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Imaging, Microbiology, Stanford News

When bacteria swarm: H. pylori home in on our stomach cells

Imagine you’re thrown into wild ocean waters, battered by waves until you can’t tell which way is up. Your only chance of survival is to somehow sense the location of a rock outcropping and cling to it. Now factor in that the churning water is highly acidic and lethal – that’s the predicament facing Helicobacter pylori, a bacterium that makes its home in one out of every two human stomachs and, for an unfortunate 20 percent of its hosts, causes ulcers.

H. pyloris safe haven is our stomach’s lining with its protective mucus and nutrient-rich cells. New research from the lab of Stanford microbiologist Manuel Amieva, MD, PhD, published today in Cell Host & Microbe demonstrates that the bacteria are able to detect and home in on metabolic molecules released by human stomach cells. The behavior, captured in the video above, shows H. pylori swarming to a microscopic needle releasing either a solution collected from stomach cells or the molecule urea.

The corkscrew-shaped bacterium moves with the help of its tail-like flagella. The bundle of flagella spin in one direction to propel the bacteria forward. When they reverse the spin, said Amieva, the flagella become like helicopter blades, pulling H. pylori backwards.

Previous experiments have shown the bacteria swim away from acid and H. pylori is known to have four chemical sensing receptors. “But this is the first time we’ve observed in real time the bacteria swimming towards something,” said graduate student and lead author, Julie Huang, referring to the technique that allowed the lab to watch H. pylori’s swimming behavior directly.

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Imaging, Microbiology, Research, Science, Stanford News, Technology

3-D structure of key signaling protein and receptor revealed

3-D structure of key signaling protein and receptor revealed

Using ultra-bright X-rays at SLAC National Accelerator Laboratory, a team of international researchers has captured the 3-D structure of a key signaling protein and its receptor for the first time.

The discovery provides new insight into the functioning of a common cell receptor called a G protein-coupled receptor or GPCR. Researchers estimate this protein, and its relatives, are the targets of about 40 percent of pharmaceuticals. From a SLAC release:

“This work has tremendous therapeutic implications,” said Jeffrey Benovic, PhD, a biochemist who was not involved with the study. “The study is a critical first step and provides key insight into the structural interactions in these protein complexes.”

Specifically, the researchers were able to illuminate the structure of the GPCR bonded with a signaling protein called arrestin. Arrestins and G proteins both dock with the GPCRs, however, researchers had previously only examined a bonded G protein. G proteins are generally the “on” switch, while arrestins usually signal the GPCR to turn off:

Many of the available drugs that activate or deactivate GPCRs block both G proteins and arrestins from docking.

“The new paradigm in drug discovery is that you want to find this selective pathway – how to activate either the arrestin pathway or the G-protein pathway but not both — for a better effect,” said Eric Xu, PhD, a scientist at the Van Andel Research Institute in Michigan who led the experiment. The study notes that a wide range of drugs would likely be more effective and have fewer side effects with this selective activation.

Previously: Why Stanford Nobel Prize winner Brian Kobilka is a “tour de force of science”, Funding basic science leads to clinical discoveries, eventually and Video of Brian Kobilka’s Nobel lecture
Video by SLAC National Accelerator Laboratory

Cardiovascular Medicine, Chronic Disease, Imaging, Research, Stanford News, Technology

DNA damage seen after CT scanning, study shows

DNA damage seen after CT scanning, study shows

16288548276_e155ec8843_zUsing new laboratory techniques, Stanford scientists have been able to get a closer look at what happens inside the cells of patients undergoing medical imaging techniques. In a study published today, their research clearly shows that there is cellular damage in heart patients after CT scanning.

The researchers explained to me in interviews for a press release on the study that this doesn’t link CT scans to cancer. But as Patricia Nguyen, MD, lead author said in the release, it is further indication for caution:

“Whether or not this (cellular damage) causes cancer or any negative effect to the patient is still not clear, but these results should encourage physicians toward adhering to dose reduction strategies.”

