Wound-healing intestinal bacteria: like shrubs after a forest fire

In injured mouse intestines, specific types of bacteria step forward to promote healing. One oxygen-shy type of bacteria that grows in the hypoxic wound-healing environment, Akkermansia muciniphila, has already attracted attention for its relative scarcity in both animal and human obesity.

Oxidative stress ain't about free radicals, it's about sulfur

Dean Jones says: don't worry about free radicals. Worry about the oxidized form of sulfur-containing amino acids, such as cystine, a useful biomarker for cardiovascular risk.

When genes forget to forget

In ancient Greek mythology, the souls of the dead were made to drink from the river Lethe, so that they would forget their past lives. Something analogous happens to genes at the very beginning of life. Photo of one- and two-cell mouse embryos courtesy of Todd Macfarlan at NICHD.

Yerkes National Primate Research Center

‘Mountain of data’ on flu vaccine responses

Bali Pulendran’s lab at Emory Vaccine Center teamed up with UCSD researchers and recently published a huge analysis of immune responses after seasonal flu vaccination (Immunity is making it available free this week, no subscription needed). Hundreds of volunteers at the Vaccine Center’s Hope Clinic took part in this study.

Note — this study looked at antibody responses to flu vaccines, but didn’t assess protection: whether study participants actually became sick with flu or not.

Our write-up is hereImmunity’s preview, from the Karolinska Institute’s Petter Brodin, is here, Cell Press’s press release is here.

Three points we wanted to call attention to:

*Long-lasting antibodies A surprising finding was how the “molecular signatures” that predict the strength of the immune response a few weeks after vaccination did not predict how long anti-flu antibodies stayed around. Instead, a separate set of signatures predicted the durability of antibody levels.

These distinct signatures may be connected with how plasma cells, responsible for antibody production, need to find homes in the bone marrow. That sounds like the process highlighted by Eun-Hyung Lee and colleagues in an Immunity paper published in July. In bone marrow samples from middle-aged volunteers, her team had found antibody-secreting cells that survive from childhood infections.

*Interfering (?) activation of NK cells/monocytes in elderly While the researchers found people older than 65 tended to have weaker antibody responses to vaccination, there were common elements of molecular signatures that predicted strong antibody responses in younger and older volunteers. However, elderly volunteers tended to have stronger signatures from immune cells that are not directly involved in producing antibodies (monocytes and ‘natural killer’ cells), both at baseline and after vaccination.

From the discussion: “This indicates a potential connection between the baseline state of the immune system in the elderly and reduced responsiveness to vaccination.” Additional comments on this from Shane Crotty in Brad Fikes’ article for the Union Tribune.

*The mountain of data from this and similar studies is available for use by other researchers on the web site ImmPort.

Posted on by Quinn Eastman in Immunology Leave a comment

Graft vs host? Target the aurora

 

Graft-vs-host disease is a common and potentially deadly complication following bone marrow transplants, in which immune cells from the donated bone marrow attack the recipient’s body.

Winship Cancer Institute’s Ned Waller and researchers from Children’s Healthcare of Atlanta and Yerkes National Primate Research Center were part of a recent Science Translational Medicine paper that draws a bright red circle around aurora kinase A as a likely drug target in graft-vs-host disease.

Aurora kinases are enzymes that control mitosis, the process of cell division, and were first discovered in the 1990s in yeast, flies and frogs. Now drugs that inhibit aurora kinase A are in clinical trials for several types of cancer, and clinicans are planning to examine whether the same type of drugs could help with graft-vs-host disease.

Leslie Kean, a pediatric cancer specialist at Seattle Children’s who was at Emory until 2013, is the senior author of the STM paper. Seattle Childrens’ press release says that Kean wears a bracelet around her badge from a pediatric patient cured of leukemia one year ago, but who is still in the hospital due to complications from graft-vs-host. Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Everything in moderation, especially TH17 cells

I was struck by one part of Mirko Paiardini’s paper that was published this week in Journal of Clinical Investigation. It describes a treatment aimed at repairing immune function in SIV-infected monkeys, with an eye toward helping people with HIV one day. One of the goals of their IL-21 treatment is to restore intestinal Th17 cells, which are depleted by viral infection. In this context, IL-21’s effect is anti-inflammatory.

