cool materials, vegetation types and energy retrofitting levels, found it’s possible to decrease the outdoor temperature in the city by nearly 4.5°C during summer. The strategy would also improve cooling energy conservation for the city by up to 16 per cent.

    The recommended heat mitigation (or cooling) scenario for Riyadh includes using super cool materials implemented in the roof of the buildings and more than doubling the number of irrigated trees to improve transpiration cooling. 

    On the contrary, a blind implementation of urban cooling techniques not based on detailed and advanced scientific optimisation, like the use of non-irrigated greenery, may result in a substantial increase in the city’s temperature. 

    “By implementing the right combination of advanced heat mitigation technologies and techniques, it is possible to decrease the ambient temperature at the precinct scale,” says Prof. Santamouris. “For a sweltering city the size of Riyadh, significantly reducing cooling needs is also tremendous for sustainability.”

    Prof. Santamouris says lowering the temperature of the city helps increase thermal comfort for people as well as reduce health issues from severe heat, decrease the concentration of pollutants and improve human productivity. While not a part of this study, previous research found implementing similar cooling strategies in other cities can help reduce heat-related deaths.

    Reducing energy demand at the urban scale 

    The research also simulated the energy impact of retrofitting measures for all 3323 buildings, alongside heat mitigation technologies implemented at the urban scale. Combining the optimal cooling technologies with energy retrofitting options – namely, improving the building envelope through better windows, insulation, solar and cool roofs – could decrease the cooling demand by up to 35 per cent.

    “This represents a substantial reduction to the energy needs for Riyadh that would help further reduce costs associated with cooling for the city while improving the quality of life for the local population,” says Prof. Santamouris.

    The researchers now hope to work with the Royal Commission of Riyadh to begin implementing the tailored heat mitigation plan in the city, which would be the largest of its kind in the world.

    “Once implemented at the city scale, these advanced heat mitigation technologies will deliver important health, sustainability and economic outcomes for the city for years to come,” says Prof. Santamouris. 

    The research team also included researchers from the University of Sydney, Lawrence Berkeley National Laboratory, the Royal Commission of Riyadh City, the University of Calcutta and the University of Athens. 

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    University of New South Wales

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  • Research volunteers combat Parkinson’s.

    Research volunteers combat Parkinson’s.

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    Newswise — About three years before he retired, David Campbell noticed something weird happening as he typed. Whenever he tried to hit a letter, say “a,” he’d get “aaa,” like the keyboard was jamming or his finger was triple-tapping the key. That wasn’t the only thing that seemed off—his sense of smell was faltering. “Little things,” he says, “that I didn’t think of as being a big deal.”

    A couple of weeks after he retired in fall 2020, Campbell learned the little things weren’t so little—they were life-changing. He was diagnosed with Parkinson’s disease. The repeated “a” was caused by a slight tremor as nerve cells in his brain degenerated or died, interrupting the signals controlling his muscles. A tremor is many patients’ first Parkinson’s symptom, followed by a raft of other steadily worsening neurological issues, such as a quieter voice, slower movement, stiffer limbs, and tighter facial expressions. Almost all patients will suffer some loss of smell too.

    Although therapy and medications can bring some relief from the neurodegenerative disorder, there’s no cure. Somewhere between 500,000 and 1 million Americans have Parkinson’s, including actor Michael J. Fox, singer Neil Diamond, and civil rights activist Jesse Jackson.

    For Campbell, it was a pretty shabby retirement gift. As he tried to adjust to his new reality, the former Boston University laboratory engineer joined a support group and decided to volunteer for research studies that aimed to improve treatment—perhaps even plot the route to a cure. “I figured, I have the disease,” he says, “I might as well try to do something good with it.”

    That decision is already having an impact. With the help of volunteers like Campbell, researchers at Boston University’s Center for Neurorehabilitation, a hub for Parkinson’s research, education, and clinical care, have made two important advances that may help people with the disease walk more smoothly, even turn their shuffled steps into confident strides. In one study, they used wearable soft robotic apparel—a series of fabric wraps, cables, actuators, and sensors—to help patients walk farther and faster. A second study used a music-based technology to increase walking duration and distance—controlling a song’s beats per minute to keep the steps up.

    Based at BU Sargent College of Health & Rehabilitation Sciences, the center has been at the forefront of research establishing the benefits of exercise and physical therapy in taming Parkinson’s disease’s impact and improving quality of life. And both of the newly tested therapies could find their way into patients’ everyday lives relatively quickly. The robotic device uses technology that’s already commercially available; the musical intervention uses store-bought headphones. But, says Terry Ellis, the Center for Neurorehabilitation’s director, without the volunteers who give up hours of their time to participate in research studies or help her team test ideas and tweak gadgets, none of it would be possible.

    That’s a story told across BU. Volunteers join research studies—as well as classroom discussions and clinical training programs—on a wide range of topics, participating in person or from home. Some even do it over decades, like those who’ve given their time to the long-running Framingham Heart Study and BU’s Black Women’s Health Study.

    “Most of our research is intervention studies, so there’s hypothetically some benefit for them,” says Ellis of her center’s work. Their fitness may improve, they may get to try out some symptom-relieving tools. “But without them, we couldn’t do the work. I’m always saying to [volunteers], the work wouldn’t exist without your participation and contribution.”

    Robotic Apparel Eliminates Freezing of Gait

    Being a research study guinea pig can be rewarding, and might even save or improve lives, but it’s hardly glamorous work. For most of the apparel study, the main volunteer (unnamed in the final paper to protect their privacy) spent his time walking back and forth—again, and again, and again. At first, it was to get a baseline of his walking ability, then to allow the researchers to monitor the robotic tech’s effectiveness at shifting his stride and fine-tune the technology.

    The patient, a 73-year-old male who’d been diagnosed with Parkinson’s 10 years earlier, was struggling with a common Parkinson’s problem known as freezing of gait. During a freezing episode, thought to be caused by a malfunction in the brain’s locomotor circuitry, a patient’s stride shortens, their walking speed tumbles, and their muscle coordination falls out of whack. Then they just stop—it reportedly feels like their feet are glued to the floor. Things had gotten so bad for the patient working with Ellis—more than 10 freezing episodes a day, resulting in multiple falls—he’d taken to getting around on a kick scooter.

    “It’s just devastating,” says Ellis (CAMED’05), a Sargent professor and chair of physical therapy. “There’s really no medicine or surgery that improves this. It interferes tremendously with people’s everyday life.”

    She and her colleagues had tried wearable robotic apparel with people recovering from a stroke—finding it helped some regain their pre-stroke walking speeds—and wondered if similar technology might work for Parkinson’s too. That exosuit, which is now commercially available for stroke rehabilitation from medical device company ReWalk Robotics, was derived from a model developed for the military by Harvard University’s Biodesign Lab to increase service members’ endurance.

    In most iterations, the robotic apparel looks like a highly engineered sports brace, using an algorithm to drive motors and cables that strategically apply forces to supplement muscles and joints. The version the researchers tailored for the Parkinson’s study featured two bands: one around the waist, the other around the thigh, each connected by a spooled cable. When activated, the spool turns, retracting the cable and pulling the thigh up. Ellis calls it a mechanical assist: “It provides a little bit of force—it’s perceptible, but at a very low level.” The algorithm helps time the assistance to the users’ steps and tailor the amount of force needed.

    As the study progressed, the researchers put their volunteer through his paces with a range of different tasks, including timed walking tests in the lab and outside in the community, adjusting the force provided by the suit—and its timing—and assessing the biomechanics of his walking.

    The results were striking: when the suit was on, the volunteer strolled easily down the corridor, arms and legs swinging with a natural confidence; when it was powered down, the change was almost instant—he staggered, stumbled, shuffled, and grabbed at the wall for balance.

    When switched on, the robotic apparel eliminated his freezing of gait—the first time any study has shown a potential way to overcome the debilitating symptom. The findings were published in Nature Medicine.

    “It’s pretty amazing,” says Ellis, who collaborated with researchers from BU and Harvard University. “We think we’re driving an increase in step length and that’s preventing the shortening of the steps that leads to freezing. In future, we envision you could wear this like underclothes.” Her coauthors include Conor Walsh, a Harvard University professor of engineering and applied sciences; Franchino Porciuncula, a Sargent research scientist; and Jinsoo Kim, a Stanford University postdoctoral scholar and recent Harvard PhD student.

    The researchers even did an informal test outside the study, letting the volunteer take the apparel for a spin at home. “And he did pretty well,” says Ellis. “There were certain tight spots where it didn’t work as well as we would want, so we talked about playing with the algorithm to make it work better.”

    This was just a small study with one patient, so the next stage would be scaling the project up with more volunteers. But Ellis says because the base technology is already commercially available through ReWalk, there aren’t many barriers to getting the suit into clinics. She pictures a near future where a patient visits a physical therapist, their walking is assessed, and they get robotic apparel tailored for their needs. Even without the tech, the team’s findings on the biomechanics of freezing gait may help therapists better target treatments to combat it.

    Walking to the Beat Improves Quality of Life with Parkinson’s

    Another volunteer being helped to hit her stride is Ann Greehy. A former school guidance counselor, she was diagnosed with Parkinson’s in 2015 and began volunteering at BU three years later. Her most recent contribution was as a volunteer on a project examining the use of music as a walking aid.

    In a new study published in the Journal of Parkinson’s Disease, Ellis and Porciuncula found they could use a song’s beats per minute to help people increase their gait speed and stride length, and cut out variability in their walking patterns. Greehy was one of those who’d helped them assess the technology.

    During the study, researchers placed sensors in subjects’ shoes to monitor their gait and gave them an Android device loaded with a music software app. The proprietary system, which uses a technique known as rhythmic auditory stimulation, plays music with beats per minute tailored to a patients’ natural walking cadence, helping them gradually increase their pace session by session; all the participants were asked to plug in their headphones and walk for 30 minutes, five days a week.

    “It was amazing when the beats started—it was a whole new experience,” says Greehy. “You put your shoulders back and you’re up walking.”

