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.

HIV vaccine insight via Rwanda

Rebuilding a shattered society is compatible with HIV vaccine research

Cardiac cell therapy: three papers at a glance

Cardiac cell therapy sounds like a promising idea: use the patients’ own cells to enhance healing or even regenerate the damaged heart muscle. Doctors have taken up the promise, testing it in clinical trials involving thousands of patients. But a basic problem facing the field is this: naked cells don’t appear to stay in the heart or stay alive for long enough to provide a sustained benefit. Three labs at Emory have published papers in the last year addressing this problem. All describe some kind of supportive biomaterials, consisting of capsules or a gel, which help cells stay put and stay alive, in experiments where recovery from a heart attack is modeled in rodents. The most recent comes from cardiologist Young-sup Yoon and colleagues, in ACS Nano. The first author is Kiwon Ban, a senior postdoc in Yoon’s laboratory. Ban and his team use self-assembling peptides, developed in collaboration with biomaterials engineer Ho-wook Jun at UAB (see figure). The peptides form a gel that both physically keeps cardiac muscle cells in the heart and eases their integration into the heart tissue over a period of weeks. As Katie Bourzac explains in Chemical & Engineering News: One peptide acts like a natural protein that adheres to cells and promotes cell survival. The second peptide is readily broken down by a protease. The team designed the gel so that when it is implanted, it begins to degrade a bit, allowing cells from the body to migrate in. Eventually the gel should disintegrate completely as the heart tissue builds its own extracellular matrix. This particular gel has already performed well as a support for other kinds of cells grown from stem cells, including pancreatic and muscle cells. We thought it may be useful to readers to be able to compare and contrast these papers in chart form.  Levit et al. JAHA 2013 (blog post) Boopathy et al Biomaterials 2014 (blog post) Ban et al ACS Nano 2014 (discussed here) Source of cells Mesenchymal stem cells Cardiac progenitor cells, derived from cardiac tissue Differentiated cardiac muscle cells, derived from embryonic stem cells Supportive technology Alginate encapsulation Self-assembling peptides with Notch ligand Self-assembling peptides with RGDS (fibronectin ligand), MMP degradable Experimental model Immunodeficient rat myocardial infarction Rat myocardial infarction Immunodeficient mouse myocardial infarction How therapeutic effect assessed Cell retention, ejection fraction, scar size, new blood vessels Retention in heart, ejection fraction, scar size Retention in heart, ejection fraction, scar size Other distinctive aspects Capsules were combined with a hydrogel patch, which dissolves in 1 week Gel composition can modulate cell behavior Only gel allowed cells to last >3 weeks + engraft into heart The main differences are apparent in two areas: the supportive material and in the source of cells. With mesenchymal stem cells, the paracrine effect -- providing growth and survival factors -- is the name of the game, not becoming part of the cardiac tissue permanently. Mesenchymal stem cells, potentially available in the clinic through tapping patients’ bone marrow, are not going to be able to engraft into the heart because they can't become cardiac muscle, or new blood vessels. But with cardiac progenitor cells or differentiated cardiac muscle cells, engraftment is researchers' goal.  Cardiac progenitor cells can be purified from cardiac tissue biopsies and then grown in culture. Doctors could obtain differentiated cardiac muscle cells by generating induced pluripotent stem cells from patients’ skin or blood cells, and then differentiating those cells into cardiac muscle cells (a process Yoon, Ban and Gang Bao's lab at Georgia Tech have also described in a 2013 paper).

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.

Read more

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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

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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

Posted on by Quinn Eastman in Immunology Leave a comment

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.

Read more

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Anti-inflammatory drug prevents neuron loss in Parkinson’s model

A lot of evidence has piled up suggesting that inflammation plays a big role in the progression of Parkinson’s.

Immune system genes are linked to disease risk. People who regularly take NSAIDs such as ibuprofen have lower risk. Microglia, the immune system’s ambassadors to the brain, have been observed in PD patients.

Malu Tansey and her postdoc CJ Barnum make a convincing case for an anti-inflammatory — specifically, anti-TNF– therapy to Parkinson’s. They’ve been working with the Michael J. Fox Foundation for Parkinson’s Research to push this promising approach forward. Please check it out.

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

Potential anticancer drugs from humble sources

Jing Chen and colleagues at Winship Cancer Institute recently published a paper in Molecular CellMost of the paper deals with a metabolic enzyme, 6PGD (6-phosphogluconate dehydrogenase), and how it is more active in cancer cells.

Rhubarb_Flower

Rheum palmatum/Chinese rhubarb/da-huang

Tucked in at the end is a note that an inhibitor of 6GPD with an odd name, physcion, has anticancer activity in Chen’s team’s hands. Physcion, also known as parietin, is an orange-yellow pigment extractable from lichens and Chinese rhubarb that has been employed as an anti-mildew agent.

Probing cancer cells’ warped metabolism is a promising approach, for both drug discovery and finding effective ways to combine existing drugs, because of the Warburg effect: cancer cells’ tendency to suck up lots of sugar and use it in energy-inefficient ways. Read more

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