However, Th17 cells are also involved in autoimmune disease. A recent Cell Metabolism paper from endocrinologist Roberto Pacifici and colleagues examines Th17 cells, with the goal of treating bone loss coming from an overactive parathyroid. In that situation, too many Th17 cells are bad and they need to be beaten back. Fortunately, both an inexpensive blood pressure medication and a drug under development for psoriasis seem to do just that.

Note for microbiome fans: connections between Th17 cells and intestinal microbes (segmented filamentous bacteria) are strengthening. It gets complicated because gut microbiota, together with Th17 cells, may influence metabolic disease and Th17-like cells are also in the skin — location matters.

Posted on by Quinn Eastman in Immunology Leave a comment

Epigenetic inheritance via sperm RNA

In 2013, Brian Dias (at Yerkes) and Kerry Ressler (now at Harvard) described a surprising example of epigenetic inheritance.

They found that a mouse, exposed to a smell in combination with stress, could transmit the resulting sensitivity to that smell to its offspring. At the time, there wasn’t a lot of information about mechanism.

Now other scientists have substantiated a proposal that micro RNA in playing a role in sperm. See this story (“Sperm RNAs transmit stress”) from Kate Yandell in The Scientist or this one from Rachel Zamzow at Spectrum, the Simons Foundation’s autism news site, for more. An added wrinkle is that this research shows that descendants of stress-exposed mice show a muted response to stress.

Note for Emory readers: Dias is scheduled to give a Frontiers in Neuroscience talk on Friday.

Posted on by Quinn Eastman in Neuro Leave a comment

HIV vaccine news: a glass half full

This week, researchers from Yerkes and Emory Vaccine Center led by Cindy Derdeyn published a paper that I first thought was disturbing. It describes how monkeys vaccinated against HIV’s relative SIV (simian immunodeficiency virus) still become infected when challenged with the virus. Moreover, it’s not clear whether the vaccine-induced antibodies are exerting any selective pressure on the virus that gets through.

But then I realized that this might be an example of “burying the lead,” since we haven’t made a big hoopla about the underlying vaccine studies, conducted by Rama Amara. Some of these studies showed that a majority of monkeys can be protected from repeated viral challenge. The more effective vaccine regimens include adjuvants such as the immune-stimulating molecules GM-CSF or CD40L (links are the papers on the protective effects). Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Do Alzheimer’s proteins share properties with prions?

If you’ve come anywhere near Alzheimer’s research, you’ve come across the “amyloid hypothesis” or “amyloid cascade hypothesis.”

This is the proposal that deposition of amyloid-beta, a major protein ingredient of the plaques that accumulate in the brains of Alzheimer’s patients, is a central event in the pathology of the disease. Lots of supporting evidence exists, but several therapies that target beta-amyloid, such as antibodies, have failed in large clinical trials.

Jucker_Walker_May_2014

Lary Walker and Matthias Jucker in Tübingen, 2014

In a recent Nature News article, Boer Deng highlights an emerging idea in the Alzheimer’s field that may partly explain why: not all forms of aggregated amyloid-beta are the same. Moreover, some “strains” of amyloid-beta may resemble spooky prions in their ability to spread within the brain, even if they can’t infect other people (important!).

Prions are the “infectious proteins” behind diseases such as bovine spongiform encephalopathy. They fold into a particular structure, aggregate and then propagate by attracting more proteins into that structure.

Lary Walker at Yerkes National Primate Research Center has been a key proponent of this provocative idea as it applies to Alzheimer’s. To conduct key experiments supporting the prion-like properties of amyloid-beta, Walker has been collaborating with Matthias Jucker in Tübingen, Germany and spent four months there on a sabbatical last year. Their paper, describing how aggregated amyloid-beta is “seeded” and spreads through the brain in mice, was recently published in Brain Pathology.
Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Effects of cocaine exposure in adolescent rodents

Much of neuroscientist Shannon Gourley’s work focuses on the idea that adolescence is a vulnerable time for the developing brain. She and graduate student Lauren DePoy recently published a paper in Frontiers in Pharmacology showing that in adolescent rodents, cocaine exposure can cause the loss of dendritic arbors in part of the brain important for decision-making.

The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for “linking reward to hedonic experience.” It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.

