This popular series features presentations by and for the Interfaces community served alongside lunch (except, of course, during COVID). Each session is usually about an hour long and provides for 2 speakers to present for about 20 minutes each, followed by a short Q&A discussion. The most current presentations are listed below and provide an abstract for each speaker's talk. Upcoming presentations are announced on the home page. If you have any questions about, or ideas for, the Student Seminars please email interfaces@ucsd.edu.

 

Tue, May 17 2022
  • 12:30 pm

    Andrew Nguyen

    Developing a Predictive Model of Circadian Effects on Synaptic Plasticity

    Event Location: UC San Diego

    Andrew Nguyen, Mechanical and Aerospace Engineering Ph.D. Program, UC San Diego

    Advisor: Professor Padmini Rangamani, Mechanical and Aerospace Engineering

    Synaptic plasticity is important for learning and memory. With increasing evidence linking sleep states to changes in synaptic strength, an emerging view is that sleep promotes learning and memory, by facilitating experience-induced synaptic plasticity. Adenosine, a neuromodulator often associated with the regulation of sleep, and its receptors (A1R and A2AR) have been found to be responsible for the potentiation or inhibition of synaptic transmission in the context of calcium signaling in neurons. In my work, I hypothesize that the interactions between adenosine and various calcium-mediated signaling pathways, such as glutamate-mediated calcium signaling, will give rise to the modulation of synaptic plasticity in neurons. To investigate this hypothesis I have been developing a quantitative model of signaling crosstalk between adenosine receptors and Glutamate receptors (mGluR5) to capture the connection between the molecular machinery associated with circadian adenosine to the molecular machinery associated with synaptic plasticity.

  • 12:01 pm

    Dr. Zeinab Jahed

    Nanoscale Electronics for Sensing and Manipulation of Single Cells with Applications in Neuronal, Cardiac and Biofilm Electrophysiology

    Event Location: UC San Diego

    Assistant Professor of Nanoengineering, Affiliate Professor of Nanoengineering, UC San Diego

     

    The goal of our lab at the University of California, San Diego (called the Bio-Nano-Electronics or BioNE Lab) is to “Engineer nanoscale electronics for higher throughput cellular- and molecular-scale sensing, to accelerate scientific discoveries related to human health and disease”.  To design more intelligent nano-electronics we first carefully characterize the complex nano-bio interface. Next, we use this knowledge to design our nano-electronics to be higher throughput, accurate, sensitive, with minimal perturbations to the biological system. Finally, with confidence in our biological read-outs from these high-throughput tools, there is a need to develop algorithms that can “learn” from our big dataset to answer fundamental biological questions. In this seminar I will present our recent advances using the above approach to design a nanoscale platform for recording electrical signals in parallel from hundreds to thousands of cardiac cells for cardiotoxicity screening. I will also briefly discuss ongoing efforts in our lab to utilize our platform for neuronal and biofilm electrophysiology. 

Tue, May 3 2022
  • 12:01 pm

    Leigh-Ana Rossitto

    Stool Metaproteomics to Uncover Gut Microbial Effectors in Disease: Past, Present, & Future

    Event Location: UC San Diego

    Metaproteomics is a mass spectrometry method to unbiasedly analyze the proteins expressed by a community of organisms. Stool metaproteomics is an emerging technique for the analysis of microbial protein abundance in human feces. Up to half of the dry solids in stool are bacterial biomass, almost exclusively from the digestive tract, making stool ideal biomaterial to analyze gut microbial proteins, as well as host and dietary proteins and other biomolecules. A recent study from the Gonzalez Lab employed stool metaproteomics to study inflammatory bowel disease, revealing that Bacteroides spp. proteases are elevated in disease and colitis phenotypes can be rescued with protease inhibitor treatment. In this talk, I will be discussing recent advances in stool metaproteomics, including high-throughput workflows, database development, and bioinformatic pipelines. I will also describe how I am addressing persistent limitations in stool metaproteomics and how I am applying this methodology to uncover protein effectors in the gut-brain axis in health and disease. 

