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See the Human Cardiovascular System in a Whole New Way

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Watch this brief video and you might guess you’re seeing an animated line drawing, gradually revealing a delicate take on a familiar system: the internal structures of the human body. But this movie doesn’t capture the work of a talented sketch artist. It was created using the first 3D, full-body imaging device using positron emission tomography (PET).

The device is called an EXPLORER (EXtreme Performance LOng axial REsearch scanneR) total-body PET scanner. By pairing this scanner with an advanced method for reconstructing images from vast quantities of data, the researchers can make movies.

For this movie in particular, the researchers injected small amounts of a short-lived radioactive tracer—an essential component of all PET scans—into the lower leg of a study volunteer. They then sat back as the scanner captured images of the tracer moving up the leg and into the body, where it enters the heart. The tracer moves through the heart’s right ventricle to the lungs, back through the left ventricle, and up to the brain. Keep watching, and, near the 30-second mark, you will see in closer focus a haunting capture of the beating heart.

This groundbreaking scanner was developed and tested by Jinyi Qi, Simon Cherry, Ramsey Badawi, and their colleagues at the University of California, Davis [1]. As the NIH-funded researchers reported recently in Proceedings of the National Academy of Sciences, their new scanner can capture dynamic changes in the body that take place in a tenth of a second [2]. That’s faster than the blink of an eye!

This movie is composed of frames captured at 0.1-second intervals. It highlights a feature that makes this scanner so unique: its ability to visualize the whole body at once. Other medical imaging methods, including MRI, CT, and traditional PET scans, can be used to capture beautiful images of the heart or the brain, for example. But they can’t show what’s happening in the heart and brain at the same time.

The ability to capture the dynamics of radioactive tracers in multiple organs at once opens a new window into human biology. For example, the EXPLORER system makes it possible to measure inflammation that occurs in many parts of the body after a heart attack, as well as to study interactions between the brain and gut in Parkinson’s disease and other disorders.

EXPLORER also offers other advantages. It’s extra sensitive, which enables it to capture images other scanners would miss—and with a lower dose of radiation. It’s also much faster than a regular PET scanner, making it especially useful for imaging wiggly kids. And it expands the realm of research possibilities for PET imaging studies. For instance, researchers might repeatedly image a person with arthritis over time to observe changes that may be related to treatments or exercise.

Currently, the UC Davis team is working with colleagues at the University of California, San Francisco to use EXPLORER to enhance our understanding of HIV infection. Their preliminary findings show that the scanner makes it easier to capture where the human immunodeficiency virus (HIV), the cause of AIDS, is lurking in the body by picking up on signals too weak to be seen on traditional PET scans.

While the research potential for this scanner is clearly vast, it also holds promise for clinical use. In fact, a commercial version of the scanner, called uEXPLORER, has been approved by the FDA and is in use at UC Davis [3]. The researchers have found that its improved sensitivity makes it much easier to detect cancers in patients who are obese and, therefore, harder to image well using traditional PET scanners.

As soon as the COVID-19 outbreak subsides enough to allow clinical research to resume, the researchers say they’ll begin recruiting patients with cancer into a clinical study designed to compare traditional PET and EXPLORER scans directly.

As these researchers, and other researchers around the world, begin to put this new scanner to use, we can look forward to seeing many more remarkable movies like this one. Imagine what they will reveal!

References:

[1] First human imaging studies with the EXPLORER total-body PET scanner. Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, Ding Y, Spencer BA, Nardo L, Liu W, Bao J, Jones T, Li H, Cherry SR. J Nucl Med. 2019 Mar;60(3):299-303.

[2] Subsecond total-body imaging using ultrasensitive positron emission tomography. Zhang X, Cherry SR, Xie Z, Shi H, Badawi RD, Qi J. Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2265-2267.

[3] “United Imaging Healthcare uEXPLORER Total-body Scanner Cleared by FDA, Available in U.S. Early 2019.” Cision PR Newswire. January 22, 2019.

Links:

Positron Emission Tomography (PET) (NIH Clinical Center)

EXPLORER Total-Body PET Scanner (University of California, Davis)

Cherry Lab (UC Davis)

Badawi Lab (UC Davis Medical Center, Sacramento)

NIH Support: National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; Common Fund


Finding Beauty in Cell Stress

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Most stressful situations that we experience in daily life aren’t ones that we’d choose to repeat. But the cellular stress response captured in this video is certainly worth repeating a few times, so you can track what happens when two cancer cells get hit with stressors.

