computational methods

The Role of the Intestinal Microbiota in Sepsis Mortality

Project Summary/Abstract Sepsis is a life-threatening condition characterized by a dysregulated host response to infection that can cause multi-organ damage and death. As the leading cause of in-hospital mortality, sepsis mortality rates reach up to 50%, and account for approximately 270,000 deaths and $38 billion annually in health care costs in the United States. Notably, patients with similar medical backgrounds can have vastly different sepsis outcomes— some survive with medical treatment while others die. The reasons for this dichotomy are unknown but is seen across all forms of bacterial bloodstream infections, is not specific to any strain-level differences in the infecting pathogen and cannot be explained by human genetic differences. Human microbiota studies suggest that gut microbial dysbiosis is associated with sepsis mortality and that these alterations influence gut barrier breakdown, leading to gram-negative bacteremia—one of the most common causes of sepsis and mortality. However, there are a lack of studies that investigate the causal role of the intestinal microbiota in sepsis mortality. This K08 proposal will elucidate the role of the intestinal microbiota in sepsis mortality. Utilizing the well- established murine model of sepsis by intraperitoneal injection of lipopolysaccharide (LPS), we combine microbiota taxonomic sequencing and metagenomics, advanced bioinformatic techniques and prediction modeling, with knowledge of mucosal immunity and germ-free mouse systems to characterize the microbiota features and members that correlate with, predict, and cause sepsis mortality. This proposal is organized into two specific aims: (1) identify baseline stool microbial features associated with and predictive of sepsis outcomes and (2) determine how colonization with immunostimulatory microbes heightens sepsis mortality. In this work, I will holistically characterize the host immunologic and microbiota features that are associated with and predictive of mortality and experimentally identify microbes and microbial pathways that cause death in our model. These findings will reveal new microbial and host biomarkers of sepsis mortality and identify novel targets for sepsis prevention and treatment to reduce the overall mortality rate of this deadly disease. My long-term goal is to become an independent physician-scientist who integrates cutting-edge computational methods with experimental biology to identify predictive biomarkers of disease onset and outcomes, investigate how they influence disease processes, and develop novel therapeutic and preventive strategies to improve patient care. This proposal details specific research aims and a structured career development and training plan that will allow me to acquire focused, in-depth and multidisciplinary training under the guidance of an internationally recognized team of experts in clinical infectious diseases, host-microbiota interactions, immunology, immunometabolism, and computational biology. The knowledge generated will address the fundamental role of the microbiota in sepsis outcomes and inform future preventative and therapeutic strategies that will lower the sepsis mortality rate worldwide.

Lifelong Learning AI via neuro inspired solutions

AI embedded in real systems, such as in satellites, robots and other autonomous devices, must make fast, safe decisions even when the environment changes, or under limitations on the available power; to do so, such systems must be adaptive in real time. To date, edge computing has no real adaptivity – rather the AI must be trained in advance, typically on a large dataset with much computational power needed; once fielded, the AI is frozen: It is unable to use its experience to operate if environment proves outside its training or to improve its expertise; and worse, since datasets cannot cover all possible real-world situations, systems with such frozen intelligent control are likely to fail. Lifelong Learning is the cutting edge of artificial intelligence - encompassing computational methods that allow systems to learn in runtime and incorporate learning for application in new, unanticipated situations. Until recently, this sort of computation has been found exclusively in nature; thus, Lifelong Learning looks to nature, and in particular neuroscience, for its underlying principles and mechanisms and then translates them to this new technology. Our presentation will introduce a number of state-of-the-art approaches to achieve AI adaptive learning, including from the DARPA’s L2M program and subsequent developments. Many environments are affected by temporal changes, such as the time of day, week, season, etc. A way to create adaptive systems which are both small and robust is by making them aware of time and able to comprehend temporal patterns in the environment. We will describe our current research in temporal AI, while also considering power constraints.

Machine learning for measuring and modeling the motor system

If we can make computers play chess, why can't we make them see?

If we can make computers play chess and even Jeopardy and Go, then why can't we make them see like us? How does our brain solve the problem of seeing? I will describe some of our recent insights into understanding object recognition in the brain using behavioral, neuronal and computational methods.

A Changing View of Vision: From Molecules to Behavior in Zebrafish

All sensory perception and every coordinated movement, as well as feelings, memories and motivation, arise from the bustling activity of many millions of interconnected cells in the brain. The ultimate function of this elaborate network is to generate behavior. We use zebrafish as our experimental model, employing a diverse array of molecular, genetic, optical, connectomic, behavioral and computational approaches. The goal of our research is to understand how neuronal circuits integrate sensory inputs and internal state and convert this information into behavioral responses.

Neural circuit parameter variability, robustness, and homeostasis

Neurons and neural circuits can produce stereotyped and reliable output activity on the basis of highly variable cellular, synaptic, and circuit properties. This is crucial for proper nervous system function throughout an animal’s life in the face of growth, perturbations, and molecular turnover. But how can reliable output arise from neurons and synapses whose parameter vary between individuals in a population, and within an individual over time? I will review how a combination of experimental and computational methods can be used to examine how neuron and network function depends on the underlying parameters, such as neuronal membrane conductances and synaptic strengths. Within the high-dimensional parameter space of a neural system, the subset of parameter combinations that produce biologically functional neuron or circuit activity is captured by the notion of a ‘solution space’. I will describe solution space structures determined from electrophysiology data, ion channel expression levels across populations of neurons and animals, and computational parameter space explorations. A key finding centers on experimental and computational evidence for parameter correlations that give structure to solution spaces. Computational modeling suggests that such parameter correlations can be beneficial for constraining neuron and circuit properties to functional regimes, while experimental results indicate that neural circuits may have evolved to implement some of these beneficial parameter correlations at the cellular level. Finally, I will review modeling work and experiments that seek to illuminate how neural systems can homeostatically navigate their parameter spaces to stably remain within their solution space and reliably produce functional output, or to return to their solution space after perturbations that temporarily disrupt proper neuron or network function.

Multiplexing and Demultiplexing with cerebral organoids for neurological diseases