Mon, Feb 28 2022
  • 4:30 pm

    Abigail Teitgen

    2-deoxy-ATP improves systolic ventricular function in failing hearts by synergistic effects on calcium handling, crossbridge cycling, and recruitment of myosin from the super-relaxed state

    Event Location: UC San Diego

    Heart failure remains a significant cause of morbidity, mortality, and medical costs. 2-deoxy-ATP (dATP), a novel heart failure therapeutic, has been shown to improve contractile function without impairing relaxation. Previous studies in our group have shown that elevated dATP increases the rate of crossbridge binding cycling and the rate of calcium transient decay. However, the precise molecular mechanisms of these effects and how therapeutic responses are achieved when dATP is only a small fraction of the total ATP pool are unknown. We used multiscale computational modeling to integrate a filament-scale model of acto-myosin interactions, whole myocyte model, organ scale model of biventricular mechanoenergetics, and whole body circulatory model to predict the effects of dATP on ventricular mechanics in normal and heart failure conditions. We discovered synergistic interactions between calcium dynamics and force development that leads to improvements in myocyte contractility and lusitropy. Simulations also predicted that increased transition out of the super-relaxed state of myosin with elevated dATP can explain the large increases in force observed at low percentages of dATP. We further showed that this effect likely depends on both nearest neighbor cooperativity and thick filament mechanosensing. We predicted improvements in ventricular function consistent with experimental data in both healthy and failing conditions, with no additional impairment of metabolic state. Ventricular function was improved to a greater degree in failure than in healthy conditions, due at least in part to improved energy efficiency with elevated dATP.

  • 4:00 pm

    Miriam Bell

    Crosstalk between signaling and trafficking of AMPAR during synaptic plasticity

    Event Location: UC San Diego

    AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, is a receptor concentrated at the postsynaptic density (PSD) of dendritic spines. AMPAR is often used as a readout for synaptic plasticity since increased AMPAR density at the PSD leads to a stronger synaptic response to a stimulus while decreased AMPAR density leads to a weaker response. Changes in AMPAR density during synaptic plasticity involve numerous complex signaling pathways, many of which have been studied both experimentally and computationally. However, there are still open questions regarding how the dynamics of several key components upstream of AMPAR, including CaMKII and phosphatase dynamics, influence the mechanisms and dynamics of AMPAR trafficking. Here we construct both a deterministic compartmental ordinary differential equations model and a deterministic reaction-diffusion model of the simplified signaling network underlying AMPAR dynamics during synaptic plasticity to probe how upstream kinase and phosphatase dynamics influence AMPAR dynamics and trafficking. We find that key signaling components and trafficking mechanisms act over different timescales to modulate AMPAR density at the PSD. In particular, AMPAR temporal dynamics show two timescales associated with endo/exocytosis and total available AMPAR sources, while there is a strong relationship between total AMPAR number at the PSD and the spine volume to surface area ratio.

Mon, Feb 7 2022
  • 4:00 pm

    Stephanie Sincomb

    A one-dimensional model for the pulsating flow of cerebrospinal fluid in the spinal canal

    Event Location: UC San Diego

    The monitoring of intracranial pressure (ICP) fluctuations, which is needed in the context of a number of neurological diseases, requires the insertion of pressure sensors, an invasive procedure with considerable risk factors. ICP fluctuations drive the wave-like pulsatile motion  of  cerebrospinal  fluid  (CSF)  along  the  compliant  spinal  canal.  Systematically derived simplified models relating the ICP fluctuations with the resulting CSF flow rate can be useful in enabling indirect evaluations of the former from non-invasive magnetic resonance imaging (MRI) measurements of the latter. As a preliminary step in enabling these  predictive  efforts,  a  model  is  developed for  the  pulsating  viscous  motion of  CSF  in  the  spinal  canal,  assumed  to  be  a  linearly  elastic  compliant  tube  of  slowly varying section, with a Darcy pressure-loss term included to model the fluid resistance introduced  by  the  trabeculae,  which  are  thin  collagen-reinforced  columns  that  forma  weblike  structure  stretching  across  the  subarachnoid  space  (SSAS).  Use  of  Fourier-series  expansions  enables  predictions  of  CSF  flow  rate  for  realistic  anharmonic  ICP fluctuations. The flow rate predicted using a representative ICP waveform together with a realistic canal anatomy is seen to compare favorably with in-vivo phase-contrast MRI measurements at multiple sections along the spinal canal. The results indicate that the proposed model, involving a limited number of parameters, can serve as a basis for future quantitative analyses targeting predictions of ICP temporal fluctuations based on MRI measurements of spinal-canal anatomy and CSF flow rate.