    After four weeks of using the system, which was developed by neurorehab company MedRhythms, the 23 study participants had a similar experience to Greehy. The researchers found that, compared to baseline, they had higher rates of daily moderate intensity walking (up by an average of 21.44 minutes) and more steps (up by 3,384 steps). In the paper, they noted “quality of life, disease severity, walking endurance, and functional mobility were improved after four weeks.”

    “People with Parkinson’s can’t move automatically—they have to think about the movement,” says Ellis, who collaborated on the study with researchers from the University of New England, Johns Hopkins University, and MedRhythms. The part of the brain, the basal ganglia, that sends the signals that help people walk without deliberate thought is dysfunctional. “You can’t possibly keep that level of attention to the task of walking, so we were trying to figure out how to provide an external signal if the internal signal is not working.”

    The music provided that signal—in the same way your workout playlist gets your feet moving on the gym treadmill. “You’re not thinking, ‘Oh, I want to run to the beat of the music,’” says Ellis. “It just happens, and so it takes a lot less cognitive energy.”

    Making Sense of Life with Parkinson’s

    One of Greehy’s highlights of the music study was making Ellis’ students laugh by sharing her favorite track: rapper Flo Rida’s “Club Can’t Handle Me.” They were “on the floor laughing at this old lady who likes Flo Rida,” she says. Like Greehy, many of the volunteers also come into BU to work with students, sitting in on classes and panels, talking to them about living with Parkinson’s disease, answering their questions, and giving them a chance to practice their care skills. Some volunteers also attend the Center for Neurorehabilitation as a patient, receiving physical therapy services.

    “Our research and clinic are one and the same,” says Ellis. “That chasm that can exist between research and clinical practice doesn’t exist here. The questions we try to answer with research come from our interactions with patients in the clinic—it’s their challenges and problems that they bring to us that make us curious about how to solve them.” And when they find a solution, they take it straight into the clinic.

    Another of the music study volunteers and clinic patients, retired psychologist Ed Hattauer, appreciates that focus on making lives better—including his own. “As an old-time PhD researcher, I really relish in the importance of doing research, but research that’s very practically oriented toward helping people do things.” Hattauer says that when he comes to the center, there’s “really a sense of personal caring that gets communicated. And I think what I carry away is a sense of hope. It helps sustain my hope and my feeling of emotional connection.”

    Greehy says there are a whole bunch of factors that keep her coming back: “I’ve gotten so much out of this it’s not even funny.” She loves working with students, she gets great tips from the therapists about maintaining her hobbies, like gardening, and she feels good being part of the push for a solution to the disease. Most importantly, volunteering has helped her make sense of life after her diagnosis.

    “What are you going to do with this disease?” says Greehy. “Are you just going to sit back or are we going to jump in? I want us to do more to wipe this thing out. I think it’s time.”

    Like other volunteers, Greehy knows the disease probably won’t be cured in her lifetime, but it won’t stop her trying.

    “I don’t know if they’ll find a cure for me necessarily,” says Campbell, “but I’ve been around research and development my whole life and it feels good to contribute in whatever way possible. I could just sit at home and wallow in pity and do nothing, but it feels proactive to go out and make an effort to advance the science.”

     

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    Boston University

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  • Scientists Probe the Emergent Structure of the Carbon Nucleus

    Scientists Probe the Emergent Structure of the Carbon Nucleus

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    The Science

    Newswise — The element carbon is critical to organic chemistry and life as we know it. The physics of its most common isotope, carbon-12, are extremely complex. Many experimental and theoretical investigations have been devoted to determining the energies and underlying structures of the nuclear states of carbon-12. In this work, researchers computed these states from first principles—the most basic components of physics theory. The approach used supercomputers and nuclear lattice simulations to calculate the three-dimensional shape formed by the protons and neutrons comprising the nucleus. The results show that all of the low-lying energy states of carbon-12 have a substructure where the six protons and six neutrons cluster together into alpha particles. Alpha particles are helium-4 nuclei, which contain two protons and two neutrons.

    The Impact

    One well-known nuclear state of carbon-12 is the Hoyle state. This state has an energy that sits near the energy threshold for three alpha particles or helium nuclei. This energy thereby greatly enhances the production of carbon in helium-burning stars. This helps to explain the presence of carbon in the Universe. The results obtained in this research show that the Hoyle state is composed of a “bent arm” or obtuse triangular arrangement of alpha particles. All the low-lying energy states of carbon-12 have an intrinsic shape composed of three alpha particles forming either an equilateral triangle or an obtuse triangle. The new results give information about the possible geometrical shapes of nuclear states.

    Summary

    The carbon atom provides the backbone for the complex organic chemistry composing the building blocks of life. The physics of the carbon nucleus in its predominant isotope, carbon-12, are also full of complexity. Researchers from the University of Bonn, Forschungszentrum Jülich in Germany, the Gaziantep Islamic Science and Technology University in Turkey, the Graduate School of China Academy of Engineering Physics, Tbilisi State University, and the Facility for Rare Isotope Beams at Michigan State University calculated the structure of the nuclear states of carbon-12 using the ab initio framework of nuclear lattice effective field theory.

    The research found that all the low-lying states of carbon-12 have an intrinsic shape composed of three alpha clusters forming either an equilateral triangle or an obtuse triangle. The states with the equilateral triangle shape also have a dual description in terms of particle-hole excitations in a mean-field picture. The results agree with experimental data and provide the first model-independent density map of the nuclear states of carbon-12. The results help to explain the origins of carbon from the helium and hydrogen that made up the Universe shortly after the Big Bang.

    Funding

    This research was funded by the Deutsche Forschungsgemeinschaft (the German Research Foundation), the National Natural Science Foundation of China , the Chinese Academy of Sciences President’s International Fellowship Initiative, the National Security Academic Fund of China, Volkswagen Stiftung, the European Research Council, the Department of Energy, and the Nuclear Computational Low-Energy Initiative SciDAC-4 project, as well as computational resources provided by the Gauss Centre for Supercomputing e.V. and the Oak Ridge Leadership Computing Facility.


    Journal Link: Nature Communications, May-2023

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    Department of Energy, Office of Science

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  • Inside the Matrix: Nanoscale Patterns Revealed Within Model Research Organism

    Inside the Matrix: Nanoscale Patterns Revealed Within Model Research Organism

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    BYLINE: Mario Aguilera

    Newswise — Species throughout the animal kingdom feature vital interfaces between the outermost layers of their bodies and the environment. Intricate microscopic structures—featured on the outer skin layers of humans, as one example—are known to assemble in matrix patterns.

    But how these complex structures, known as apical extracellular matrices (aECMs) are assembled into elaborately woven architectures has remained an elusive question.

    Now, following years of research and the power of a technologically advanced instrument, University of California San Diego scientists have unraveled the underpinnings of such matrices in a tiny nematode. The roundworm Caenorhabditis elegans has been studied extensively for decades due to its transparent structure that allows researchers to peer inside its body and examine its skin.

    Described in the journal Nature Communications, School of Biological Sciences researchers have now deciphered the assemblage of aECM patterns in roundworms at the nanoscale. A powerful, super-resolution microscope helped reveal previously unseen patterns related to columns, known as struts, that are key to the proper development and functioning of aECMs.

    “Struts are like tiny pillars that connect the different layers of the matrix and serve as a type of scaffolding,” said Andrew Chisholm, a professor in the School of Biological Sciences and the paper’s senior author.

    Although roundworms serve as a model organism for laboratory studies due to their simple, transparent bodies, below the surface they feature intricate architectures. They also have nearly 20,000 genes, not unlike the number of human genes, and therefore provide lessons on structure and function of more advanced organisms.

    Focusing on the roundworm exoskeleton known as the cuticle, the researchers found that defects in struts result in unnatural layer swelling, or “blistering.” Within the cuticle layer, the research study focused on collagens, which are the most abundant family of proteins in our bodies and help keep bodily materials conjoined.

    “The struts hold the critical layers together,” said Chisholm. “Without them, the layers separate and cause disorders such as blistering. In blistering mutants you don’t see any struts.”

    Conventional laboratory instruments had previously imaged struts without detail, often resulting in undefined blobs. But through Biological Sciences Assistant Professor Andreas Ernst’s laboratory they accessed advanced instrumentation—known as 3D-structured illumination super resolution microscopy (3D-SIM)—which put the struts into stunning focus and allowed their functions to be more easily defined. The researchers were then able to solve the nanoscale organization of struts and previously undocumented levels of patterning in the cuticle layer.

    “We could see exactly where these proteins were going in the matrix,” said Chisholm. “This is potentially a paradigm for how the matrix assembles into very complex structures and very intricate patterning.”

    The two first authors, Jennifer Adams (senior research associate) and Murugesan Pooranachithra (postdoctoral fellow), contributed equally to the paper. Other coauthors are Erin Jyo, Sherry Li Zheng, Alexandr Goncharov, Jennifer Crew, James Kramer, Professor of Neurobiology Yishi Jin, Assistant Professor of Cell and Developmental Biology Andreas Ernst and Andrew Chisholm.

    Sherry Zheng was a UC San Diego Triton Research and Experiential Learning Scholar and received the Gabriele Wienhausen Biological Sciences Scholarship. Funding for the research was provided by the Howard Hughes Medical Institute; the National Institutes of Health  (R35 GM142433, R01 GM054657 and R35 GM134970).

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    University of California San Diego

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  • Boosting engagement in heterosexual men may reduce HIV in Uganda

    Boosting engagement in heterosexual men may reduce HIV in Uganda

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    Newswise — A study looking at 15 years of HIV transmission and suppression in Uganda reveals how closing gender gaps in treatment could slash infection rates.

    Providing more heterosexual men with easy access to HIV treatment and care could help to suppress the virus and rapidly cut transmission to their female partners, shows a new study published in Nature Microbiology.

    The research, led by scientists from Imperial College London and the Rakai Health Sciences Program in Uganda, analysed 15 years of data from 2003-2018, during which the US President’s Emergency Plan For AIDS Relief (PEPFAR) has delivered an extensive programme of HIV/AIDS testing, prevention, and treatment.