In this movie of two highly stressed osteosarcoma cells, you first see the appearance of many droplet-like structures (green). This is followed by a second set of droplets (magenta) and, finally, the fusion of both types of droplets.

These droplets are composed of fluorescently labeled stress-response proteins, either G3BP or UBQLN2 (Ubiquilin-2). Each protein is undergoing a fascinating process, called phase separation, in which a non-membrane bound compartment of the cytoplasm emerges and constrains the motion of proteins within it. Subsequently, the proteins fuse with like proteins to form larger droplets, in much the same way that raindrops merge on a car’s windshield.

Julia Riley, an undergraduate student in the NIH-supported lab of Heidi Hehnly and lab of Carlos Castañeda, Syracuse University, NY, shot this movie using the sophisticated tools of fluorescence microscopy. It’s the next installment in our series featuring winners of the 2019 Green Fluorescent Protein Image and Video Contest, sponsored by the American Society for Cell Biology. The contest honors the discovery of green fluorescent protein (GFP), which—together with a rainbow of other fluorescent proteins—has enabled researchers to visualize proteins and their dynamic activities inside cells for the last 25 years.

Riley and colleagues suspect that, in this case, phase separation is a protective measure that allows proteins to wall themselves off from the rest of the cell during stressful conditions. In this way, the proteins can create new functional units within the cell. The researchers are working to learn much more about what this interesting behavior entails as a basic organizing principle in the cell and how it works.

Even more intriguing is that similar stress-responding proteins are commonly altered in people with the devastating neurologic condition known as amyotrophic lateral sclerosis (ALS). ALS is a group of rare neurological diseases that involve the progressive deterioration of neurons responsible for voluntary movements such as chewing, walking, and talking. There’s been the suggestion that these phase separation droplets may seed the formation of the larger protein aggregates that accumulate in the motor neurons of people with this debilitating and fatal condition.

Castañeda and Hehnly, working with J. Paul Taylor at St. Jude Children’s Research Hospital, Memphis, earlier reported that Ubiquilin-2 forms stress-induced droplets in multiple cell types [1]. More recently, they showed that mutations in Ubiquilin-2 have been linked to ALS changes in the way that the protein undergoes phase separation in a test tube [2].

While the proteins in this award-winning video aren’t mutant forms, Riley is now working on the sequel, featuring versions of the Ubiquilin-2 protein that you’d find in some people with ALS. She hopes to capture how those mutations might produce a different movie and what that might mean for understanding ALS.

References:

[1] Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Dao TP, Kolaitis R-M, Kim HJ, O’Donovan K, Martyniak B, Colicino E, Hehnly H, Taylor JP, Castañeda CA. Molecular Cell. 2018 Mar 15;69(6):965-978.e6.

[2] ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner. Dao TP, Martyniak B, Canning AJ, Lei Y, Colicino EG, Cosgrove MS, Hehnly H, Castañeda CA. Structure. 2019 Jun 4;27(6):937-951.e5.

Links:

Amyotrophic Lateral Sclerosis (ALS) (National Institute of Neurological Disorders and Stroke/NIH)

Castañeda Lab (Syracuse University, NY)

Hehnly Lab (Syracuse University)

Green Fluorescent Protein Image and Video Contest (American Society for Cell Biology, Bethesda, MD)

2008 Nobel Prize in Chemistry (Nobel Foundation, Stockholm, Sweden)

NIH Support: National Institute of General Medical Sciences


Discovering the Brain’s Nightly “Rinse Cycle”

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Getting plenty of deep, restful sleep is essential for our physical and mental health. Now comes word of yet another way that sleep is good for us: it triggers rhythmic waves of blood and cerebrospinal fluid (CSF) that appear to function much like a washing machine’s rinse cycle, which may help to clear the brain of toxic waste on a regular basis.

The video above uses functional magnetic resonance imaging (fMRI) to take you inside a person’s brain to see this newly discovered rinse cycle in action. First, you see a wave of blood flow (red, yellow) that’s closely tied to an underlying slow-wave of electrical activity (not visible). As the blood recedes, CSF (blue) increases and then drops back again. Then, the cycle—lasting about 20 seconds—starts over again.

