Give a zap to Emory brain research for #STATMadness

Vote for Emory neuroscience research next week as part of Read more

Nox-ious link to cancer Warburg effect

Invitation from a talk by San Martin recently gave in Read more

Viral vectors ready for delivery

The phrase “viral vector” sounds ominous, like something from a movie about spies and Internet intrigue. It refers to a practical delivery system for the gene of your Read more

Give a zap to Emory brain research for #STATMadness

Next week, we will be asking the Emory research community to support Emory’s entry in a contest. It’s like “Battle of the Bands.” Whoever gets the loudest cheers wins. We have some intriguing neuroscience research. Please help!

STAT Madness is a “March Madness” style bracket competition, but with biomedical research advances as competitors. Universities or research institutes nominate their champions, research that was published the previous year.

Our entry for 2018:

Direct amygdala stimulation can enhance human memory

The findings, from Cory Inman, Jon Willie and colleagues from the Department of Neurosurgery and Joe Manns from Psychology, were the first published example of electrical brain stimulation in humans giving an event-specific boost to memory lasting overnight. The research was conducted with epilepsy patients undergoing an invasive procedure for seizure diagnosis. However, the technology could one day be incorporated into a device aimed at helping those with memory impairments, such as people with traumatic brain injury or neurodegenerative diseases.

Extra note: you may have seen similar neuroscience research in a recent Nature Communications paper, which was described in the New York Times. Cory Inman had some comments below — he and neurosurgeon Robert Gross were co-authors:

The localization to the left lateral temporal cortex was interesting, because it hadn’t been identified as a region that modulates episodic or hippocampus-dependent memory. [The Emory authors stimulated the amygdala.] The more recent paper found a similar size of memory enhancement, with a slightly different and harder memory task of free recall, using “closed-loop” stimulation based on whether the brain is in a ‘bad’ encoding state. It’s possible that closed-loop stimulation could be used with the amygdala as well. 

As far as voting, you can fill out a whole bracket or you can just vote for Emory, along with other places you may feel an allegiance to. The contest will go several rounds. The first round begins on February 26. If Emory advances, then people will be able to continue voting for us starting March 2.

At the moment, you can sign up to be reminded to vote with an email address at:
https://signup.statnews.com/stat-madness

Starting Monday, February 26, you can follow the 2018 STAT Madness bracket and vote here:
https://www.statnews.com/feature/stat-madness/bracket/

Please share on social media using the hashtag #statmadness2018.

STAT is a life sciences-focused news site, launched in 2015 by the owner of the Boston Globe. It covers medical research and biotech nationally and internationally. Emory took part in 2017’s contest, with Tab Ansari’s groundbreaking work on SIV remission, a collaboration with Tony Fauci’s lab at NIAID.

 

 

Posted on by Quinn Eastman in Neuro Leave a comment

Nox-ious link to cancer Warburg effect

At Emory, Kathy Griendling’s group is well known for studying NADPH oxidases (also known as Nox), enzymes which generate reactive oxygen species. In 2009, they published a paper on a regulator of Nox enzymes called Poldip2. Griendling’s former postdoc, now assistant professor, Alejandra San Martin has taken up Poldip2.

Griendling first came to Nox enzymes from a cardiology/vascular biology perspective, but they have links to cancer. Nox enzymes are multifarious and it appears that Poldip2 is too. As its full name suggests, Poldip2 (polymerase delta interacting protein 2) was first identified as interacting with DNA replication enzymes.  Poldip2 also appears in mitochondria, indirectly regulating the process of lipoylation — attachment of a fatty acid to proteins anchoring them in membranes. That’s where a recent PNAS paper from San Martin, Griendling and colleagues comes in. It identifies Poldip2 as playing a role in hypoxia and cancer cell metabolic adaptation.

Part of the PNAS paper focuses on Poldip2 in triple-negative breast cancer, more difficult to treat. In TNBC cells, Poldip2’s absence appears to be part of the warped cancer cell metabolism known as the Warburg effect. Lab Land has explored the Warburg effect with Winship’s Jing Chen.

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

Viral vectors ready for delivery

The phrase “viral vector” sounds ominous, like something from a movie about spies and internet intrigue. It refers to a practical delivery system for the gene of your choice. If you are a biomedical researcher and you want to tweak genes in a particular part of the body in an experimental animal, viral vectors are the way to go.