    This included distributing Antiretroviral Therapy (ART) drugs, which supress the virus so a person is no longer infectious. The analysis shows that the PEPFAR program and other services have greatly reduced new infections among young women and heterosexual men, but that reductions were less substantial in women aged 25 and above.

    This is thought to be because women are more likely to reach viral suppression through uptake and effective use of HIV treatment, preventing them from passing HIV to their male partners, but that the same is not true the other way around.

    Gender disparity

    The analysis showed that the number of women reaching and maintaining undetectable (non-transmissible) levels of HIV infection were 1.5 to 2 times higher than men across all ages by the year 2018. The analysis shows that had men reached the same levels of virus suppression as women, around half the new infections that occurred between 2016 and 2018 could have been avoided.

    The team also reconstructed transmission networks based on the genetic code of the virus from thousands of participants, which confirmed that overall, the proportion of transmissions from men is increasing and is now at 63% of all transmissions in the area – even though a greater number of women are living with HIV than men.

    The team say the disparity could be because men need to travel for work, that clinics are closed when they are back home, or for other reasons, including social stigma.

    Dr Oliver Ratmann, senior author of the study from the Department of Mathematics at Imperial, said: “In this evolving battle against HIV, it is critical we adapt our strategies, bridge gaps in care, and ensure that individuals, regardless of their gender, have access to the lifesaving benefits of ART.

    “It is important to design services in a way that everybody who would like to use them is able and feels empowered to do so. By routinely monitoring the changing dynamics of the epidemic and striving for equity in HIV care, we can move closer to the ultimate goal of controlling and, one day, eliminating HIV transmission.”

    Dr Kate Grabowski, a co-author of the study from the Johns Hopkins School of Medicine, added: “The continued success of the President’s Emergency Plan for AIDS Relief (PEPFAR) in reducing infections and saving lives is crucial for ending HIV transmission. With United States Congress currently evaluating PEPFAR funding, our evidence strongly supports the program’s efficacy and provides a clear roadmap to ending the pandemic through enhanced HIV treatment coverage, particularly among men.”

    Closing the gap in transmission

    The team used data from the Rakai Community Cohort Study (RCCS) in southern Uganda, a region where more than 9% of adults are living with HIV – approximately 20 times higher than in the US. Since 2003, a period predating the widespread availability of ART in Africa, RCCS has enrolled nearly 37,000 individuals, tracking changes in HIV infection as new interventions came on board.

    The analysis tracked evolving heterosexual HIV epidemic dynamics in 36 communities over a 15-year span of RCCS surveillance data, including records of new infections, deep sequence HIV genomic data, HIV treatment uptake, viral suppression, and behavioural information.

    Analyses in earlier years showed that the highest number of new HIV cases in southern Uganda was among adolescent girls and young women aged 15-24 years. In more recent years tracked in the new study, women 25-34 years old have become a new focal group, experiencing a slower decline in new infections than other age groups. This is alongside a significant difference in the declines in new infections between men and women, with those among boys and men declining much faster.

    To estimate the likely impact of getting men to the same level of viral suppression, the team applied statistical models based on the data about transmission dynamics. The resulting projections indicate that closing the viral suppression gap in men could have effectively halved rates of new infections among women and eliminated gender disparities in acquiring HIV.

    Dr Joseph Kagaayi, previous director of the Rakai Health Sciences program and senior co-author of the study, said: “Our study findings emphasise the importance of addressing disparities in ART uptake and viral suppression between men and women. By doing so, we can not only reduce HIV infections among women but also work towards closing the gender gap in HIV transmission. Achieving these goals will require concerted efforts, informed policies, and strengthened healthcare services.”

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    Imperial College London

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  • Bird feeding may give humans something to chirp about

    Bird feeding may give humans something to chirp about

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    BYLINE: Travis Williams

    Newswise — Ashley Dayer hopes to peck away at the notion that bird feeding is simply for the birds.

    An associate professor in the Department of Fish and Wildlife Conservation at Virginia Tech, Dayer is the lead author of an article published in People and Nature that argues not only for the acknowledgment of the activity’s benefit to humans, but that it should play a role in public guidance and policy.

    “Wildlife agencies and others making decisions on managing bird feeding need to be considering not only what the science is behind what’s going on with birds, but also the science behind what’s going on with people,” Dayer said.

    The article also encourages additional research to better understand how human well-being is impacted by regularly feeding birds, and Dayer and a team of researchers both in and outside of Virginia Tech are leading the way. The group is conducting what is perhaps the first large-scale bird feeding research that also incorporates observing humans.

    “People are not only reporting what they see at their bird feeders, but also their emotional responses to it,” Dayer said. “It’s pretty fun because most citizen science projects focus just on the natural or physical science, but we’re now able to look at the human piece of it.”

    Funded recently as part of a more than $1.5 million National Science Foundation grant led by Dayer and Dana Hawley, professor of biological sciences, the four-year project aims to engage more than 10,000 bird feeders across the United States.

    Other collaborators on the article and project include

    • Christy Pototsky, a graduate student studying fish and wildlife conservation at Virginia Tech
    • Richard Hall, associate professor at the University of Georgia
    • Alia Dietsch, associate professor at Ohio State University
    • Tina Phillips, David Bonter, Emma Greig, and Wesley Hochachka of the Cornell Lab of Ornithology

    Dayer said interest in the topic began in 2021, when the researchers began to notice state agencies advising people to stop feeding birds in response to various avian disease outbreaks. After looking into it, they found that 23 states had made such recommendations without evidence it would decrease disease spread, with varying levels of pushback, and with no real method of gauging compliance, much less its impact on people.

    The new project is an extension of the work Dayer and Hawley began about six years ago with the help of a joint seed grant from the Global Change Center of the Fralin Life Sciences Institute and the Institute for Society, Culture, and the Environment.

    Hawley said the lack of information about humans related to bird feeing was something she’d not previously considered, and she found it a strong motivator for this project.

    “In all my years of studying how bird feeding impacts wild birds, I didn’t give much thought to how it can also impact the people that spend their time and money feeding and watching birds,” Hawley said. “I get calls every year from people who see a sick bird at their feeder and want to know how they can help prevent disease spread. All in all, this made me wonder about how policy decisions that aim to minimize disease spread can inadvertently impact the people who feed the birds.”

    To help find those answers, the research team will utilize Project FeederWatch’s existing network of bird enthusiasts. Operated by the Cornell Lab of Ornithology and Birds Canada, FeederWatch has tasked people with asks participants to observe and report what they see at their feeders from November to April for the past 37 years.

    “FeederWatch is such a versatile data set even though, at its core, it is based on simple bird counts,” said Emma Greig, co-author and project leader for FeederWatch. “When you overlay information about behavior, disease, habitat, and climate change with those bird counts, we can get amazing insights into ecology and evolution.”

    During this project, FeederWatch participants also will be asked to observe their own well-being. Dayer said about 8,000 submissions came in in from the first week of this season alone.

    Such passion for birds is something Dayer understands very well. She said her mother always made sure they had bird feeders outside their family’s home, and when she became an “empty nester,” the birds became almost like children.

    “She’ll go on vacation and cut the vacation short because she needs to go home and feed her birds,” Dayer said. “So I’ve lived with someone who was really into bird feeding and have seen how important it can be to them.”

    But Dayer believes the positive impact of bird feeding isn’t limited to enthusiasts and is important in proving one of the most widely accessible connection to wildlife.

    “People in urban areas can feed birds. People with just a deck can feed birds. People with a wide range of physical abilities can feed birds. So it’s just a great way to keep that human connection to wildlife,” Dayer said.

    Hawley agreed with that sentiment, and said she hopes their work helps advance policies that will foster both health and healthy relationships.

    “In a world where so many of us live in cities or suburbs, having birds visit feeders in our yards or on our balconies is one of the only ways we get to connect daily with wildlife. But people want to be able to feed birds in ways that keep wild bird populations healthy and thriving,” Hawley said. “Our work will ideally help us develop guidelines for bird feeding that minimize risk to wild birds and maximize the benefits to the people that feed them.”

    The Department of Fish and Wildlife Conservation is in the College of Natural Resources and Environment. The Department of Biological Sciences is in the College of Science.
     

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    Virginia Tech

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  • Chemists craft colorful organic molecules.

    Chemists craft colorful organic molecules.

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    Newswise — CAMBRIDGE, MA — Chains of fused carbon-containing rings have unique optoelectronic properties that make them useful as semiconductors. These chains, known as acenes, can also be tuned to emit different colors of light, which makes them good candidates for use in organic light-emitting diodes.

    The color of light emitted by an acene is determined by its length, but as the molecules become longer, they also become less stable, which has hindered their widespread use in light-emitting applications.

    MIT chemists have now come up with a way to make these molecules more stable, allowing them to synthesize acenes of varying lengths. Using their new approach, they were able to build molecules that emit red, orange, yellow, green, or blue light, which could make acenes easier to deploy in a variety of applications.

    “This class of molecules, despite their utility, have challenges in terms of their reactivity profile,” says Robert Gilliard, the Novartis Associate Professor of Chemistry at MIT and the senior author of the new study. “What we tried to address in this study first was the stability problem, and second, we wanted to make compounds where you could have a tunable range of light emission.”

    MIT research scientist Chun-Lin Deng is the lead author of the paper, which appears today in Nature Chemistry.

    Colorful molecules

    Acenes consist of benzene molecules — rings made of carbon and hydrogen — fused together in a linear fashion. Because they are rich in sharable electrons and can efficiently transport an electric charge, they have been used as semiconductors and field-effect transistors (transistors that use an electric field to control the flow of current in a semiconductor).

    Recent work has shown that acenes in which some of the carbon atoms are replaced, or “doped,” with boron and nitrogen have even more useful electronic properties. However, like traditional acenes, these molecules are unstable when exposed to air or light. Often, acenes have to be synthesized within a sealed container called a glovebox to protect them from air exposure, which can lead them to break down. The longer the acenes are, the more susceptible they are to unwanted reactions initiated by oxygen, water, or light.