The findings, published recently in the journal Science, are the first to suggest that the brain’s well-known ebb and flow of blood and electrical activity during sleep may also trigger cleansing waves of blood and CSF. While the experiments were conducted in healthy adults, further study of this phenomenon may help explain why poor sleep or loss of sleep has previously been associated with the spread of toxic proteins and worsening memory loss in people with Alzheimer’s disease.

In the new study, Laura Lewis, Boston University, MA, and her colleagues at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston. recorded the electrical activity and took fMRI images of the brains of 13 young, healthy adults as they slept. The NIH-funded team also built a computer model to learn more about the fluid dynamics of what goes on in the brain during sleep. And, as it turns out, their sophisticated model predicted exactly what they observed in the brains of living humans: slow waves of electrical activity followed by alternating waves of blood and CSF.

Lewis says her team is now working to come up with even better ways to capture CSF flow in the brain during sleep. Currently, people who volunteer for such experiments have to be able to fall asleep while wearing an electroencephalogram (EEG) cap inside of a noisy MRI machine—no easy feat. The researchers are also recruiting older adults to begin exploring how age-related changes in brain activity during sleep may affect the associated fluid dynamics.

Reference:

[1] Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Science. 2019 Nov 1;366(6465):628-631.

Links:

Sleep and Memory (National Institute of Mental Health/NIH)

Sleep Deprivation and Deficiency (National Heart, Lung, and Blood Institute/NIH)

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

NIH Support: National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke


The Perfect Cytoskeletal Storm

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Ever thought about giving cell biology a whirl? If so, I suggest you sit down and take a look at this full-blown cytoskeletal “storm,” which provides a spectacular dynamic view of the choreography of life.

Before a cell divides, it undergoes a process called mitosis that copies its chromosomes and produces two identical nuclei. As part of this process, microtubules, which are structural proteins that help make up the cell’s cytoskeleton, reorganize the newly copied chromosomes into a dense, football-shaped spindle. The position of this mitotic spindle tells the cell where to divide, allowing each daughter cell to contain its own identical set of DNA.

To gain a more detailed view of microtubules in action, researchers designed an experimental system that utilizes an extract of cells from the African clawed frog (Xenopus laevis). As the video begins, a star-like array of microtubules (red) radiate outward in an apparent effort to prepare for cell division. In this configuration, the microtubules continually adjust their lengths with the help of the protein EB-1 (green) at their tips. As the microtubules grow and bump into the walls of a lab-generated, jelly-textured enclosure (dark outline), they buckle—and the whole array then whirls around the center.

Abdullah Bashar Sami, a Ph.D. student in the NIH-supported lab of Jesse “Jay” Gatlin, University of Wyoming, Laramie, shot this movie as a part his basic research to explore the still poorly understood physical forces generated by microtubules. The movie won first place in the 2019 Green Fluorescent Protein Image and Video Contest sponsored by the American Society for Cell Biology. The contest honors the 25th anniversary of the discovery of green fluorescent protein (GFP), which transformed cell biology and earned the 2008 Nobel Prize in Chemistry for three scientists who had been supported by NIH.

Like many movies, the setting was key to this video’s success. The video was shot inside a microfluidic chamber, designed in the Gatlin lab, to study the physics of microtubule assembly just before cells divide. The tiny chamber holds a liquid droplet filled with the cell extract.

When the liquid is exposed to an ultra-thin beam of light, it forms a jelly-textured wall, which traps the molecular contents inside [1]. Then, using time-lapse microscopy, the researchers watch the mechanical behavior of GFP-labeled microtubules [2] to see how they work to position the mitotic spindle. To do this, microtubules act like shapeshifters—scaling to adjust to differences in cell size and geometry.

The Gatlin lab is continuing to use their X. laevis system to ask fundamental questions about microtubule assembly. For many decades, both GFP and this amphibian model have provided cell biologists with important insights into the choreography of life, and, as this work shows, we can expect much more to come!

References:

[1] Microtubule growth rates are sensitive to global and local changes in microtubule plus-end density. Geisterfer ZM, Zhu D, Mitchison T, Oakey J, Gatlin JC. November 20, 2019.