Viral vector-transduced retinal ganglion cell; dendrites and axons labeled with GFP. Courtesy Felix Struebling via Xinping Huang

Emory’s Viral Vector Core was started when eminent neuroscientist Kerry Ressler was at Emory and is now overseen by geneticist Peng Jin. Technical director Xinping Huang and her colleagues can produce high-titer viral vectors, lentivirus and AAV. Discuss with her the best choice. It may depend on the size of the genetic payload you want to deliver and whether you want the gene to integrate into the genome of the target cell.

As gene therapy and CRISPR/Cas9-style gene editing research progresses, we can anticipate demand for services such as those provided by the Viral Vector Core. [Clinical applications are close, but will not be dealt with in the same place!]

Shi-Hua Li’s and Xiao-Jiang Li’s paper on CRISPR/Cas9 gene editing in a mouse model of Huntington’s disease, featured by NBC News last year, credits the Viral Vector Core. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Exotic immune systems are big business

What timing! Just when our feature on Max Cooper and lamprey immunology was scheduled for publication, the Japan Prize Foundation announced it would honor Cooper and his achievements.

Cooper was one of the founders of modern immunology. We connect his early work with his lab’s more recent focus on lampreys, primitive parasites with surprisingly sophisticated immune systems.

Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

Read more

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

Calming an electrical storm in the heart

AT = anterior tubercle of C6, C = carotid artery, LC = longus colli muscle, T = thyroid gland, IJ = internal jugular vein, compressed

The most recent issue of Emory Medicine features a story that first came to Lab Land’s attention when it was presented as an abstract at the 2017 American College of Cardiology Scientific Sessions meeting.

Emory doctors were challenged by a patient who repeatedly developed cardiac arrhythmias, called “refractory electrical storm.” They used a local anesthesia procedure called stellate ganglion block — normally used for complex pain — to calm the storm. Cardiac electrophysiologist Michael Lloyd, who likes solving puzzles, was the one who decided to try it.

Emory anesthesiologist Boris Spektor provided this ultrasound picture of the procedure. Stellate ganglion block is also being tested for conditions such as PTSD. Please read the whole story!

Posted on by Quinn Eastman in Heart Leave a comment

Sifting proteomes for copper nuggets

Just because scientists know the gene responsible for a rare disease doesn’t mean they know what’s going on. NGLY1 is a good example. A handful of children around the world have an inherited deficiency in NGLY1, leading to a complex neurodevelopmental disorder. A family diagnosed at Emory thought their older affected daughter had cerebral palsy for most of her childhood. How the loss of an enzyme that removes sugar tags from certain proteins causes problems is still being uncovered.

More broadly, geneticists can read a family’s DNA sequences and find the differences, but figuring out what they mean is still a challenge. That’s where the approach taken in a recent paper in Cell Systems, by Emory cell biologist Victor Faundez and colleagues at Illinois State, comes in.

His lab used a comparison of proteomes to dissect Menkes disease, a rare inherited deficiency in a copper transport enzyme called ATP7A. This means they didn’t compare genes; instead, they compared the proteins produced by patients’ cells with those in their unaffected relatives.

Copper is an essential part of the diet and can be found at the active sites of several enzymes. The symptoms of Menkes disease arise because of a lack of copper in the body, although cultured cells lacking ATP7A actually accumulate copper. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Navigating monstrous anticancer obstacles

A new PNAS paper from geneticist Tamara Caspary’s lab identifies a possible drug target in medulloblastoma, the most common pediatric brain tumor. Come aboard to understand the obstacles this research seeks to navigate. Emory library link here.

Standard treatment for children with medulloblastoma consists of surgery in combination with radiation and chemotherapy. Alternatives are needed, because survivors can experience side effects such as neurocognitive impairment. One possibility has emerged in the last decade: inhibitors of the Hedgehog pathway, whose aberrant activation drives growth in medulloblastoma.

Medulloblastoma patients are caught “between Scylla and Charybdis”: facing a deadly disease, the side effects of radiation and/or existing Hedgehog inhibitors. From Wikimedia.

As this 2017 Oncotarget paper from St. Jude’s describes, Hedgehog inhibitors are no fun either. In adults, these agents cause muscle spasms, hair loss, distorted sense of taste, fatigue, and weight loss. In a pediatric clinical trial, the St. Jude group observed growth plate fusions, resulting in short stature. The drug described in the paper was approved in 2012 for basal cell carcinoma, a form of cancer whose growth is also driven by the Hedgehog pathway. Basal cell carcinoma is actually the most common form of human cancer, although it is often caught at an early stage that doesn’t require harsh treatment.