    To try to make acenes more stable, Gilliard decided to use a ligand that his lab has previously worked with, known as carbodicarbenes. In a study published last year, they used this ligand to stabilize borafluorenium ions, organic compounds that can emit different colors of light in response to temperature changes.

    For this study, Gilliard and his co-authors developed a new synthesis that allowed them to add carbodicarbenes to acenes that are also doped with boron and nitrogen. With the addition of the new ligand, the acenes became positively charged, which improved their stability and also gave them unique electronic properties.

    Using this approach, the researchers created acenes that produce different colors, depending on their length and the types of chemical groups attached to the carbodicarbene. Until now, most of the boron, nitrogen-doped acenes that had been synthesized could emit only blue light.

    “Red emission is very important for wide-ranging applications, including biological applications like imaging,” Gilliard says. “A lot of human tissue emits blue light, so it’s difficult to use blue-fluorescent probes for imaging, which is one of the many reasons why people are looking for red emitters.”

     

    Better stability

    Another important feature of these acenes is that they remain stable in both air and water. Boron-containing charged molecules with a low coordination number (meaning the central boron atom has few neighbors) are often highly unstable in water, so the acenes’ stability in water is notable and could make it feasible to use them for imaging and other medical applications.

    “One of the reasons why we’re excited about the class of compounds that we’re reporting in this paper is that they can be suspended in water. That opens up a wide range of possibilities,” Gilliard says.

    The researchers now plan to try incorporating different types of carbodicarbenes to see if they can create additional acenes with even better stability and quantum efficiency (a measure of how much light is emitted from the material).

    “We think it will be possible to make a lot of different derivatives that we haven’t even synthesized yet,” Gilliard says. “There are a lot of optoelectronic properties that can be dialed in that we have yet to explore, and we’re excited about that as well.”

    Gilliard also plans to work with Marc Baldo, an MIT professor of electrical engineering, to try incorporating the new acenes into a type of solar cell known as a single-fission-based solar cell. This type of solar cell can produce two electrons from one photon, making the cell much more efficient.

    These types of compounds could also be developed for use as light-emitting diodes for television and computer screens, Gilliard says. Organic light-emitting diodes are lighter and more flexible than traditional LEDs, produce brighter images, and consume less power.

    “We’re still in the very early stages of developing the specific applications, whether it’s organic semiconductors, light-emitting devices, or singlet-fission-based solar cells, but due to their stability, the device fabrication should be much smoother than typical for these kinds of compounds,” Gilliard says.

    ###

    The research was funded by the Arnold and Mabel Beckman Foundation and the National Science Foundation Major Research Instrumentation Program.

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    Massachusetts Institute of Technology (MIT)

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  • Nutrient found in beef and dairy improves immune response to cancer

    Nutrient found in beef and dairy improves immune response to cancer

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    Newswise — Trans-vaccenic acid (TVA), a long-chain fatty acid found in meat and dairy products from grazing animals such as cows and sheep, improves the ability of CD8+ T cells to infiltrate tumors and kill cancer cells, according to a new study by researchers from the University of Chicago.

    The research, published this week in Nature, also shows that patients with higher levels of TVA circulating in the blood responded better to immunotherapy, suggesting that it could have potential as a nutritional supplement to complement clinical treatments for cancer.

    “There are many studies trying to decipher the link between diet and human health, and it’s very difficult to understand the underlying mechanisms because of the wide variety of foods people eat. But if we focus on just the nutrients and metabolites derived from food, we begin to see how they influence physiology and pathology,” said Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the senior authors of the new study. “By focusing on nutrients that can activate T cell responses, we found one that actually enhances anti-tumor immunity by activating an important immune pathway.”

    Finding nutrients that activate immune cells

    Chen’s lab focuses on understanding how metabolites, nutrients and other molecules circulating in the blood influence the development of cancer and response to cancer treatments. For the new study, two postdoctoral fellows, Hao Fan, PhD and Siyuan Xia, PhD, both co-first authors, started with a database of around 700 known metabolites that come from food and assembled a “blood nutrient” compound library consisting of 235 bioactive molecules derived from nutrients. They screened the compounds in this new library for their ability to influence anti-tumor immunity by activating CD8+ T cells, a group of immune cells critical for killing cancerous or virally infected cells.

    After the scientists evaluated the top six candidates in both human and mouse cells, they saw that TVA performed the best. TVA is the most abundant trans fatty acid present in human milk, but the body cannot produce it on its own. Only about 20% of TVA is broken down into other byproducts, leaving 80% circulating in the blood. “That means there must be something else it does, so we started working on it more,” Chen said.

    The researchers then conducted a series of experiments with cells and mouse models of diverse tumor types. Feeding mice a diet enriched with TVA significantly reduced the tumor growth potential of melanoma and colon cancer cells compared to mice fed a control diet. The TVA diet also enhanced the ability of CD8+ T cells to infiltrate tumors.

    The team also performed a series of molecular and genetic analyses to understand how TVA was affecting the T cells. These included a new technique for monitoring transcription of single-stranded DNA called kethoxal-assisted single-stranded DNA sequencing, or KAS-seq, developed by Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago and another senior author of the study. These additional assays, done by both the Chen and He labs, showed that TVA inactivates a receptor on the cell surface called GPR43 which is usually activated by short-chain fatty acids often produced by gut microbiota. TVA overpowers these short-chain fatty acids and activates a cellular signaling process known as the CREB pathway, which is involved in a variety of functions including cellular growth, survival, and differentiation. The team also showed that mouse models where the GPR43 receptor was exclusively removed from CD8+ T cells also lacked their improved tumor fighting ability.

    Finally, the team also worked with Justin Kline, MD, Professor of Medicine at UChicago, to analyze blood samples taken from patients undergoing CAR-T cell immunotherapy treatment for lymphoma. They saw that patients with higher levels of TVA tended to respond to treatment better than those with lower levels. They also tested cell lines from leukemia by working with Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine, and saw that TVA enhanced the ability of an immunotherapy drug to kill leukemia cells.

    Focus on the nutrients, not the food

    The study suggests that TVA could be used as a dietary supplement to help various T cell-based cancer treatments, although Chen points out that it is important to determine the optimized amount of the nutrient itself, not the food source. There is a growing body of evidence about the detrimental health effects of consuming too much red meat and dairy, so this study shouldn’t be taken as an excuse to eat more cheeseburgers and pizza; rather, it indicates that nutrient supplements such as TVA could be used to promote T cell activity. Chen thinks there may be other nutrients that can do the same.

    “There is early data showing that other fatty acids from plants signal through a similar receptor, so we believe there is a high possibility that nutrients from plants can do the same thing by activating the CREB pathway as well,” he said.

    The new research also highlights the promise of this “metabolomic” approach to understanding how the building blocks of diet affect our health. Chen said his team hopes to build a comprehensive library of nutrients circulating in the blood to understand their impact on immunity and other biological processes like aging.

    “After millions of years of evolution, there are only a couple hundred metabolites derived from food that end up circulating in the blood, so that means they could have some importance in our biology,” Chen said. “To see that a single nutrient like TVA has a very targeted mechanism on a targeted immune cell type, with a very profound physiological response at the whole organism level—I find that really amazing and intriguing.”

    The study, “Trans-vaccenic acid reprograms CD8+ T cells and anti-tumor immunity,” was supported by the National Institutes of Health (grants CA140515, CA174786, CA276568, 1375 HG006827, K99ES034084), a UChicago Biological Sciences Division Pilot Project Award, the Ludwig Center at UChicago, the Sigal Fellowship in Immuno-oncology, the Margaret E. Early Medical Research Trust, the AASLD Foundation a Harborview Foundation Gift Fund, and the Howard Hughes Medical Institute.

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    University of Chicago Medical Center

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  • When baby stars fledge

    When baby stars fledge

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    Newswise — A team of astrophysicists led by Núria Miret-Roig from the University of Vienna found that two methods for determining the age of stars measure different things: Isochronous measurement thereby determines the birth date of stars, while dynamical tracking provides information on when stars “leave their nest”, about 5.5 million years later in the star clusters studied. The study, which makes it possible to determine the earliest stages of a star’s life, is currently published in the scientific journal “Nature Astronomy”.

    The age of stars is a fundamental parameter in astrophysics, but it is still relatively difficult to measure. The best approximations to date have been for so-called star clusters, i.e. groups of stars of the same age with a common origin. The age of six relatively close and young star clusters has now been analysed as part of a study at the Institute of Astrophysics at the University of Vienna. It was found that two of the most reliable methods for determining the age of stars – isochronous measurement and dynamic tracing – were systematically and consistently different: The stars were each around 5.5 million years younger according to the dynamic tracing method than with the isochronous measurement.

    When the clock starts ticking

    “This indicates that the two measurement methods measure different things,” explains astrophysicist Núria Miret-Roig from the University of Vienna, first author of the study. According to the new study, the isochronous “clock” starts ticking from the time of star formation, but the “clock” of dynamic backtracking only starts ticking when a star cluster begins to expand after leaving its parent cloud. “This finding has significant implications for our understanding of star formation and stellar evolution, including planet formation and the formation of galaxies, and opens up a new perspective on the chronology of star formation. For example, the length of the so-called “embedded phase”, during which baby stars remain within the parental gas cloud, can be estimated,” explains João Alves, co-author and professor at the University of Vienna.

    Measuring how long baby stars stay in the nest

    “This age difference between the two methods represents a new and much-needed tool to quantify the earliest stages in a star’s life,” says Alves. “Specifically, we can use it to measure how long the baby stars take before they leave their nest.” The measurements were made possible by the high-resolution data from the Gaia special mission in conjunction with ground-based radial velocities (e.g. from the APOGEE catalogue). “This combination allows us to trace the positions of stars back to their birthplace with the accuracy of 3D velocities,” explains Miret-Roig. New and upcoming spectroscopic surveys such as WEAVE, 4MOST and SDSS-V will make this investigation possible for the entire solar neighbourhood.

