Interdisciplinary

Determining the kinetic parameters of CD39 – an enzyme with multiple substrates and products

Enzyme kinetics are often summarized in the form a Michaelis-Menten type model with parameters representing the maximum velocity of the reaction and concentration of substrate where the reaction is at half of the maximum velocity. Traditionally, these parameters can be experimentally determined by using linear regression between the reciprocal of the rate of reaction and reciprocal of the concentration of substrate (ex: Woolf-Augustinsson-Hofstee plot, Lineweaver-Burk plot). Implicit within these methods is the assumption that the enzyme of interest has a single substrate and single product. For enzymes such as CD39 with multiple substrates and products, these methods are likely inappropriate to accurately determine their Michaelis-Menten parameters. CD39 is an ectonucleotides that can hydrolyze ATP and ADP into ADP and AMP, respectively. In this study, we develop and analyze the behavior of a model of CD39 enzyme kinetics accounting for substrate competition. Simulations with our model using Michaelis-Menten parameters for CD39 ATPase and ADPase activity determined by the Woolf-Augustinsson-Hofstee method do not acutely explain kinetic data of ATP, ADP, and AMP concentrations reported by Kukukski et al. Using non-linear parameter estimation, we determine parameters for our CD39 model that accurately capture the kinetic data. Uncertainty in our model predictions is quantified using 95% confidence and prediction intervals.

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Unravelling the organizing principles of chromosomes in Vibrio cholera

jsadda

Bacteria have long been an important area of study. Working with the Freddolino Lab at the University of Michigan, this project focuses on “Unravelling the organizing principles of bacterial chromosomes.” We have studied Vibrio cholerae and their mechanisms of horizontal gene transfer, as about 1 in 100 attack and usurp genes from neighboring bacteria. We seek to understand how the PLE islands, which are normally dormant, become activated after injecting a phage, and looking at how this response is happening. PLE islands (phage-inducible chromosomal island-like elements) are widespread genomic islands which are useful to phage defense in Vibrio cholerae. In this study, we selected and regulated for the PLE island to be inserted and integrated into the superintegron region of the chromosome. We have measured the protein occupancy of the bacterial chromosome, and the data shows that there is a large amount of protein in the PLE island region, which signifies that it is probably silenced. Thus far, we believe that the Vibrio cholera has a “default off” system regarding protein expression, because we found that when the bacteria is infected with the phage, the PLE islands become active and silence the entire superrintegron region. We seek to understand the mechanism of this possible silencing, and whether there is a true “default off” system. There are many further directions to take this study, such as what happens if the PLE island is inserted outside of the superintegron. This research is important for the general field of bacteriology, along with the creation of novel medicines and antibiotic developments. If we can learn more about how gene transfer works and how genes uptaken are turned on and off, it can be effective in terms of antibiotic development and even preventing antibiotic resistance.

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Skeletal Growth Abnormalities in TSP1/2 Double-Knockout Mice

wesselse

Thrombospondins (TSPs) are proteins crucial to the development of bone. In mice with TSP1 and TSP2 knockout genotypes, referred to as double knock-outs (DKOs), exostoses, or bone growth outside of normal bone (particularly in soft tissues), and other abnormal skeletal growth phenotypes have been observed in the femoral-tibial joint, particularly the patellar region, specifically extending proximally in the quadricep tendon of older cohorts. To further explore these abnormalities, longitudinal radiographs of DKO mice and wild-types (WT), consisting of C57/Bl6 and functional WT were obtained. These X-ray images were taken of mice at 6 weeks, 9 weeks, 12 weeks, and 20 weeks old, in addition to images collected while conducting fracture research, which span from 13 to 94 weeks old. Mice from fracture surgeries consist of TSP1-null, TSP2-null, and CD47-null genotypes in addition to DKO and WT. All of the radiographs were then collated to compare development of these exostoses in relation to age and genotype, and semiquantitative analysis was performed to gain a better understanding of the severity of the observed abnormalities and determine the age at which they begin to develop. Overall, the current data leads us to conclude that exostoses is present by 24 weeks of age by radiography, with potential of developing even earlier.

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Percolation modeling

magizhao

Under Professor Ziff, our research group devised various methods of modeling types of percolation. These models were initially based in C and were unoptimized for large-scale run times. We rewrote these programs in C++ and implemented various algorithms and memory structures which helped reduce the runtime of the simulation algorithms. These small improvements yielded a boost in productivity as percolation models have to be run for hours on end to yield large enough outputs to provide viable research data. These small improvements are very important, as improvements in program runtime compounded over hours can have a huge impact and allow researchers to get more done in less time.

