Nicolas Bazan, MD, PhD, Boyd Professor, Professor of Neurology and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience, Neurology, and Neurosurgery, discovered this novel therapeutic strategy for ischemic stroke using an experimental model.

During an ischemic stroke, signals are produced from arriving blood white cells and primary brain immune cells called microglia that cause neuroinflammation leading to a buildup of chemicals that harm the brain. Platelet-activating factor (PAF) accumulates, and inhibition of this process plays a critical role in neuronal survival. Dr. Bazan’s earlier studies also showed that in addition to its anti-inflammatory properties, DHA, an essential omega-3 fatty acid, stimulates the production of Neuroprotectin D1 (NPD1), a molecule that protects brain cells and promotes their survival. One complicating factor in developing neuroprotective strategies for stroke are the multiple routes and events that occur in the brain during a stroke, which has been approached mainly by monotherapeutic agents that were mostly unsuccessful.

Because no single therapy has proven effective in treating the complexity of stroke, the team aimed at two different events — blocking pro-inflammatory platelet-activating factor receptors (PAF-R) and activating cell-survival pathways. They found that treatment with LAU-0901, a synthetic molecule discovered in the Bazan lab that blocks pro-inflammatory platelet-activating factor, plus aspirin-triggered NPD1 (AT-NPD1) reduced the size of the damaged area in the brain, initiated repair mechanisms, and remarkably improved behavioral recovery.

Total lesion volumes were reduced with LAU‑0901 plus NPD1 by 62% and LAU‑0901 plus AT‑NPD1 by 90%. Combinatory treatment with LAU‑0901 plus AT‑NPD1 improved the behavioral score up to 54% on day three. LAU‑0901 and LAU‑0901 plus DHA decreased the production of 12‑hydroxyeicosatetraenoic acid, a pro‑inflammatory mediator.

“The biological activity of LAU-0901 and AT-NPD1 is due to specific activation or modulation of signaling pathways associated with the immune system, inflammation, cell survival, and cell-cell interactions,” notes Dr. Bazan. “These findings provide a major conceptual advance of broad therapeutic relevance for cell survival, brain function and, particularly, stroke and neurodegenerative diseases.”

“We discovered that these novel molecules promote neuronal cell survival with important anti-inflammatory activity,” explains Dr. Belayev. “This combinatorial therapy may hold promise for future therapeutic development against ischemic stroke.”

According to the Centers for Disease Control and Prevention, someone in the United States has a stroke every 40 seconds. Every 4 minutes, someone dies of stroke. Every year, more than 795,000 people in the United States have a stroke. About 87% of all strokes are ischemic strokes, in which blood flow to the brain is blocked. Stroke-related costs in the United States came to nearly $46 billion between 2014 and 2015. This total includes the cost of health care services, medicines to treat stroke, and missed days of work. Stroke is a leading cause of serious long-term disability. Stroke reduces mobility in more than half of stroke survivors age 65 and over.

Other LSU Health authors include Drs. Pranab K. Mukherjee, Eric J. Knott and Reinaldo B. Oria, along with Larissa Khoutorova and graduate students Madigan M. Reid and Cassia R. Roque. Dr. Andre Obenaus, Lawrence Nguyen, and Jeong Bin Lee from the University of California Irvine School of Medicine, and Dr. Nicos A. Petasis of the University of Southern California, are also co-authors.

This research was supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and Brazilian CAPES.

A study, published today in the journal Cell Reports, describes how the new UCLA-developed device, called MitoPunch, transfers mitochondria into 100,000 or more recipient cells simultaneously, which is a significant improvement from existing mitochondrial transfer technologies. The device is part of the continued effort by UCLA scientists to understand mutations in mitochondrial DNA by developing controlled, manipulative approaches that improve the function of human cells or model human mitochondrial diseases better.

“The ability to generate cells with desired mitochondrial DNA sequences is powerful for studying how genomes in the mitochondria and nucleus interact to regulate cell functions, which can be critical for understanding and potentially treating diseases in patients,” said Alexander Sercel, a doctoral candidate at the David Geffen School of Medicine at UCLA and co-first author of the study.

Mitochondria, often known as the ‘powerplant’ of a cell, are inherited from a person’s mother. They rely on the integrity of the mitochondrial DNA to perform their essential functions. Inherited or acquired mutations of the mitochondrial DNA can significantly impair energy production and may result in debilitating diseases.

Technologies for manipulating mitochondrial DNA lag behind advances for manipulating DNA in the nucleus of a cell and could potentially help scientists develop disease models and regenerative therapies for disorders caused by these mutations. Current approaches, however, are limited and complex, and for the most part can only deliver mitochondria with desired mitochondrial DNA sequences into a limited number and variety of cells.

The MitoPunch device is simple to operate and allows for consistent mitochondrial transfers from a wide range of mitochondria isolated from different donor cell types into a multitude of recipient cell types, even for non-human species, including for cells isolated from mice.

“What sets MitoPunch apart from other technologies is an ability to engineer non-immortal, non-malignant cells, such as human skin cells, to generate unique mitochondrial DNA-nuclear genome combinations,” said co-first author Alexander Patananan, a UCLA postdoctoral scholar, who now works at Amgen. “This advance allowed us to study the impact of specific mitochondrial DNA sequences on cell functions by also enabling the reprogramming of these cells into induced pluripotent stem cells that were then differentiated into functioning fat, cartilage, and bone cells.”

MitoPunch was created in the labs of Dr. Michael Teitell, director of the Jonsson Cancer Center and professor of pathology and laboratory medicine, Pei-Yu (Eric) Chiou, professor of mechanical and aerospace engineering at the UCLA Henry Samueli School of Engineering and Applied Science, and Ting-Hsiang Wu, from ImmunityBio, Inc., Culver City, CA.