Due to an explosion in the use CT scans for heart patients over the past decade, public health concerns have been raised over whether there might be a causal link with cancer. But until now, little has been known about exactly what happens at a cellular level when patients undergo CT scanning, a type of medical imaging which exposes them to low-dose radiation. This study took advantage of new laboratory techniques that made it possible to look inside cells of patients after they underwent CT scanning. As Nguyen explained in my release:

“Because we don’t know much about the effects of low-dose radiation — all we know is about high doses from atomic bomb blast survivors — we just assume it’s directly proportional to the dose. We wanted to see what really happens at the cellular level.”

Researchers examined the blood of 67 patients undergoing cardiac CT angiography using such techniques as whole-genome sequencing and flow cytometery to measure biomarkers of DNA damage. The results:

… showed an increase in DNA damage and cell death, as well as increased expression of genes involved in cell repair and death, the study said. Although most cells damaged by the scan were repaired, a small percentage of the cells died, the study said.

“These findings raise the possibility that radiation exposure from cardiac CT angiography may cause DNA damage that can lead to mutations if damaged cells are not repaired or eliminated properly,” the study said.

Photo by frankieleon

Imaging, Immunology, Mental Health, Neuroscience, Research, Stanford News

Are iron, and the scavenger cells that eat it, critical links to Alzheimer’s?

Are iron, and the scavenger cells that eat it, critical links to Alzheimer's?

iron linkIf you’ve been riding the Alzheimer’s-research roller-coaster, brace yourself for a new twist on that wrenching disease of old age.

In a study published in Neurobiology of Aging, Stanford radiologists Mike Zeineh, MD, PhD,  and Brian Rutt, PhD, and their colleagues used a ultra-powerful magnetic-resonance-imaging (MRI) system to closely scrutinize postmortem tissue from the brains of people with and without Alzheimer’s disease. In four out of five of the Alzheimer’s brains they looked at, but in none of the five non-Alzheimer’s brains, they found what appear to be iron-containing microglia – specialized scavenger cells in the brain that can sometimes become inflammatory – in a particular part of the hippocampus, a key brain structure that’s absolutely crucial to memory formation as well as spatial orientation and navigation.

Zeineh and Rutt told me they don’t know how the iron gets into brain tissue, or why it accumulates where it does. But iron, which in certain chemical forms can be highly reactive and inflammation-inducing, is ubiquitous throughout the body. Every red blood cell that courses through our microvasculature is filled with it. So one possibility – not yet demonstrated – is that iron deposits in the hippocampus could result from micro-injury to small cerebral blood vessels there.

As surprising as the iron-laden, inflamed microglia Zeineh, Rutt and their associates saw in Alzheimer’s but not normal brains was what they didn’t see. Surprisingly, in the brain region of interest there was no consistent overlap of either iron or microglia with the notorious amyloid plaques that have been long held by many neuroscientists and pharmaceutical companies to be the main cause of the disorder. These plaques are extracellular aggregations of a small protein called beta-amyloid that are prominent in Alheimer’s patients’ brains, as well as in mouse models of the disease.

Because they weren’t able to visualize small, soluble beta-amyloid clusters (now believed to to be the truly toxic form of the protein), Rutt and Zeineh don’t rule out a major role for beta-amyloid in the early developmental stages of pathology in Alzheimer’s.

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Events, Imaging, Neuroscience, Research

Physician-monk leads Stanford doctors in meditation

Physician-monk leads Stanford doctors in meditation

Kerzin and Verghese - smallAfter he finished his recent Grand Rounds talk here at the medical school, and before he opened the room to questions, physician Barry Kerzin, MD, asked the audience of doctors, residents, and a PBS film crew, to silence their cell phones, focus on their breath, and join him for five minutes of meditation.