    Puzzling difference

    “Astronomers have been using isochronous ages for as long as we have known how stars work, but these ages depend on the particular stellar model we use,” says Miret-Roig. “The high-quality data from the Gaia satellite has now allowed us to measure ages dynamically, independently of the stellar models, and we were excited to synchronise the two clocks.” During the calculations, however, a consistent and puzzling difference between the two age determination methods emerged. “And eventually we reached a point where we could no longer blame the discrepancy on observational errors – that’s when we realised that the two clocks were most likely measuring two different things,” says the astrophysicist.

    For the study, the research team analysed six nearby and young star clusters (up to 490 light years away and 50 million years old). The time scale of the embedded phase was found to be around 5.5 million years (plus/minus 1.1 million years) and could depend on the mass of the star cluster and the amount of stellar feedback.

    Applying this new technique to other young and nearby star clusters promises new insights into the star formation process and the drifting apart of stars, Miret-Roig hopes: “Our work paves the way for future research into star formation and provides a clearer picture of how stars and star clusters evolve. This is an important step in our endeavour to understand the formation of the Milky Way and other galaxies.”

    This publication has been co-funded by the European Union (ERC, ISM-FLOW, 101055318, PI: J. Alves). However, the views and opinions expressed are solely those of the author(s) and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.

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    University of Vienna

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  • Taste guides our eating pace from the first bite

    Taste guides our eating pace from the first bite

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    Newswise — When you eagerly dig into a long-awaited dinner, signals from your stomach to your brain keep you from eating so much you’ll regret it – or so it’s been thought. That theory had never really been directly tested until a team of scientists at UC San Francisco recently took up the question.  
     
    The picture, it turns out, is a little different. 
     
    The team, led by Zachary Knight, PhD, a UCSF professor of physiology in the Kavli Institute for Fundamental Neuroscience, discovered that it’s our sense of taste that pulls us back from the brink of food inhalation on a hungry day. Stimulated by the perception of flavor, a set of neurons – a type of brain cell – leaps to attention almost immediately to curtail our food intake.  
     
    “We’ve uncovered a logic the brainstem uses to control how fast and how much we eat, using two different kinds of signals, one coming from the mouth, and one coming much later from the gut,” said Knight, who is also an investigator with the Howard Hughes Medical Institute and a member of the UCSF Weill Institute for Neurosciences. “This discovery gives us a new framework to understand how we control our eating.” 
     
    The study, which appears Nov. 22, 2023 in Nature, could help reveal exactly how weight-loss drugs like Ozempic work, and how to make them more effective. 
     
    New views into the brainstem 
     
    Pavlov proposed over a century ago that the sight, smell and taste of food are important for regulating digestion. More recent studies in the 1970s and 1980s have also suggested that the taste of food may restrain how fast we eat, but it’s been impossible to study the relevant brain activity during eating because the brain cells that control this process are located deep in the brainstem, making them hard to access or record in an animal that’s awake. 
     
    Over the years, the idea had been forgotten, Knight said.  
     
    New techniques developed by lead author Truong Ly, PhD, a graduate student in Knight’s lab, allowed for the first-ever imaging and recording of a brainstem structure critical for feeling full, called the nucleus of the solitary tract, or NTS, in an awake, active mouse. He used those techniques to look at two types of neurons that have been known for decades to have a role in food intake. 
     
    The team found that when they put food directly into the mouse’s stomach, brain cells called PRLH (for prolactin-releasing hormone) were activated by nutrient signals sent from the GI tract, in line with traditional thinking and the results of prior studies. 
     
    However, when they allowed the mice to eat the food as they normally would, those signals from the gut didn’t show up. Instead, the PRLH brain cells switched to a new activity pattern that was entirely controlled by signals from the mouth.  
     
    “It was a total surprise that these cells were activated by the perception of taste,” said Ly. “It shows that there are other components of the appetite-control system that we should be thinking about.” 
     
    While it may seem counterintuitive for our brains to slow eating when we’re hungry, the brain is actually using the taste of food in two different ways at the same time. One part is saying, “This tastes good, eat more,” and another part is watching how fast you’re eating and saying, “Slow down or you’re going to be sick.” 
     
    “The balance between those is how fast you eat,” said Knight. 
     
    The activity of the PRLH neurons seems to affect how palatable the mice found the food, Ly said. That meshes with our human experience that food is less appetizing once you’ve had your fill of it.  
     
    Brain cells that inspire weight-loss drugs 
     
    The PRLH-neuron-induced slowdown also makes sense in terms of timing. The taste of food triggers these neurons to switch their activity in seconds, from keeping tabs on the gut to responding to signals from the mouth.  
     
    Meanwhile, it takes many minutes for a different group of brain cells, called CGC neurons, to begin responding to signals from the stomach and intestines. These cells act over much slower time scales – tens of minutes – and can hold back hunger for a much longer period of time. 
     
    “Together, these two sets of neurons create a feed-forward, feed-back loop,” said Knight. “One is using taste to slow things down and anticipate what’s coming. The other is using a gut signal to say, ‘This is how much I really ate. Ok, I’m full now!’”  
     
    The CGC brain cells’ response to stretch signals from the gut is to release GLP-1, the hormone mimicked by Ozempic, Wegovy and other new weight-loss drugs.  
     
    These drugs act on the same region of the brainstem that Ly’s technology has finally allowed researchers to study. “Now we have a way of teasing apart what’s happening in the brain that makes these drugs work,” he said.  
     
    A deeper understanding of how signals from different parts of the body control appetite would open doors to designing weight-loss regimens designed for the individual ways people eat by optimizing how the signals from the two sets of brain cells interact, the researchers said. 
     
    The team plans to investigate those interactions, seeking to better understand how taste signals from food interact with feedback from the gut to suppress our appetite during a meal. 

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    University of California, San Francisco (UCSF)

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  • Cancer cells exploit cell competition to survive and spread

    Cancer cells exploit cell competition to survive and spread

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    Newswise — Living cells compete with each other and try to adapt to the local environment. Cells that are unable to do so are eliminated eventually. This cellular competition is crucial as the surrounding normal epithelial cells use it to identify and eliminate mutant cancer cells.  Studies have reported that when activating mutants of “Ras” proteins are expressed in mammalian epithelial cells, they are pushed toward the lumen, excreted along with other bodily waste, and eliminated by competition. Epithelial cells containing Ras mutants have been reported to be removed in this manner in several organs, including the small intestine, stomach, pancreas, and lungs. This suggests that cell competition is an innate defense system orchestrated by epithelial cells to prevent the accumulation of incidentally produced cancerous cells and thereby suppress cancer formation.

    In general, mutations in multiple genes accumulate in a stepwise manner when normal cells become cancerous. However, it is not known how cell competition is affected by this process. For instance, human colorectal cancer develops when the adenomatous polyposis coli (APC) gene becomes dysfunctional and activates “Wnt signaling,” followed by the activation of Ras signaling.

    In a recent study, a team of researchers from Japan, led by Associate Professor Shunsuke Kon of the Department of Cancer Biology, Institute of Biomedical Research and Innovation, Tokyo University of Science (TUS), examined the effects of the accumulation of stepwise gene mutations on cell competition and investigated the role of cell competition in the actual cancer formation process. Their study was published in Nature Communications on November 3, 2023 with Mr. Kazuki Nakai, a third year PhD student at the Graduate School of Life Sciences in TUS, as the lead author.

    The study results showed that when Wnt signals were activated in epithelial cells, cell competition function was altered. Activated Ras mutant epithelial cells, which would normally be eliminated into the lumen, instead infiltrated diffusely into the tissue to form highly invasive cancerous tumors.

    As senior author Dr. Kon explains, “We discovered that in epithelial tissues where Wnt and Ras signals, which commonly occur in human colorectal cancer, are activated in stages, the function of cell competition is altered. It was revealed that the production of cancer cells that diffusely infiltrate into the interstitium is promoted.”

    Further, the research team identified an increased expression of matrix metalloproteinase 21 (MMP21) as one of the mechanisms underlying the production of diffusely invasive cancer cells in early colorectal cancer due to abnormal cell competition. This, in turn, was shown to be directly caused by activation of nuclear factor kappa B (NF-κB) signals via the innate immune system. Blocking NF-κB signaling restored the luminal elimination of Ras mutant epithelial cells. These findings raise some intriguing questions, such as “How do transformed cells sense the cellular content that leads to the NF-B-MMP21 pathway?” and “How do surrounding cells recognize transformed cells and prepare them for cellular extrusion?” These questions will almost certainly need to be addressed in the future.

    The results of this research show that cancer cells with accumulated, sequential genetic mutations, alter the function of cell competition and use it to enhance their own invasive ability. Instead of being eliminated to the lumen, they infiltrate into the tissue, producing high-grade cancer cells. While the research team did note that the cancer histopathology of the mice used in this study resembled diffuse-type cancer in humans, future research is needed to determine whether the NF-κB-MMP21 pathway is relevant to other cancers. For instance, investigating scirrhous gastric cancer, a typical diffuse-type cancer, would be particularly interesting. 

    Overall, these findings demonstrate that Wnt activation disrupts cell competition, and confers invasive properties on transformed cells to escape primary epithelial sites. Understanding how the molecular landscape is re-modeled to change the fate of cancer cells with high mutational burdens could be used for therapeutic purposes. This could be of interest to researchers focused on Wnt signaling or cancer research, such as those at the Koch Institute for Integrative Cancer Research at MIT and Cancer Research UK, who are working towards common goals.

    Dr. Kon concludes by saying, “This study further brings forth the prospect that cell competition constrains the order of appearance of mutations during tumor development, highlighting a link between cell competition and carcinogenesis. We hope that this will pave the way for the development of new cancer treatments from the standpoint of cell competition and infiltration for the benefit of our society.”

     

    ***

    Reference                     

    DOI: https://doi.org/10.1038/s41467-023-42774-6

     

    About The Tokyo University of Science

    Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan’s development in science through inculcating the love for science in researchers, technicians, and educators.