MitoPunch builds upon prior technology and a device called a photothermal nanoblade, which the team developed in 2016. But unlike the photothermal nanoblade, which requires sophisticated lasers and optical systems to operate, MitoPunch works by using pressure to propel an isolated mitochondrial suspension through a porous membrane coated with cells. The researchers propose that this applied pressure gradient creates the ability to puncture cell membranes at discrete locations, allowing the mitochondria direct entry into recipient cells, followed by cell membrane repair.

“We knew when we first created the photothermal nanoblade that we would need a higher-throughput, simpler to use system that is more accessible for other laboratories to assemble and operate,” said Teitell, who is also the chief of the division of pediatric and developmental pathology and a member of the UCLA Broad Stem Cell Research Center. “This new device is very efficient and allows researchers to study the mitochondrial genome in a simple way — swapping it from one cell into another — which can be used to uncover the basic biology that governs a broad range of cell functions and could, one day, offer hope for treating mitochondrial DNA diseases.”

The research was supported by the National Institutes of Health, by the American Heart Association and by the Human Performance and Biosystems division of the US Air Force Office of Scientific Research.

Christine Baugh, PhD, MPH, assistant professor of medicine at the University of Colorado School of Medicine and member of the CU Center for Bioethics and Humanities, is the corresponding author of the article, “Accuracy of US College Football Players’ Estimates of Their Risk of Concussion or Injury.”

Baugh and co-authors report on survey results of 296 college football players from four teams in the Power 5 Conferences of the National Collegiate Athletic Association. Athletes were surveyed in 2017. The researchers found that between 43 percent and 91 percent of respondents underestimated their risk of injury and between 42 percent and 63 percent underestimated their risk of concussion.

To measure the accuracy of football players’ risk estimations, the researchers modeled individual athletes’ probabilities of sustaining a concussion or injury and compared model estimates to athlete perceptions. While recognizing that many people underestimate health risks, the authors point out that the risks college football athletes face may be more severe or debilitating than those faced by many in the general population. Given this elevated risk profile, they say it is concerning that athletes tend to underestimate the likelihood of these risks. These results raise questions about informed consent and how much risk should be acceptable in the context of a game, Baugh and her co-authors write.

“That athletes underestimated their risk of concussion and injury in this study raises important ethical considerations,” Baugh and her colleagues write. “What is the threshold for college athletes to be sufficiently informed of the risks and benefits of football to make decisions that align with their values and preferences?”

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These learning components will permit autonomous agents to reason and adapt to changing battlefield conditions, said Army researcher Dr. Alec Koppel from the U.S. Army Combat Capabilities Development Command, now known as DEVCOM, Army Research Laboratory.

The underlying adaptation and re-planning mechanism consists of reinforcement learning-based policies. Making these policies efficiently obtainable is critical to making the MDO operating concept a reality, he said.

According to Koppel, policy gradient methods in reinforcement learning are the foundation for scalable algorithms for continuous spaces, but existing techniques cannot incorporate broader decision-making goals such as risk sensitivity, safety constraints, exploration and divergence to a prior.

Designing autonomous behaviors when the relationship between dynamics and goals are complex may be addressed with reinforcement learning, which has gained attention recently for solving previously intractable tasks such as strategy games like go, chess and videogames such as Atari and Starcraft II, Koppel said.

Prevailing practice, unfortunately, demands astronomical sample complexity, such as thousands of years of simulated gameplay, he said. This sample complexity renders many common training mechanisms inapplicable to data-starved settings required by MDO context for the Next-Generation Combat Vehicle, or NGCV.

“To facilitate reinforcement learning for MDO and NGCV, training mechanisms must improve sample efficiency and reliability in continuous spaces,” Koppel said. “Through the generalization of existing policy search schemes to general utilities, we take a step towards breaking existing sample efficiency barriers of prevailing practice in reinforcement learning.”

Koppel and his research team developed new policy search schemes for general utilities, whose sample complexity is also established. They observed that the resulting policy search schemes reduce the volatility of reward accumulation, yield efficient exploration of an unknown domains and a mechanism for incorporating prior experience.

“This research contributes an augmentation of the classical Policy Gradient Theorem in reinforcement learning,” Koppel said. “It presents new policy search schemes for general utilities, whose sample complexity is also established. These innovations are impactful to the U.S. Army through their enabling of reinforcement learning objectives beyond the standard cumulative return, such as risk sensitivity, safety constraints, exploration and divergence to a prior.”

Notably, in the context of ground robots, he said, data is costly to acquire.

“Reducing the volatility of reward accumulation, ensuring one explores an unknown domain in an efficient manner, or incorporating prior experience, all contribute towards breaking existing sample efficiency barriers of prevailing practice in reinforcement learning by alleviating the amount of random sampling one requires in order to complete policy optimization,” Koppel said.

The future of this research is very bright, and Koppel has dedicated his efforts towards making his findings applicable for innovative technology for Soldiers on the battlefield.

“I am optimistic that reinforcement-learning equipped autonomous robots will be able to assist the warfighter in exploration, reconnaissance and risk assessment on the future battlefield,” Koppel said. “That this vision is made a reality is essential to what motivates which research problems I dedicate my efforts.”

The next step for this research is to incorporate the broader decision-making goals enabled by general utilities in reinforcement learning into multi-agent settings and investigate how interactive settings between reinforcement learning agents give rise to synergistic and antagonistic reasoning among teams.

According to Koppel, the technology that results from this research will be capable of reasoning under uncertainty in team scenarios.