Key to universal flu vaccine: embrace the unfamiliar

Vaccination against H5N1 induced antibodies against the stem region of the viral hemagglutinin protein

Catching up on Emory transplant advances

Fecal microbiota transplant in organ transplant recipients, without infectious complications + taking off the training wheels with belatacept

Maturing brain flips function of amygdala in regulating stress hormones

Scientists are still discovering new information about the function of the amygdala, a region of the brain important for learning about threats

Key to universal flu vaccine: embrace the unfamiliar

Vaccine researchers have developed a strategy aimed at generating broadly cross-reactive antibodies against the influenza virus: embrace the unfamiliar.

In recent years, researchers interested in a “universal flu vaccine” identified a region of the viral hemagglutinin protein called the stem or stalk, which doesn’t mutate and change as much as other regions and could be the basis for a vaccine that is protective against a variety of flu strains.

In an Emory Vaccine Center study, human volunteers immunized against the avian flu virus H5N1 readily developed antibodies against the stem region of the viral hemagglutinin protein. In contrast, those immunized with standard seasonal trivalent vaccines did not, instead developing most of their antibodies against the more variable head region. H5N1, regarded as a potential pandemic strain, is not currently circulating in the United States and the volunteers had not been exposed to it before.

The results were published Monday, August 25 in PNAS.

The key to having volunteers’ bodies produce antibodies against the stem region seemed to be their immune systems’ unfamiliarity with the H5N1 type of virus, says lead author Ali Ellebedy, PhD, postdoctoral fellow in the laboratory of Rafi Ahmed, PhD, director of Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

Note: for a counterpoint, check out this 2013 Science Translational Medicine paper on how vaccination that induces anti-stem antibodies contributes to enhanced respiratory disease in pigs.

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Posted on by Quinn Eastman in Immunology Leave a comment

Catching up on Emory transplant advances

While preparing to discuss Ebola virology with Emory infectious disease specialist Aneesh Mehta next week, we noticed two recent research papers on which he is a co-author. Both have to do with organ transplantation, since Mehta is Assistant Director of Transplant Infectious Diseases.

Fecal microbiota transplantation for refractory Clostridium difficile colitis in solid organ transplant recipients

Fecal transplant is gaining ground as a remedy for C. difficile-driven diarrheal infections, which can appear in patients whose normal intestinal bacteria are wiped out by antibiotics. Fecal transplant has not been widely studied in organ transplant recipients, who must take drugs to keep their immune systems from rejecting the transplanted organ, because of concerns about infectious disease complications. This paper describes two patients, one a lung transplant recipient and one a kidney transplant recipient, who received fecal transplants to resolve their C. difficile diarrhea without complications. The lead authors are infectious disease specialists Rachel Friedman-Moraco and Colleen Kraft. Kraft has been a pioneer in this area of research.

Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors

Medical school dean Chris Larsen and Emory Transplant Center executive director Tom Pearson (both co-authors) were key members on the team that developed belatacept, a FDA-approved drug since 2011. Belatacept was designed to get away from the cruel paradox where a kidney recipient, to prevent transplant rejection, has to take calcineurin inhibitor drugs that slowly poison the kidney and cardiovascular health. Belatacept inhibits the immune response by a different mechanism. Yet transplant specialists have generally been cautious in moving toward a regimen that relies on it.

As reported in this paper, Emory transplant doctors took off the training wheels, aiming to get to the point where kidney transplant recipients are taking a once-a-month infusion of belatacept only. With some patients, it was possible to reach that goal, but not all. In fact, as the authors describe, some patients chose not to try to wean themselves off the other drugs, and doctors advised against the attempt for a handful. This clinical trial was also notable because some transplant recipients received immune-educational cells from their organ donors in the form of bone marrow.

The lead author, former Emory Transplant Center scientific director Allan Kirk, moved to Duke this spring.

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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

Posted on by Quinn Eastman in Neuro Leave a comment

A new frame of reference — on ribosome frameshifting

It’s a fundamental rule governing how the genetic code works. Ribosomes, the factories that assemble proteins in all types of living cells, read three letters (or nucleotides) of messenger RNA at a time.

In some instances, the ribosome can bend its rules, and read either two or four nucleotides, altering how downstream information is read. Biologists call this normally rare event ribosomal frameshifting. For an ordinary gene, the event of a frameshift turns the rest of the ensuing protein into nonsense. However, many viruses exploit frameshifting, because they can then have overlapping genes and fit more information into a limited space.

Regulated frameshifting takes place in human genes too, and understanding frameshifting is key to recent efforts to expand the genetic code. Researchers are aiming to use the process to customize proteins for industrial and pharmaceutical applications, by inserting amino acid building blocks not found in nature.

“Going back to the 1960s, when the genetic code was first revealed, there were many studies on ribosomal frameshifting, yet no-one really knows how it works on a molecular and mechanistic level,” says Christine Dunham, PhD, assistant professor of biochemistry at Emory University School of Medicine. “What we do know is that the ‘yardstick’ model that appears in a lot of textbooks, saying that the anticodon loop dictates the number of nucleotides decoded, while elegant, is probably incorrect.”

Dunham, who first studied the topic as a postdoc, and her colleagues published a paper this week in PNAS where they outline a model for how ribosomal frameshifting occurs, based on structural studies of the ribosome interacting with some of its helper machinery. Co-first authors of the paper are postdoctoral fellows Tatsuya Maehigashi, PhD and Jack Dunkle, PhD.

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Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Contraception and HIV risk

Does hormonal contraception increase the risk for a woman to acquire HIV from an infected partner?