Mon, Jan 24 2022
  • 11:00 am

    Emma Boyd

    Characterizing white matter cerebrovascular physiology in healthy aging using velocity-selective Arterial Spin Labeling MRI

    Event Location: UC San Diego

    Mounting evidence suggests cerebrovascular dysfunction plays an important mechanistic role in the development of Alzheimer’s disease (AD), and that cerebral white matter (WM) is especially vulnerable to the effects of microvascular dysfunction. Arterial Spin Labeling (ASL), a class of Magnetic Resonance Imaging (MRI) techniques, is a popular method for assessing cerebral hemodynamics due to its non-invasive nature. However, inaccurate ASL methodology has prevented the systematic characterization of WM microvascular health and hemodynamics, even across healthy aging, thus hindering our understanding of cerebrovascular contributions to AD development. My project investigates whether velocity-selective ASL (VSASL) is a more robust measure of WM cerebral blood flow (CBF) than conventional techniques and can better capture age-related change in CBF.

  • 10:30 am

    Sean Reardon

    Consequences of phosphorylation and acetylation of mitochondrial transcription factor A to DNA packaging, transcription initiation and processivity

    Event Location: UC San Diego

    Mitochondrial transcription factor A (TFAM) plays important roles in mitochondrial DNA (mtDNA) compaction, transcription initiation, and regulation of processes like transcription and replication processivity. Possible modes of local regulation of TFAM function within the mitochondrial matrix include phosphorylation by protein kinase A (PKA) and non-enzymatic acetylation by acetyl-CoA. Here we present that DNA-bound TFAM is less susceptible to these modifications. We confirm that phosphorylated or acetylated TFAM compact circular double-stranded DNA just as well as unmodified TFAM and provide an in-depth analysis of acetylated sites on TFAM. We show that both modifications of TFAM increase the processivity of mitochondrial RNA polymerase during transcription through TFAM-imposed barriers on DNA, but that each version of modified TFAM retains its full activity in transcription initiation. We conclude that TFAM phosphorylation by PKA and non-enzymatic acetylation are unlikely to occur at the mtDNA and that modified free TFAM retains its vital functionalities like compaction and transcription initiation while allowing transcription processivity enhancement.

Mon, Jan 10 2022
  • 11:00 am

    Nathaniel Linden

    Bayesian Parameter Estimation from Sparse and Noisy Measurement Data in Systems Biology

    Event Location: UC San Diego

    I propose a Bayesian parameter estimation framework to facilitate model calibration and uncertainty analysis for predictive models of biological systems. Many of these models are nonlinear differential equations that characterize the dynamics of the relevant biochemical species. System biologists need to estimate many free parameters from sparse and noisy experimental data to calibrate these models. Despite the uncertainties associated with this data, systems biologists directly fit the free parameters, typically ignoring any uncertainty altogether. My work moves past this traditional model-fitting paradigm by adapting an approximate marginal Markov chain Monte Carlo (MCMC) method for Bayesian parameter estimation. I find that this method can recover the posterior parameter distribution from experimental data for a well-known biological system, the mitogen-activated protein kinase (MAPK) signaling pathway. This work introduces a new modeling paradigm that bridges the gap between standard systems biology modeling practices and rigorous uncertainty quantification.