“To make an analogy, it’s like a tree losing some of its leaves,” Gourley writes. “Lauren’s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors – as if entire branches are being cut from the tree.”

The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.

The findings suggest a partial explanation for the increased risk of dependence in people who start using cocaine during adolescence.

Posted on by Quinn Eastman in Neuro Leave a comment

Nobel Prize for place cells + grid cells

Congratulations to John O’Keefe, May-Britt Moser and Edvard Moser for receiving the 2014 Nobel Prize in Medicine. The prize is for discovering “the brain’s navigation system”: place cells, cells in the hippocampus which are active whenever a rat is in a particular place, and grid cells, cells in the entorhinal cortex which are active when the animal is at multiple locations in a grid pattern.

Former Yerkes researcher Beth Buffalo and her graduate student Nathan Killian were the first to directly detect, via electrode recordings, grid cells in the brains of non-human primates. Buffalo is now at the University of Washington and Killian is at Harvard Medical School.

A significant difference about their experiments was that they could identify grid cells when monkeys were moving their eyes, suggesting that primates don’t have to actually visit a place to construct the same kind of mental map. Another aspect of grid cells in non-human primates not previously seen with rodents is that the cells’ responses change when monkeys are seeing an image for the second time.

Following that report, grid cells were also directly detected in human epilepsy patients. The Mosers themselves noted in a 2014 review, “It will be interesting to see whether the same cells that respond to visual movement in monkeys also respond to locomotion, or whether there is a separate system of grid cells that is responsive to locomotion.”

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From Berlin to Yerkes

Yerkes immunologist Guido Silvestri and colleagues have a paper in PLOS Pathogens shedding light on the still singular example of Timothy Brown, aka “the Berlin patient”, the only human cured of HIV. Hat tip to Jon Cohen of Science, who has a great explanatory article.

Recall that Brown had lived with HIV for several years, controlling it with antiretroviral drugs, before developing acute myeloid leukemia. In Berlin, as treatment for the leukemia, he received a bone marrow transplant — and not just from any donor; the donor had a HIV-resistance mutation. What was the critical ingredient that enabled HIV to be purged from his body?

Conditioning: the chemotherapy/radiation treatment that eliminates the recipient’s immune system before transplant? HIV-resistant donor cells? Or graft-vs-host disease: the new immune system attacking the old?

Silvestri and colleagues performed experiments with SHIV-infected non-human primates that duplicate most, but not all, of the elements of Brown’s odyssey. The results demonstrate that conditioning, by itself, does not eliminate the virus from the body. But in one animal, it came close. Frustratingly, that animal’s kidneys failed and researchers had to euthanize it. In two others, the virus came back after transplant.

A critical difference from Brown’s experience is that monkeys received their own virus-free blood-forming stem cells instead of virus-resistant cells. Cohen reports that Silvestri hopes to do future monkey experiments that test more of these variables, including transplanting the animals with viral-resistant blood cells that mimic the ones that Brown received. 

Posted on by Quinn Eastman in Immunology Leave a comment

Maturing brain flips function of amygdala in regulating stress hormones

In contrast to evidence that the amygdala stimulates stress responses in adults, researchers at Yerkes National Primate Research Center, Emory University have found that the amygdala has an inhibitory effect on stress hormones during the early development of nonhuman primates.

The results are published this week in Journal of Neuroscience.

The amygdala is a region of the brain known to be important for responses to threatening situations and learning about threats. Alterations in the amygdala have been reported in psychiatric disorders such as depression, anxiety disorders like PTSD, schizophrenia and autism spectrum disorder. However, much of what is known about the amygdala comes from research on adults.

“Our findings fit into an emerging theme in neuroscience research: that during childhood, there is a switch in amygdala function and connectivity with other brain regions, particularly the prefrontal cortex,” says Mar Sanchez, PhD, neuroscience researcher at Yerkes and associate professor of psychiatry and behavioral sciences at Emory University School of Medicine. The first author of the paper is postdoctoral fellow Jessica Raper, PhD.

Some notable links on the amygdala:

*An effort to correct simplistic views of amygdala as the “fear center” of the brain

*Collection of papers mentioning patient SM, an adult human with an amygdala lesion

*Recent Nature Neuroscience paper on amygdala’s role in appetite control

*Evidence for changing amygdala-prefrontal connectivity in humans during development Read more

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