This topic, with implications for public health in countries where HIV risk is high, has been contentious. Some previous studies had found the answer to be yes, for methods involving injectable progesterone such as Depo-Provera. This led the World Health Organization in 2012 to advise women using progesterone-only injections to use condoms to prevent HIV infection.

At the recent AIDS 2014 meeting in Australia, Emory epidemiologist Kristin Wall presented data from public health programs in Zambia. This is another study emerging from the Zambia-Emory HIV Research Project directed by Susan Allen.

Wall’s presentation is available here.

Studying 1393 heterosexual couples with a HIV-positive male partner over 17 years, Wall and her colleagues found no significant difference in incidence rate per 100 couple years between hormonal and non-hormonal forms of contraception. Read more

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Antibiotic resistance enzyme caught in the act

Resistance to an entire class of antibiotics – aminoglycosides — has the potential to spread to many types of bacteria, according to new biochemistry research.

A mobile gene called NpmA was discovered in E. coli bacteria isolated from a Japanese patient several years ago. Global spread of NpmA and related antibiotic resistance enzymes could disable an entire class of tools doctors use to fight serious or life-threatening infections.

Using X-ray crystallography, researchers at Emory made an atomic-scale snapshot of how the enzyme encoded by NpmA interacts with part of the ribosome, protein factories essential for all cells to function. NpmA imparts a tiny chemical change that makes the ribosome, and the bacteria, resistant to the drugs’ effects.

The results, published in PNAS, provide clues to the threat NpmA poses, but also reveal potential targets to develop drugs that could overcome resistance from this group of enzymes.

First author of the paper is postdoctoral fellow Jack Dunkle, PhD. Co-senior authors are assistant professor of biochemistry Christine Dunham, PhD and associate professor of biochemistry Graeme Conn, PhD. Read more

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Fighting HIV, biomedical and behavioral hand in hand

In the HIV/AIDS arena, the idea of “treatment as prevention” has been gaining strength. Multiple studies have shown that treatment with anti-retroviral drugs can dramatically reduce the likelihood that someone infected with HIV will be able to pass the virus to someone else.

However, a recent strategy document for HIV/AIDS prevention developed by a International Antiviral Society–USA panel, co-led by Rollins Global Health chair Carlos Del Rio, puts biomedical interventions hand in hand with psychosocial measures such as couples counseling and treatment for drug dependence.

Why? Because people everywhere can have trouble sticking to antiretroviral treatment, even if drugs are available. And couples counseling by itself is valuable.

A powerful example of how this plays out, and of the importance of couples counseling to the effectiveness of antiretroviral drugs in prevention, comes from a recent presentation from Emory epidemiologist Kristin Wall at the AIDS 2014 meeting in Australia. The website NAM Aidsmap had a helpful write-up of her presentation, which is available here. Thanks to co-author Susan Allen for alerting us to this.

CVCT (couples voluntary counseling and treatment) greatly enhanced the preventive effect of antiretroviral treatment, when compared to treatment without counselling, Wall’s analysis of a large cohort of couples in Zambia showed. 

Update: Allen points out that couples counseling by itself was effective in helping people avoid HIV, with a 75 percent reduction in incidence for couples where the HIV+ partner was not receiving antiviral therapy or with HIV negative couples.  Read more

Posted on by Quinn Eastman in Immunology 2 Comments

Socialization relative strength in fragile X longitudinal study

A study published in Pediatrics this week tracks “adaptive behavior” as children and adolescents with fragile X syndrome are growing up. This is the largest longitudinal study to date in fragile X, which is the leading inherited cause of intellectual disability and the leading single-gene risk factor for autism spectrum disorder.

Adaptive behavior covers a range of everyday social and practical skills, including communication, socialization, and completing tasks of daily living such as getting dressed. In this study, socialization emerged as a relative strength in boys with fragile X, in that it did not decline as much as the other two domains of adaptive behavior measured: communication and daily living skills.

The lead author of the paper is Cheryl Klaiman, formerly of the Stanford University Center for Interdisciplinary Brain Sciences, now senior psychologist at Marcus Autism Center.

The “socialization as relative strength in fragile X” findings meshes with a growing awareness in the autism field, summarized nicely here by Jessica Wright at the Simons Foundation Autism Research Initiative, that fragile X syndrome symptoms are often distinct from those in autism spectrum disorder.

One key distinction between the disorders, for example, is in social interactions. Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them.

But children with fragile X syndrome often sneak a peek when the other person turns his back, researchers say. Children with autism, in contrast, seem mostly uninterested in social interactions.

“Children with fragile X syndrome all have very severe social anxiety that plays a big role in the perception that they have autism,” says Stephen Warren, professor of human genetics at Emory University School of Medicine in Atlanta. “They are actually interested in their environment; they are just very shy and anxious about it.”

Posted on by Quinn Eastman in Neuro Leave a comment

Debunking detour to DNA

Debunking the idea that most humans only use 10 percent of our brains, which is a starting point for the Scarlett Johansson/Luc Besson movie Lucy, was popular last week.
Many media outlets and popular Web sites took on this task. Emory’s Krish Sathian – known for his work on rehabilitation, how the brain processes sensory experiences and how we understand metaphors – does an able job of it in the video below.

But a related question is still a matter of debate: how much of our DNA do we “use”? This is an important question for geneticists because it seeks to define the most productive mutation hunting grounds.

A study published in PLOS Genetics last week concluded that just 8.2 percent of the human genome is constrained during evolution and is likely to be “functional”. The press release on this paper pointed out sharply that this contrasts with the more expansive analysis from the multinational ENCODE project, which assigned some biochemical function to 80 percent of the human genome.

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