It made sense because Kerzin, who provides medical care to His Holiness the Dalai Lama and is also a Buddhist monk, had just spent time explaining the central ideas of mindfulness meditation and highlighting the results from various scientific studies on brain changes and the benefits that mindfulness training can bring. Kerzin’s familiarity with the work comes partly from his participation in two of these studies.

As Stanford’s Abraham Verghese, MD, said when introducing Kerzin, many people in the audience may have had their work published in journals like Nature or PNAS, but “who has had [their] brain appear in one of these publications?”

Kerzin’s brain was part of research that compared those of long-term meditators (people who had clocked more than 10,000 hours meditating) to novices’ brains. MRI brain scans revealed increases in size and activity in Kerzin’s and the other monks’ prefrontal cortex, the part of the brain involved with planning and reasoning, as well as empathy and imagination. In one of the studies, Kerzin was hooked up to an EEG machine to demonstrate that when engaged in mindfulness meditation, his brain gave out bursts of high frequency signals called gamma waves, an unusual brain pattern thought to be linked to neural synchrony.

While these studies’ findings pertained to experienced meditators, Kerzin also presented a study where beginners were given either meditation training or health education for six weeks. At the end, when given a stress test, people in the meditation group produced statistically less stress hormones.

Although the most striking differences weren’t seen in beginning meditators, Kerzin also presented a study were volunteers where given either meditation training or health education for six weeks. At the end, when given a stress test, people in the meditation group produced statistically less stress hormones.

Last year I myself participated in a meditation study similar to the ones presented by Kerzin, although the final test in my case was an observation session of the participating parents’ interactions with their toddlers, and measuring stress hormone levels in both. That study hasn’t been published yet, but the subjective view of my husband is that I’m a lot calmer these days as a result of my continued meditation.

Given my experience, I wish I could say I rocked the group meditation at the talk, but I had a hard time concentrating. By focusing on my breathing I could mostly ignore the presentation and applause coming from the room next door. What was harder was blocking out my own thoughts, thoughts of the future – and specifically of writing this blog post. But overall, it was nice to take a moment and try to live in the present.

Kerzin’s talk, called “The science behind meditation,” is available here. Kerzin is also speaking on “Compassionate living” at a Center for Compassion and Altruism Research and Education event this evening; video of that talk will be available on the CCARE website in coming weeks.

Kim Smuga-Otto is a student in UC Santa Cruz’s science communication program and a writing intern in the medical school’s Office of Communication and Public Affairs.

Previous: What the world needs now: altruism/A conversation with Buddhist monk-author Matthieu Ricard, From suffering to compassion: Meditation teacher-author Sharon Salzberg shares her storyHis Holiness the 17th Karmapa discusses the nature of compassionResearch brings meditation’s health benefits into focus and 10% happier? Count me in!
Photo of Barry Kerzin (left) and Abraham Verghese by Margarita Gallardo

Bioengineering, Cancer, Imaging, Microbiology, Research, Science, Stanford News

Stanford team develops technique to magnetically levitate single cells

Stanford team develops technique to magnetically levitate single cells

Remember the levitating frog? That feat — the levitation of a live frog using a powerful magnet — was awarded the 2000 Ig Nobel Prize. Fascinating to watch, the demonstration also cemented a longstanding belief that levitating anything smaller than 20 microns was flat-out impossible. Much less something alive.

Not so, a team of Stanford-based researchers showed in a paper published today in the Proceedings of the National Academy of Sciences (PNAS). Using a 2-inch-long device made of two magnets affixed with plastic, the team showed it’s possible to levitate individual cells.

The video above demonstrates the technique in a population of breast cancer cells. Originally, the cells hover, suspended between the two magnets. But when exposed to an acid, they start to die and fall as their density increases.

“It has very broad implications in multiple diseases including cancer, especially for point-of-care applications where it can bring the central lab diagnostics to the comfort of patients’ homes or physicians’ office,” Utkan Demirci, PhD, a co-senior author and associate professor of radiology, told me.