  • 10:30 am

    Joseph Sawires

    Design and Synthesis of Novel Agonists for the Treatment of Gut Disorders

    Event Location: UC San Diego

    AMP-Kinase (AMPK) is the master sensor for the organism’s metabolism and energy, and has many diseases linked to both its activation and inhibition, including cancer, gastrointestinal, heart, and even neurodegenerative diseases. My main research project involves designing and synthesizing potent activators selective for α1β1γ1 and α2β1γ1 isoforms. The gene encoding the β1 subunit of AMPK, PRKAB1, was first discovered as a viable drug target for inflammatory bowel disease (IBD) by our collaborators, the Ghosh lab (UCSD School of Medicine). Using Boolean implication networks to analyze gene clusters, the continuum states of IBD-related diseases were more easily differentiated between disease and health states of patients. Recent efforts in medicinal chemistry in collaboration with the Ghosh lab has opened up some exciting new opportunities in drug design to target proteins such as APMK. Using in silico docking experiments, along with previously published ligand-protein pair co-crystal structures as references, we were able to create a robust model for predicting the binding affinity and selectivity for novel β1 selective agonists. I have established the chemistry and methodology for synthesizing these agonists, and intend to both synthesize and test (in vitro) these novel β1 selective agonists designed in silico.

Mon, Jan 3 2022
  • 11:00 am

    Marcus Hock

    Multiscale Molecular Modeling of dATP and DCM Mutations

    Event Location: UC San Diego

    Dilated and hypertrophic cardiomyopathies (DCM and HCM) affect 1 in 500 Americans. Current treatments only slow disease progression without treating underlying mechanisms; therefore, novel therapeutics are needed to treat HCM and DCM. 2’-deoxy-adeninetripohsphate is a naturally occurring myosin activator, and proposed heart failure and DCM therapeutic. In this work, I use molecular simulations to understand the mechanism by which dATP increase cardiac contractile force and function. Specifically, I have used molecular dynamics simulations to build Markov models of protein kinetics, that can be used with Brownian dynamics simulations to understand actin-myosin kinetics. Through this work, have shown that dATP functions by increasing the association rate of myosin to actin in the pre-powerstroke state. The DCM mutations A223T and S532P found cardiac myosin heavy chain were also modeled with this framework and found to have diverging effects on the association rate of myosin to actin. Specifically, dATP, S532P and A223T have 5.3-, 3.0-, and 0.56-time fold changes to the association rate respectively. These simulations help to predict organ level function, and lead to improved mechanistic understandings of actin-myosin interactions.

  • 10:30 am

    Kristen Garcia

    Estrogens Effect on Right Ventricular Remodeling in Pulmonary Arterial Hypertension

    Event Location: UC San Diego

    Pulmonary arterial hypertension (PAH) is a life-threatening progressive disease that is  characterized by pulmonary vascular remodeling and is represented by narrowing of blood  vessels in the lungs. PAH effects females four times more likely than males, specifically females  between the ages of 30-60 years old, leading to an interesting paradox known as the estrogen  puzzle. Past research has resulted in contradicting conclusions; some of which show a  protective effect of estrogen on PAH versus others showing a disease promoting effect. It is  known that right ventricular (RV) function and morphology are important indicators of the  severity of PAH. I am interested in determining the role that estrogen plays on the right  ventricle during the progression of PAH. I hypothesize that estrogen plays a major role in the  remodeling of the RV leading to an overall protective effect against right heart failure. I aim to  quantify the hemodynamics of the right ventricle throughout the progression of PAH using a rat  model and to identify the sex dependent effects of estrogen in the remodeling and mechanics  of the RV. After the induction of PAH using a Sugen-Hypoxia protocol, terminal procedures are  conducted, in which in vivo blood pressure-volume relationships are measured, with the goal of  investigating changes due to pressure overload. I am currently focusing on these pressure volume loops for each subset of animals with the goal of finding patterns to describe the  differences in the hearts function for males, non-ovariectomized females, and ovariectomized  females. I am looking at the PV loop as a whole, the slope of the isovolumic contraction and  relaxation phases, and am attempting to determine if we can expect to see a specific range of  values for the PV curves for a given group. My future plans are to dive more into the estrogen  component of RV remodeling in PAH and relate estrogen levels to PV loops and overall heart  function.