[2] Tau-based fluorescent protein fusions to visualize microtubules. Mooney P, Sulerud T, Pelletier JF, Dilsaver MR, et al. Cytoskeleton (Hoboken). 2017 Jun;74(6):221-232.

Links:

Mitosis (National Human Genome Research Institute/NIH)

Gatlin Lab (University of Wyoming, Laramie)

Green Fluorescent Protein Image and Video Contest (American Society for Cell Biology, Bethesda, MD)

2008 Nobel Prize in Chemistry (Nobel Foundation, Stockholm, Sweden)

NIH Support: National Institute of General Medical Sciences


Why Flies and Humans Freeze When Startled

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When faced with something unexpected and potentially ominous, like a sudden, loud noise or a threat of danger, humans often freeze before we act. This is colloquially referred to as the “deer in the headlights” phenomenon. The movie of fruit flies that you see above may help explain the ancient origins of the “startle response” and other biomechanical aspects of motion.

In this video, which shows a footrace between two flies (Drosophila melanogaster), there are no winners or losers. Their dash across the screen provides a world-class view of the biomechanics of walking in these tiny, 3 millimeter-long insects that just won’t sit still.

The fly at the top zips along at about 25 millimeters per second, the normal walking speed for Drosophila. As a six-legged hexapod, the fly walks with a “tripod gait,” alternating between its stance phase—right fore (RF), left middle (LM), and right hind (RH) —and its swing phase sequence of left fore (LF), right middle (RM), and left hind (LH).

The slowpoke at the bottom of the video clocks in at a mere 15 millimeters per second. This fly’s more-tentative gait isn’t due to an injury or a natural lack of speed. What is causing the delay is the rapid release of the chemical messenger serotonin into its nervous system, which models a startle response.

You may have already heard about serotonin because of its role in regulating mood and appetite in humans. Now, a team led by Richard S. Mann and Clare Howard, Columbia University’s Zuckerman Institute, New York, has discovered that fruit flies naturally release serotonin to turn on neural circuits that downshift and steady the speed of their gait.

As detailed recently in Current Biology [1], serotonin is active under myriad conditions to tell flies to slow things down. For example, serotonin helps flies weather the stress of extreme temperatures, conserve energy during bouts of hunger, and even walk upside down on the ceiling.

But the research team, which was supported by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, found that serotonin’s most-powerful effect came during an actual startle response, prompted by a sudden, jolting vibration. Scientists suspect the release of serotonin activates motor neurons much like an emergency brake, stiffening and locking up the fly’s leg joints. When the researchers blocked the fly’s release of serotonin, it interrupted their normal startle response.

In years past, such a detailed, high-resolution “action video” of Drosophila, one of the most-popular model organisms in biology, would have been impossible to produce. Fruit flies are tiny and possess extremely high energy.

But a few years ago, the Mann lab developed the approach used in this video to bring the hurried gait of fruit flies into tight focus [2]. Their system combines an optical touch sensor and high-speed video imaging that records the footfalls of all six of a fly’s feet.

Then, using the lab’s unique software program called FlyWalker , the researchers can extract various biomechanical parameters of walking in time and space. These include step length, footprint alignment, and, as the letters in the video show, the natural sequence of a tripod gait.

Drosophila may be a very distant relative of humans. But these ubiquitous insects that sometimes buzz around our fruit bowls contain many fundamental clues into human biology, whether the area of research is genetics, nutrition, biomechanics, or even the underlying biology of the startle response.

Reference:

[1] Serotonergic Modulation of Walking in Drosophila. Howard CE, Chen CL, Tabachnik T, Hormigo R, Ramdya P, Mann RS. Curr Biol. 2019 Nov 22.

[2] Quantification of gait parameters in freely walking wild type and sensory deprived Drosophila melanogaster. Mendes CS, Bartos I, Akay T, Márka S, Mann RS. Elife. 2013 Jan 8;2:e00231.

Links:

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

Mann Lab (Columbia University’s Zuckerman Institute, New York)

MouseWalker Colored Feet (YouTube)

NIH Support: National Institute for Neurological Disorders and Stroke; National Institute of General Medical Sciences


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