    With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society,” TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today’s most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

    Website: https://www.tus.ac.jp/en/mediarelations/

     

    About Dr. Shunsuke Kon from Tokyo University of Science

    Dr. Shunsuke Kon is a Junior Associate Professor in the Cancer Biology Department of the Research Institute for Biomedical Sciences. He obtained his Ph.D. from the Tohoku University Graduate School of Life Sciences in 2008. He was previously associated with the Institute of Genetic Medicine at Hokkaido University. His primary research interest has been in the field of tumor biology. He has more than 20 publications to his credit. In addition, he has received the Best Articles of the Year award.

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    Tokyo University of Science

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  • AI system self-organises to develop features of brains of complex organisms

    AI system self-organises to develop features of brains of complex organisms

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    Newswise — Cambridge scientists have shown that placing physical constraints on an artificially-intelligent system – in much the same way that the human brain has to develop and operate within physical and biological constraints – allows it to develop features of the brains of complex organisms in order to solve tasks.

    As neural systems such as the brain organise themselves and make connections, they have to balance competing demands. For example, energy and resources are needed to grow and sustain the network in physical space, while at the same time optimising the network for information processing. This trade-off shapes all brains within and across species, which may help explain why many brains converge on similar organisational solutions.

    Jascha Achterberg, a Gates Scholar from the Medical Research Council Cognition and Brain Sciences Unit (MRC CBSU) at the University of Cambridge said: “Not only is the brain great at solving complex problems, it does so while using very little energy. In our new work we show that considering the brain’s problem solving abilities alongside its goal of spending as few resources as possible can help us understand why brains look like they do.”

    Co-lead author Dr Danyal Akarca, also from the MRC CBSU, added: “This stems from a broad principle, which is that biological systems commonly evolve to make the most of what energetic resources they have available to them. The solutions they come to are often very elegant and reflect the trade-offs between various forces imposed on them.”

    In a study published today in Nature Machine Intelligence, Achterberg, Akarca and colleagues created an artificial system intended to model a very simplified version of the brain and applied physical constraints. They found that their system went on to develop certain key characteristics and tactics similar to those found in human brains.

    Instead of real neurons, the system used computational nodes. Neurons and nodes are similar in function, in that each takes an input, transforms it, and produces an output, and a single node or neuron might connect to multiple others, all inputting information to be computed.

    In their system, however, the researchers applied a ‘physical’ constraint on the system. Each node was given a specific location in a virtual space, and the further away two nodes were, the more difficult it was for them to communicate. This is similar to how neurons in the human brain are organised.

    The researchers gave the system a simple task to complete – in this case a simplified version of a maze navigation task typically given to animals such as rats and macaques when studying the brain, where it has to combine multiple pieces of information to decide on the shortest route to get to the end point.

    One of the reasons the team chose this particular task is because to complete it, the system needs to maintain a number of elements – start location, end location and intermediate steps – and once it has learned to do the task reliably, it is possible to observe, at different moments in a trial, which nodes are important. For example, one particular cluster of nodes may encode the finish locations, while others encode the available routes, and it is possible to track which nodes are active at different stages of the task.

    Initially, the system does not know how to complete the task and makes mistakes. But when it is given feedback it gradually learns to get better at the task. It learns by changing the strength of the connections between its nodes, similar to how the strength of connections between brain cells changes as we learn. The system then repeats the task over and over again, until eventually it learns to perform it correctly.

    With their system, however, the physical constraint meant that the further away two nodes were, the more difficult it was to build a connection between the two nodes in response to the feedback. In the human brain, connections that span a large physical distance are expensive to form and maintain.

    When the system was asked to perform the task under these constraints, it used some of the same tricks used by real human brains to solve the task. For example, to get around the constraints, the artificial systems started to develop hubs – highly connected nodes that act as conduits for passing information across the network.

    More surprising, however, was that the response profiles of individual nodes themselves began to change: in other words, rather than having a system where each node codes for one particular property of the maze task, like the goal location or the next choice, nodes developed a flexible coding scheme. This means that at different moments in time nodes might be firing for a mix of the properties of the maze. For instance, the same node might be able to encode multiple locations of a maze, rather than needing specialised nodes for encoding specific locations. This is another feature seen in the brains of complex organisms.

    Co-author Professor Duncan Astle, from Cambridge’s Department of Psychiatry, said: “This simple constraint – it’s harder to wire nodes that are far apart – forces artificial systems to produce some quite complicated characteristics. Interestingly, they are characteristics shared by biological systems like the human brain. I think that tells us something fundamental about why our brains are organised the way they are.”

     

    Understanding the human brain

    The team are hopeful that their AI system could begin to shed light on how these constraints, shape differences between people’s brains, and contribute to differences seen in those that experience cognitive or mental health difficulties.

    Co-author Professor John Duncan from the MRC CBSU said: “These artificial brains give us a way to understand the rich and bewildering data we see when the activity of real neurons is recorded in real brains.”

    Achterberg added: “Artificial ‘brains’ allow us to ask questions that it would be impossible to look at in an actual biological system. We can train the system to perform tasks and then play around experimentally with the constraints we impose, to see if it begins to look more like the brains of particular individuals.”

     

    Implications for designing future AI systems

    The findings are likely to be of interest to the AI community, too, where they could allow for the development of more efficient systems, particularly in situations where there are likely to be physical constraints.

    Dr Akarca said: “AI researchers are constantly trying to work out how to make complex, neural systems that can encode and perform in a flexible way that is efficient. To achieve this, we think that neurobiology will give us a lot of inspiration. For example, the overall wiring cost of the system we’ve created is much lower than you would find in a typical AI system.”

    Many modern AI solutions involve using architectures that only superficially resemble a brain. The researchers say their works shows that the type of problem the AI is solving will influence which architecture is the most powerful to use.

    Achterberg said: “If you want to build an artificially-intelligent system that solves similar problems to humans, then ultimately the system will end up looking much closer to an actual brain than systems running on large compute cluster that specialise in very different tasks to those carried out by humans. The architecture and structure we see in our artificial ‘brain’ is there because it is beneficial for handling the specific brain-like challenges it faces.”

    This means that robots that have to process a large amount of constantly changing information with finite energetic resources could benefit from having brain structures not dissimilar to ours.

    Achterberg added: “Brains of robots that are deployed in the real physical world are probably going to look more like our brains because they might face the same challenges as us. They need to constantly process new information coming in through their sensors while controlling their bodies to move through space towards a goal. Many systems will need to run all their computations with a limited supply of electric energy and so, to balance these energetic constraints with the amount of information it needs to process, it will probably need a brain structure similar to ours.”

    The research was funded by the Medical Research Council, Gates Cambridge, the James S McDonnell Foundation, Templeton World Charity Foundation and Google DeepMind.

    Reference

    Achterberg, J & Akarca, D et al. Spatially embedded recurrent neural networks reveal widespread links between structural and functional neuroscience findings. Nature Machine Intelligence; 20 Nov 2023; DOI: 10.1038/s42256-023-00748-9

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    University of Cambridge

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  • Recent study unveils genetics behind human head shape.

    Recent study unveils genetics behind human head shape.

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    Newswise — Researchers at the University of Pittsburgh and KU Leuven have discovered a suite of genes that influence head shape in humans. These findings, published this week in Nature Communications, help explain the diversity of human head shapes and may also offer important clues about the genetic basis of conditions that affect the skull, such as craniosynostosis.

    By analyzing measurements of the cranial vault — the part of the skull that forms the rounded top of the head and protects the brain — the team identified 30 regions of the genome associated with different aspects of head shape, 29 of which have not been reported previously.

    “Anthropologists have speculated and debated the genetics of cranial vault shape since the early 20th century,” said co-senior author Seth Weinberg, Ph.D., professor of oral and craniofacial sciences in the Pitt School of Dental Medicine and co-director of the Center for Craniofacial and Dental Genetics. “We knew from certain rare human conditions and animal experiments that genes play an important role in vault size and shape, but very little was known about the genetic basis for typical features we see in the general population, such as what makes someone’s head long and narrow versus short and wide. This study reveals some of the key genes driving variation in this part of the human body.”

    According to the researchers, one application of better understanding the factors that drive natural variation in human head shape is informing paleoanthropology studies, potentially shedding light on the early development of modern humans.

    Weinberg and colleagues used magnetic resonance (MR) scans from more than 6,000 adolescents to extract 3D surfaces corresponding to the cranial vault. After dividing the 3D vault surfaces into incrementally smaller anatomical subparts and quantifying the shape of these subparts, they tested more than 10 million genetic variants for evidence of statistical association with measures of vault shape.

    “Previous genetic studies of the cranial vault involved a small number of relatively simple measures,” added Weinberg.  “While such measures are often easy to obtain, they may fail to capture features that are biologically relevant. Our analysis used an innovative approach capable of describing 3D vault shape in much more comprehensive and nuanced ways. This approach increased our ability to find genetic associations.”

    An important discovery was that many of the strong associations are near genes that play key roles in the early formation of the head and face and regulation of bone development. For example, variants in and near the gene RUNX2, a major player in coordinating development of the skull, were associated with multiple aspects of vault shape.

    While some genes, including RUNX2, had global effects involving the entire vault, others showed more localized effects that only impacted a specific portion of the vault, such as the central forehead.

    When the researchers compared the 30 genomic regions associated with head shape across participants with European, African and Indigenous American ancestry, they found that the majority of genetic associations were shared across these different ancestral groups.

    Although the study focused on healthy participants, the findings may reveal important clues about the biological basis of diseases involving the cranial vault, according to Weinberg.

    One of these conditions is craniosynostosis, which occurs when the bones of the skull fuse too early while the brain is still growing rapidly. Without neurosurgery, craniosynostosis can cause permanent disfigurement, brain damage, blindness and even death. The team showed that variants near three genes associated with vault shape, BMP2, BBS9 and ZIC2, were also associated with craniosynostosis, suggesting that these genes could play a role in the development of the disease.

    “This kind of study is possible due to the availability of publicly funded resources,” said Weinberg. “The original study that generated these MR scans is focused on understanding brain development and behavior. By creatively leveraging these resources, we have managed to advance discovery beyond that original scope.”