The technique makes it possible to distinguish healthy cells from cancerous cells, monitor the real-time response of bacteria or yeast to drugs and distinguish other differences between cells that were thought to be homogenous, said Naside Gozde Durmus, PhD, a postdoctoral research fellow and first author of the paper.

Critically, the technique does not require treating the cells with antibodies or other markers, Durmus said. That ensures the cells are not altered by any treatments and makes the technique easy to use in a variety of settings, including potentially in physicians’ offices or in resource-poor settings.

The device works by balancing the gravitational mass of a cell against its inherent magnetic signature, which is negligible when compared with the cell’s density, Durmus said.

Interestingly, however, the cells — or bacteria treated with an antibiotic — do not die at the same rate, providing hints at their individual adaptations to environmental stressors, said co-senior author Lars Steinmetz, PhD, a professor of genetics.

To enhance the precision of the technique, the researchers can tweak the concentration of the solution that holds the cells, Durmus said. A highly concentrated solution allows for the differentiation of cells of similar densities, while a less concentrated solution can be used to examine a population of heterogeneous cells.

The team plans to investigate the applications of the device next, including its use in resource-poor settings where the cells can be observed using only a lens attached to an iPhone, Durmus said.

Previously: Harnessing magnetic levitation to analyze what we eat, Researchers develop device to sort blood cells with magnetic nanoparticles and Stanford-developed smart phone blood-testing device wins international award
Video courtesy of Naside Gozde Durmus

Cancer, Imaging, Research, Stanford News, Surgery

Better tumor-imaging contrast agent: the surgical equivalent of “cut along dotted line”?

cut horseIt would be tough for most people to take a snubbed-nose scissors to an 8-1/2″ x 11″ sheet of blank paper and carve out a perfect silhouette of, say, a horse from scratch. But any kid can be an artist if it means merely cutting along a boundary separating two zones of different colors.

Tumor-excision surgery requires an artist’s touch. It can be tough to distinguish cancerous from healthy tissues, yet the surgeon needs to approach perfection in precisely removing every possible trace of the tumor while leaving as much healthy tissue intact as possible. To help surgeons out, technologists have been designing contrast agents that target only tumor cells, thus providing at least a dotted line for scalpel wielders.

Stanford pathologist and molecular-probe designer Matthew Bogyo, PhD, in a study published in ACS Chemical Biology, has now demonstrated, using mouse models of breast, lung and colon cancer, the effectiveness of a fluorescence-emitting optical contrast agent that selectively accumulates in tumors and can be used to guide surgery. In effect, the probe lights up the tumor, providing a convenient, high-resolution dotted line for its excision.

Perhaps more striking, the new study showed that this probe, designed by Bogyo’s group, is compatible with a robotic remote minimally invasive surgery system that is already enjoying widespread commercial use. Intuitive Surgical, Inc., the company that sells this system, collaborated on the study.

Previously: Stanford researchers explore new ways of identifying colon cancer, Cat guts, car crashes, and warp-speed Toxoplasma infections and Compound clogs Plasmodium’s in-house garbage disposal, hitting malaria parasite where it hurts
Photo by Merryl Zorza

Genetics, Imaging, Neuroscience, Research, Stanford News

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

phrenologyNeuroscience has come a long way since the days of phrenology, when lumps on the outside of the skull were believed to denote enhanced size and strength of the particular brain region responsible for particular individual functions. Today’s far more advanced neuroimaging technologies allow scientists to peer deep into the living brain, revealing not only its anatomical structures and the tracts connecting them but, in recent years, physiological descriptions of the brain at work.

Visualized this way, the brain appears to contain numerous “functional networks:” clusters of remote brain regions that are connected directly via white-matter tracts or indirectly through connections with mediating regions. These networks’ tightly coupled brain regions not only are wired together, but fire together. Their pulses, purrs and pauses, so to speak, are closely coordinated in phase and frequency.