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Understanding the Social Determinants of Health in Medical and Surgical Care

irvingp

Although the term social determinants of health (SDOH) has been in the social science literature for several years now, SDOH are a relatively new concept in the field of medicine, and more specifically, in surgery. Researchers are just beginning to develop an understanding on how SDOH applies to surgical patients. This literature review aggregates known research on what has already been published on SDOH in surgical care by way of a systematic literature review. Multiple peer-reviewed journal aggregation sites, including PubMed, were used to gather our results. We are currently solidifying our search terms and will be embarking on the systematic literature review process. Finalizing our search terms has provided our team valuable information on how to better narrow our research question, but also it has allowed us to be thoughtful in methods and structure. As a literature review of this type has not been published prior, it is critical that the finalized search terms capture the pertinent articles discussing SDOH within surgical care. By better understanding how SDOH impacts surgical patients, clinicians and policy makers will have more tools in their toolbox to improve patient outcomes to those most affected.

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MetabolonR: An Intuitive R Shiny Application for Metabolomics Analysis

zyads

Zyad Shehadeh Pronouns: He/Him Research Mentor(s): Fadhl Alakwaa, Research investigator Research Mentor School/College/Department: Neurology Department, Michigan Medicine Presentation Date: Thursday, April 22, 2021 Session: Session 2 (11am – 11:50am) Breakout Room: Room 11 Presenter: 1 Event Link Abstract For privacy concerns this abstract cannot be published at this time. Authors: Zyad Shehadeh, Fadhl Alakwaa Research

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Realist Synthesis Review of Post-Overdose Interventions: Quick Response Teams

marydwan

Introduction: The opioid epidemic is a public health crisis that killed over 46,000 people in the United States in 2018. Quick Response Teams (QRTs) have been formed as a community response to prevent subsequent overdoses and decrease opioid-related deaths. Each QRT is composed of interdisciplinary team members that encompass public health officials, law enforcement, EMS, and peer-recovery supports. Though each QRT differs in team composition, the primary purpose of QRTs is to engage overdose survivors with recovery support and treatment services. However, limited research exists in evaluating QRTs and understanding their successes and failures in practice. Therefore, through a realist synthesis review, we seek to identify how different QRTs operate within their communities. Methods: Realist synthesis review is useful because it investigates how and why community-based interventions with multiple components work within the context of their environments. We will begin by conducting a literature search by generating search terms and questions central to the purpose of QRTs. We will then describe the different QRTs, identify what strategies lead to positive outcomes for QRTs, and in what contexts. Results: Through our literature review, we aim to understand how, why, and under what circumstances do QRTs work in engaging overdose survivors to prevent subsequent nonfatal and fatal overdoses. Conclusions: This realist review synthesis will aid community partners and policy-makers in understanding the contextual factors of how QRTs work and do not work to inform policy and future funding.

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Utilizing bioinformatics to decipher transcriptomic networks in bone and joint development

rbhakhri

To gain a comprehensive understanding of the functions of the myriad of cell clusters within the human body, many cell biology research studies utilize a process called single cell RNA sequencing to analyze the expression of different genes across cell clusters. In order to properly analyze the information gathered from the single cell RNA sequencing process, researchers must hire an outside body to run an analytical program to develop plots and graphs to visualize the data. Problems may arise regarding the accuracy of the developed plots and graphs because of their lack of understanding of the research project itself. This may lead to incorrect assumptions regarding the gene expression and, in turn, the function of different cell clusters. For the Hankenson Lab’s work on gene expression during bone and joint development, I personally ran the analysis and developed the plots for single cell RNA sequencing. The first half of the project entailed using the Single Cell Portal to track the different expression of genes within the WNT pathway to gain a biological understanding of the study. The second part focused on utilizing the Seurat library within R Studio to run multiple analyses on different data sets involved in the study. This involves normalizing the data set, identifying variable features within the data set, running a principal component analysis, and a non-linear dimensionality reduction. All these different programs allow for the development of heat maps, violin plots, and UMAPs. These plots will then be used by Hankenson Lab to further their study in identifying different cell clusters involved in bone and joint development as well as each cell cluster’s function.

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C++ Programming for Brain-Computer Interface Calibration Innovations

aravikum

The UM Direct Brain Interface Laboratory utilizes the classifier program included in the C++ distribution of the BCI2000 v3 to calibrate a P300 BCI to the brain activity of an individual. “BCI” refers to an electroencephalogram (EEG)-based brain-computer interface which allows participants with physical impairments to directly interact with a computer interface using their brains with minimal motor demands. In order to interact with this interface, participants use the P300 component of the event-related brain potential (ERP) (Farwell and Donchin 1988). Though the technology is promising, there are barriers to clinical implementation that the UM-DBI Laboratory aims to address. It is to aid the efficiency and effectiveness of UM-DBI studies that relevant C++ tool and usability additions are proposed. The P300 BCI Classifier calibrates via machine learning and this classifier program has been the point of focus for this project. Through the addition of various practical additions and refinements, the source code for the P300 BCI classifier may be better modified to provide more meaningful output, and allow for a more accessible and functional user interface when assessing output and input. These additions are made through careful coding and testing practice. The general methodology implemented in this research project includes assessing desired changes/additions to be made, understanding the context in which this modification should be implemented, and carefully testing input and output in order to assess adequate functionality (without any unintended consequences). This work is ongoing, and it is intended that all additions will provide added usability and functionality to UM-DBI laboratory researchers.

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