    Other authors on the study were Seppe Goovaerts, Hanne Hoskens, Ph.D., Meng Yuan, Dirk Vandermeulen, Ph.D., all of KU Leuven; Ryan J. Eller, Ph.D., Noah Herrick, Ph.D., and Susan Walsh, Ph.D., all of Indiana University–Purdue University Indianapolis; Anthony M. Musolf, Ph.D., and Cristina M. Justice, Ph.D., both of the National Human Genome Research Institute; Sahin Naqvi, Ph.D., and Joanna Wysocka, Ph.D., both of Stanford University; Myoung Keun Lee, Heather L. Szabo-Rogers, Ph.D., Mary L. Marazita, Ph.D., and John R. Shaffer, Ph.D., all of Pitt; Paul A. Romitti, Ph.D., of the University of Iowa; Simeon A. Boyadjiev, M.D., of the University of California, Davis; Mark D. Shriver, Ph.D., of Penn State University; and Peter Claes, Ph.D., of KU Leuven and Murdoch Children’s Research Institute.

    This research was supported by the National Institute of Dental and Craniofacial Research (R01DE027023, R01DE016886, R03DE031061 and X01HL14053) and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health.

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    University of Pittsburgh

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  • Malnutrition linked to antibiotic resistance spike, study finds.

    Malnutrition linked to antibiotic resistance spike, study finds.

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    Newswise — University of B.C. researchers have uncovered startling connections between micronutrient deficiencies and the composition of gut microbiomes in early life that could help explain why resistance to antibiotics has been rising across the globe.

    The team investigated how deficiencies in crucial micronutrients such as vitamin A, B12, folate, iron, and zinc affected the community of bacteria, viruses, fungi and other microbes that live in the digestive system.

    They discovered that these deficiencies led to significant shifts in the gut microbiome of mice—most notably an alarming expansion of bacteria and fungi known to be opportunistic pathogens.

    Importantly, mice with micronutrient deficiencies also exhibited a higher enrichment of genes that have been linked to antibiotic resistance.

    “Micronutrient deficiency has been an overlooked factor in the conversation about global antibiotic resistance,” said Dr. Paula Littlejohn, a postdoctoral research fellow with UBC’s department of medical genetics and department of pediatrics, and the BC Children’s Hospital Research Institute. “This is a significant discovery, as it suggests that nutrient deficiencies can make the gut environment more conducive to the development of antibiotic resistance, which is a major global health concern.”

    Bacteria naturally possess these genes as a defence mechanism. Certain circumstances, such as antibiotic pressure or nutrient stress, cause an increase in these mechanisms. This poses a threat that could render many potent antibiotics ineffective and lead to a future where common infections could become deadly.

    Antibiotic resistance is often attributed to overuse and misuse of antibiotics, but the work of Dr. Littlejohn and her UBC colleagues suggests that the ‘hidden hunger’ of micronutrient deficiencies is another important factor.

    “Globally, around 340 million children under five suffer from multiple micronutrient deficiencies, which not only affect their growth but also significantly alter their gut microbiomes,” said Dr. Littlejohn. “Our findings are particularly concerning as these children are often prescribed antibiotics for malnutrition-related illnesses. Ironically, their gut microbiome may be primed for antibiotic resistance due to the underlying micronutrient deficiencies.”

    The study, published this week in Nature Microbiology, offers critical insights into the far-reaching consequences of micronutrient deficiencies in early life. It underscores the need for comprehensive strategies to address undernutrition and its ripple effects on health. Addressing micronutrient deficiencies is about more than overcoming malnutrition, it may also be a critical step in fighting the global scourge of antibiotic resistance.

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    University of British Columbia

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  • Rubber behavior: Dynamics decoded

    Rubber behavior: Dynamics decoded

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    New device could improve the outcomes of cell-based therapies

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    Northwestern University

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  • Mice’s Eating and Drinking Preferences Explored.

    Mice’s Eating and Drinking Preferences Explored.

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    Newswise — Making decisions is hard. Even when we know what we want, our choice often leaves something else on the table. For a hungry mouse, every morsel counts. But what if the decision is more consequential than choosing between crumbs and cheese?

    Stanford researchers investigated how mice resolve conflicts between basic needs in a study published in Nature on Nov. 8. They presented mice that were both hungry and thirsty with equal access to food and water and watched to see what happened next.

    The behavior of the mice surprised the scientists. Some gravitated first toward water, while others chose food. Then, with seemingly “random” periods of indulgence, they switched back and forth. In their study, PhD candidate Ethan Richman, lead author of the paper, and colleagues in the departments of Biology, Psychiatry and Behavioral Sciences, and Bioengineering explored why. This work builds on years of collaboration between co-senior authors Karl Deisseroth, the D.H. Chen Professor at Stanford Medicine, and Liqun Luo, the Ann and Bill Swindells Professor in the School of Humanities and Sciences, to understand how the brain keeps the body alive.

    Buridan’s what?

    “There’s this old philosophical quandary called Buridan’s Ass,” explained Richman, “where you have a donkey that is equally hungry and thirsty and equally far from food and water.” The concept was posited by philosophers Aristotle, Jean Buridan, and Baruch Spinoza, in different forms. The question was whether the donkey would choose one need over the other or remain stubbornly in the middle.

    But animals are constantly making choices. We must satisfy our needs to maintain homeostasis. Richman and colleagues wanted to know how the brain directs traffic through conflicting signals to flout Buridan. They call their behavioral experiment “Buridan’s Assay.”

    If hunger or thirst directly motivated a mouse to eat or drink, it would switch as soon as one need outweighed the other. When needs were equal, the mouse would be stuck. This is not what the researchers observed. “Our data indicate that thirst and hunger don’t act as direct forces on behavior,” said Richman. “Instead, they modulate behavior more indirectly. They’re influencing what we think of as the current goal of the mouse.”

    A mouse’s goal

    We often think of choices as a decisive moment. The researchers wanted to understand when and where choices between food and water originate in the brain. Using recent advances in recording technology, they monitored activity from individual neurons spread across the mouse brain.

    To their surprise, neuron activity patterns throughout the brain predicted the mouse’s choice, even before it was presented with options. “Instead of a single moment of choice, the mouse’s brain is constantly broadcasting its current goal,” said Richman. “Outcomes of the hardest choices you make – when options are closely balanced in importance, but the categories are fundamentally different – may have to do with the state your brain happened to be in, even before the choice was presented,” said Deisseroth. “That’s an interesting outcome and it helps us understand aspects of human behavior better.”

    Exploring the random

    The researchers found that hungry and thirsty mice often make the same choice repeatedly before suddenly switching. “In eating mode, the mouse will just eat and eat. In drinking mode, it will drink and drink,” said Luo. “But there is an aspect of randomness that causes them to switch between these two. That way, in the long run, they fulfill both needs, even if at any given time they are only choosing one.”

    To test this apparent randomness, the researchers ran another experiment, this time with hungry mice. As the mice ate, scientists introduced thirst through a technique called optogenetics. With optogenetics, they used light to activate neurons causing thirst. Sometimes the mice switched to water, and sometimes they ignored it and kept eating. The level of thirst was the same each time, leading the researchers to conclude there is a key randomness influencing the mouse’s goal.

    The scientists were perplexed by the interplay between this randomness and the relative intensities of hunger and thirst. To better understand it, they turned to mathematical modeling. Inspired by a conceptual resemblance between their results and a distant field of physics, the researchers borrowed, tweaked, and simulated several equations.

    “We were extremely surprised and excited to find that a few simple equations from a seemingly unrelated discipline could closely predict aspects of mouse behavior and brain activity,” said Richman. The results of their modeling suggested that the brain activity relating to the mouse’s goal is constantly in motion. It gets trapped by needs like hunger and thirst. To escape and transition from one goal to another, the mouse relies on a lucky series of random activity.

    This work establishes the importance of the brain’s shifting baseline state when it comes to decision-making. In the future, the researchers will explore what sets the tone and why decisions don’t always make sense.

    Beyond Buridan

    “In terms of Buridan’s Ass, we can say that the donkey’s mind is made up before it is given a choice,” says Richman, “and if it has to wait, then its choice may spontaneously switch.” Clinical applications for this work in the human context are a bit more complex. “As a psychiatrist, I often think about how we make healthy (adaptive) or harmful (maladaptive) decisions,” said Deisseroth. (Maladaptive behaviors impact people’s ability to make decisions in their best interest and they are common in psychiatric disorders.) “It’s very hard for family and friends to see loved ones act against their own survival drives. It may help to understand the choices made as reflecting the underlying dynamical landscape of the patient’s brain, affected by the disorder more than by the patient’s conscious volition.”

    Although this work might not explain human behavior, it begins to reveal an important framework for decision-making. “This is basic discovery science that depends on pretty advanced neuro-engineering, but at the core we address universal questions that people think about and experience all the time,” said Deisseroth. “It’s exciting to develop and apply modern tools to address these very old, deep, and personal questions.”

    Additional Stanford co-authors include former undergraduate student Nicole Ticea, BS ’20, who is now a PhD student at Stanford, and former graduate student William E. Allen, PhD ’19, who is now at Harvard University. Deisseroth is also professor of bioengineering and of psychiatry and behavioral sciences, and a member of Stanford Bio-X and the Wu Tsai Neurosciences Institute. Luo is also a professor of biology, a faculty fellow at Sarafan ChEM-H, and a member of Stanford Bio-X, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute. Deisseroth and Luo are both are investigators of the Howard Hughes Medical Institute.

    This work was funded by the National Science Foundation, the National Institutes of Health, and the Gatsby Foundation.

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    Stanford University

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  • Pathologic Scoring Shows Promise for Assessing Lung Tumor Therapy Response

    Pathologic Scoring Shows Promise for Assessing Lung Tumor Therapy Response

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    **EMBARGOED UNTIL 8 P.M. ET SATURDAY, NOV. 4**

    Newswise — A new pathologic scoring system that accurately assesses how much lung tumor is left after a patient receives presurgical cancer treatments can be used to predict survival, according to new research led by investigators at the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center and the Mark Foundation Center for Advanced Genomics and Imaging at the Johns Hopkins University.