Well over a dozen functional networks, responsible for brain operations such as memory, language processing, vision and emotion, have been identified via a technique called resting-state functional magnetic resonance imaging. In a resting-state fMRI scan, the individual is asked to simply lie still, eyes closed, for several minutes and relax. These scans indicate that even at rest, the brain’s functional networks continue to hum along — albeit at lower volumes — at distinguishable frequencies and phases, like so many different radio stations playing simultaneously on the same radio.

But whether the images obtained via resting-state fMRI truly reflect neuronal activity or are some kind of artifact has been controversial. Now, a new study led by neuroscientist Michael Greicius, MD, and just published in Science, has found genetic evidence that convincingly bolsters neuroimaging-based depictions of these brain-activity patterns.

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Ethics, Imaging, Medicine and Society, Neuroscience, Research, Stanford News, Technology

Hidden memories: A bit of coaching allows subjects to cloak memories from fMRI detector

Hidden memories: A bit of coaching allows subjects to cloak memories from fMRI detector

11501949224_dac2b41c91_zImagine the usefulness of knowing if someone is drawing on a memory or experiencing something for the first time. “No, officer, I’ve never seen that person before.” 

That’s possible, using an algorithm that interprets brain scans developed by a team of Stanford researchers led by psychology professor Anthony Wagner, PhD. But according to a Stanford Report articleit’s also possible to fool that same program when subjects are coached to hide their memory.

The program, or decoder, capitalizes on the complexity of memory, which taps many different regions of the brain. They use functional magnetic resonance imaging (fMRI) to view which parts of the brain are active.

Hoping to illustrate the limits of their own creation, the researchers asked 24 study participants to study a series of faces. The next day, they exposed them to some of the same faces mixed with entirely new faces:

“We gave them two very specific strategies: If you remember seeing the face before, conceal your memory of that face by specifically focusing on features of the photo that you hadn’t noticed before, such as the lighting or the contours of the face, anything that’s novel to distract you from attending to the memory,” said Melina Uncapher, PhD, a research scientist in Wagner’s lab. “Likewise, if you see a brand-new face, think of a memory or a person that this face reminds you of and try to generate as much rich detail about that face as you can, which will make your brain look like it’s in a state of remembering.”

With just two minutes of coaching and training, the subjects became proficient at fooling the algorithm: The accuracy of the decoder fell to 50 percent, or no better than a coin-flip decision.

The new study shows that imaging technology alone will not be able to “pull about the truth about memory in all contexts,” Wagner said. And, as pointed out in the article, he “sees [the results] as potentially troubling for the goals of one day using fMRI to judge ‘ground truth’ in law cases.”

Previously: Memory of everyday events may be compromised by sleep apnea, The rechargeable brain: Blood plasma from young mice improves old mice’s memory and learningResearchers explore the minds of man’s best friend using fMRI technology, Using fMRI for lie detection and Brain scan used in court in potential fMRI first
Photo by David Schiersner

Bioengineering, Global Health, Imaging, In the News, Science, Videos

Microscopes for the masses: How a Stanford bioengineer is helping everyone “think like scientists”

Microscopes for the masses: How a Stanford bioengineer is helping everyone "think like scientists"

In a recent KQED QUEST Science postManu Prakash, PhD, a Stanford professor of bioengineering, describes his goal of making science accessible to everyone. His lab is mailing a Foldscope to anyone who submits a question he or she would like to use it to answer, and surprising and ingenious queries have been arriving from places like South Sudan, Iran, Ukraine, and India. This is creating a network of people who “think like scientists” (that is, ask their own questions about the world), because in Prakash’s words, “science is about ideas,” not access to fancy labs. Watch the video to learn more.

Previously: Miniature chemistry kit brings science out of the lab and into the classroom or field, Foldscope beta testers share the wonders of the microcosmosManu Prakash on how growing up in India influenced his interests as a Maker and entrepreneur, Dr. Prakash goes to Washington and Stanford bioengineer develops a 50-cent paper microscope

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