Caspary’s lab studies the Hedgehog pathway in early embryonic development. In the PNAS paper, former graduate student Sarah Bay and postdoc Alyssa Long show that targeting a downstream part of the Hedgehog pathway may be a way to avoid problems presented by both radiation/chemo and existing Hedgehog inhibitors. Read more

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

Epilepsy pick up sticks

Imagine the game of pick up sticks. It’s hard to extract one stick from the pile without moving others. The same problem exists, in a much more complex way, in the brain. Pulling on one gene or neurotransmitter often nudges a lot of others.

Andrew Escayg, PhD

That’s why a recent paper from Andrew Escayg’s lab is so interesting. He studies genes involved in epilepsy. Several years ago, he showed that mice with mutations in the SCN8A gene have absence epilepsy, while also showing resistance to induced seizures. SCN8A is one of those sticks that touches many others. The gene encodes a voltage-gated sodium channel, involved in setting the thresholds for and triggering neurons’ action potentials. Mutating the gene in mice modifies sleep and even enhances spatial memory.

Escayg’s new paper, with first author Jennifer Wong, looks at the effect of “knocking down” SCN8A in the hippocampus in a mouse model of mesial temporal lobe epilepsy. This model doesn’t involve sodium channel genes; it’s generated by injection of a toxin (kainic acid) into the brain. The finding suggests that inhibiting SCN8A may be applicable to other forms of epilepsy. Escayg notes that mesial temporal lobe epilepsy is one of the most common forms of treatment-resistant epilepsy in adults.

Knocking down SCN8A in the hippocampus 24 hours after injection could prevent the development of seizures in 90 percent of the treated mice. “It is likely that selective reduction in Scn8a expression would have directly decreased neuronal excitability,” the authors write. It did not lead to increased anxiety levels or impaired learning/memory.

Currently, no available drugs target Scn8a specifically. However, antisense approaches for neurodegenerative diseases have been gaining ground – perhaps epilepsy could fit in.

Posted on by Quinn Eastman in Neuro Leave a comment

Life-saving predictions from the ICU

It’s similar to the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. That’s how Tim Buchman, director of the Emory Critical Care Center, described an emerging effort to detect and ward off sepsis in ICU patients hours before it starts to make their vital signs go haywire.

As landmark clinical studies have documented, every hour of delay in giving someone with sepsis antibiotics increases their risk of mortality. So detecting sepsis as early as possible could save lives. Many hospitals have developed “sniffer” systems that monitor patients for sepsis risk. See our 2016 feature in Emory Medicine for more details.

What Shamim Nemati and his colleagues, including bioinformatics chair Gari Clifford, have been exploring is more sophisticated. A vastly simplified way to summarize it is: if someone has a disorderly heart rate and blood pressure, those changes can be an early indicator of sepsis.* It requires continuous monitoring – not just once an hour. But in the ICU, this can be done. The algorithm uses 65 indicators, such as respiration, temperature, and oxygen levels — not only heart rate and blood pressure. See below.

Example patient graph. Green = SOFA score. Purple = Artificial Intelligence Sepsis Expert (AISE) score. Red = official definition of sepsis. Blue = antibiotics. Black + red = cultures.    Around 4 pm on December 20, roughly 8 hr prior to any change in the SOFA score, the AISE score starts to increase. The top contributing factors were slight changes in heart rate, respiration, and temperature, given that the patient had surgery in the past 12hr with a contaminated wound and was on a mechanical ventilator. Close to midnight on December 21, other factors show abnormal changes. Five hours later, the patient met the Sepsis-3 definition of sepsis.

As recently published in the journal Critical Care Medicine, Nemati’s algorithm can predict sepsis onset – with some false alarms – 4, 8 even 12 hours ahead of time. No predictor is going to be perfect, Nemati says. The paper lays out specificity, sensitivity and accuracy under various timelines. They get to an AUROC (area under receiving operating characteristic) performance of 0.83 to 0.85, which this explainer web site rates as good (B), and is better than any other previous sepsis predictor. Read more

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

Five hot projects at Emory in 2017

CRISPR-Cas9 gene editing alleviates Huntington’s in mouse model

— Shi-Hua and Xiao-Jiang Li. This project is progressing, with funding from NCATS and a pig-oriented collaboration with partners in China.

Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)

— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.

Pilot study shows direct amygdala stimulation can enhance human memory

— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.

Immune responses of five returning travelers infected by Zika virus

— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.

Frog slime kills flu virus

— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.

Posted on by Quinn Eastman in Uncategorized Leave a comment
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