    The study shows that pathologic assessment of residual viable tumor (RVT) in patients treated with immunotherapy and chemotherapy before lung cancer surgery provides a robust and efficient evaluation of patient treatment response that may be useful to guide patient therapy and predict survival. This latter finding supports pathologic evaluation of tumors as an early clinical trial endpoint and a surrogate of survival for potential accelerated regulatory approvals.

    The results were published on Nov. 4 in the journal Nature Medicine and simultaneously presented by senior study author Janis Taube, M.D., M.Sc., director of the Division of Dermatopathology at the Johns Hopkins University School of Medicine and a member of the Kimmel Cancer Center, at the Society for Immunotherapy of Cancer annual meeting in San Diego.

    Immunotherapies harness a patient’s immune system to target their tumors. These powerful drugs are often paired with conventional chemotherapies to help shrink a patient’s tumors before surgery, increasing the likelihood of successfully eliminating the cancer. To gauge treatment success, oncologists typically rely on radiologic imaging of the remaining tumor, but the results aren’t always as accurate in early-stage tumors as they are for more advanced cancers. More recently, circulating tumor DNA (ctDNA) clearance, which uses genetic sequencing to detect lung cancer-associated mutations in patient blood samples, has also shown promise, but is not yet widely available.

    For the new study, investigators performed a new analysis on data from the randomized, phase 3 CheckMate 816 study. That study found that treating presurgical non-small cell lung cancer patients with immunotherapy (nivolumab) plus chemotherapy improved event-free survival. This important surrogate endpoint can help predict long-term survival and pathologic complete response, which measures whether any tumor is left.

    “Most studies have focused on whether you have no tumor left or less than or equal to 10% of the tumor left, which is called a major pathologic response,” says lead study author Julie Stein Deutsch, M.D., an assistant professor of dermatology at Johns Hopkins.

    During the study, the investigators used a new approach, which measures residual tumor in patients who received neoadjuvant therapy, to predict outcomes in patients with a greater range of treatment responses. They used immune-related pathologic response criteria (irPRC) to look for pathologic changes that indicated the tumor had been present in the tissue before immunotherapy but was destroyed by the treatment, allowing them to measure what percentage of the tumor was left, or the RVT, ranging from 0% to 100%.

    As a result, they were able to separate patients into three groups based on how much tumor was left. In the future, data such as these may help guide the next round of clinical trials and ultimately help oncologists decide how to treat individuals in these subgroups, Deutsch says. For example, patients with no tumor left may be able to skip postsurgical immunotherapy or have a relatively limited amount, while individuals in the intermediate group may need to continue immunotherapy for longer. Those who showed a very limited response may need to switch to a new therapy or add a new therapy to their regimen. The team’s next steps will include identifying the most clinically meaningful cutoffs for RVT.

    They also looked beyond the primary tumor and used RVT to assess the immunotherapy effect on tumor in the lymph nodes, which showed additive value with the primary tumor for predicting survival. Long term, it may also be possible to strategically combine pathology, radiology and ctDNA results for the longitudinal monitoring of treatment efficacy.

    Already, the investigators demonstrated the pathologic scoring system can assess 10 types of tumors, including lung, skin and colorectal cancers, which could be another advantage over other tumor scoring systems.

    “The common features seen across these multiple tumor types means that pathologists don’t have to switch to different scoring systems for assessing pathologic response. This is similar to what already exists in radiology, where the RECIST system is used across all tumor types for determining objective response to therapy,” Taube says, noting that pathologists already are completing the necessary workflows as part of standard procedures when assessing surgically removed tumors. Assessing RVT is inexpensive and uses tools and supplies commonly used by pathologists, Deutsch says, which may also make it accessible for those working in low-resource settings.

    “It is important that as these immunotherapies move into clinical trials and become standard of care, pathologists worldwide have a standard scoring system for the assessment of treatment response,” Taube says. 

    Study co-authors were Ashley Cimino-Mathews, Elizabeth Thompson, Patrick M. Forde, Daphne Wang, Robert A. Anders, Edward Gabrielson, Peter Illei, Jaroslaw Jedrych, Ludmila Danilova and Joel Sunshine of Johns Hopkins. Other authors were from the Hospital Universitario Puerta de Hierro in Madrid, Spain; McGill University Health Center in Montreal, Canada; Institut du Thorax Curie-Montsouris in Paris, France; Aberdeen Royal Infirmary in the United Kingdom; Bristol Myers Squibb in Princeton, New Jersey; and Queen’s University in Kingston, Canada.

    The study was supported by Bristol Myers Squibb, Ono Pharmaceutical Company Ltd., the Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Mark Foundation for Cancer Research and the National Institutes of Health (grant R01 CA142779).

    Deutsch is named on a patent for system and method for annotating pathology images to predict patient outcome (U.S. Provisional Patent Application 63/313,548, filed in Feb. 2022). Taube receives support for this study from Bristol Myers Squibb; receives consulting fees from AstraZeneca, Bristol Myers Squibb, Merck and Roche; participates on advisory boards from AstraZeneca; and is named on a patent for a machine learning algorithm for irPRC. These relationships are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

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    Johns Hopkins Medicine

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  • Scientists reveal structures of neurotransmitter transporter

    Scientists reveal structures of neurotransmitter transporter

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    Newswise — (Memphis, Tenn – November 1, 2023) Neurons talk to each other using chemical signals called neurotransmitters. Scientists at St. Jude Children’s Research Hospital have drawn on structural biology expertise to determine structures of vesicular monoamine transporter 2 (VMAT2), a key component of neuronal communication. By visualizing VMAT2 in different states, scientists now better understand how it functions and how the different shapes the protein takes influence drug binding — critical information for drug development to treat hyperkinetic (excess movement) disorders such as Tourette syndrome. The work was published today in Nature.    

    How our neurons talk to each other 

    Chemical compounds called monoamines, which include dopamine, serotonin and adrenaline, play a central role in neuronal communication. These molecules affect how the brain works, controlling our emotions, sleep, movement, breathing, circulation and many other functions. Monoamines are neurotransmitters (signaling molecules) produced and released by neurons, but before they can be released, they must first be packaged into vesicles.  

    Vesicles are cellular compartments that store neurotransmitters before they are released at the synapses (the junction through which chemical signals pass from one neuron to another). Think of vesicles as the cargo ships of the neuronal cell — neurochemicals are packed inside them and taken to where they need to go. VMATs are proteins on the membrane of these vesicles that move monoamines into the space within, acting like loading cranes for the cargo ships.  

    “VMATs are transporters that are required for packing these monoamine neurotransmitters into synaptic vesicles,” explained co-corresponding author Chia-Hsueh Lee, Ph.D., St. Jude Department of Structural Biology.   

    Once the VMAT has packed the vesicle with monoamines, the “cargo ship” moves towards the synaptic gap (the space between neurons), where it releases the chemical compounds.  

    The many faces of monoamine transporters 

    There are two types of VMAT: VMAT1 and VMAT2. VMAT1 is more specialized, found only in neuroendocrine cells, whereas VMAT2 is found throughout the neuronal system and has significant clinical relevance.   

    “We knew that VMAT2 is physiologically very important,” Lee said. “This transporter is a target for pharmacologically relevant drugs used in the treatment of hyperkinetic disorders such as chorea and Tourette Syndrome.” 

    Despite their importance, the structure of VMAT2, which would allow researchers to investigate how it works fully, had remained elusive. Lee and his team used cryo-electron microscopy (cryo-EM) to obtain structures of VMAT2 bound to the monoamine serotonin and the drugs tetrabenazine and reserpine, which are used to treat chorea and hypertension, respectively. This was no easy feat.  

    “VMAT2 is a small membrane protein,” explained co-first author Yaxin Dai, PhD., St. Jude Department of Structural Biology. “This makes it a very challenging target for cryo-EM structure determination.”  

    Despite the difficulty and using some clever tricks, the team captured multiple structures of VMAT2 that allowed them to tease out how the protein functions and investigate how exactly those drugs work. “VMAT transporters adopt multiple conformations [shapes] while transporting their substrate. This is called alternating access transport, where the protein is either “outward” or “inward” facing,” explained co-first author Shabareesh Pidathala, Ph.D., St. Jude Department of Structural Biology. “To completely gain mechanistic understanding at an atomic level, we needed to capture multiple conformations of this transporter.”  

    Answering a 40-year-old question 

    The researchers discovered this dynamic mechanism means multiple opportunities for drugs to bind. They confirmed that reserpine and tetrabenazine bind two different conformations of VMAT2. “30 or 40 years of pharmacological research had suggested that these two drugs bind to the transporter in different ways,” said Pidathala, “but nobody knew the atomic details of how this works. Our structures nicely demonstrate that these two drugs stabilize two different conformations of the transporter to block its activity.” 

    The structure of VMAT2 with serotonin bound allowed the researchers to pinpoint specific amino acids that interact with the neurotransmitter and drive transport. “We believe this is a common mechanism that this transporter uses to engage all the monoamines,” said Lee.  

    While this work offers a huge leap forward in understanding monoamine transport, Lee and his team are delving deeper into its mechanism. For example, the intake of monoamines into vesicles is fueled by protons moving in the other direction. “We identified amino acids that are important for this proton-dependent process,” Lee said, “but we still don’t know how exactly protons drive this transport. Determining this mechanism is our future direction, which will help us to fully appreciate how this transporter works.”  

    Authors and funding 

    The study’s other first author is Shuyun Liao of the School of Life Sciences, Peking University. The study’s co-corresponding author is Zhe Zhang of the School of Life Sciences, Peking University. Other authors include Xiao Li and Chi-Lun Chang of St. Jude, and Changkun Long of the School of Life Sciences, Peking University.  

    The study was supported by grants from National Institutes of Health (R01GM143282), the National Key Research and Development Program of China (2021YFA1302300), the National Natural Science Foundation of China (32171201), the SLS-Qidong innovation fund, the Li Ge-Zhao Ning Life Science Youth Research Foundation, the State Key Laboratory of Membrane Biology of China, and ALSAC, the fundraising and awareness organization of St. Jude. 

     

    St. Jude Children’s Research Hospital  

    St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.   

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    St. Jude Children’s Research Hospital

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