Health Sciences

Utilizing bioinformatics to decipher transcriptomic networks in bone and joint development

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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The Effectiveness of Therapeutic Anticoagulation after Deep Vein Thrombosis in Critical COVID-19 Patients

atekumul

The novel coronavirus SARS-CoV-2 (COVID-19) is rapidly spreading around the world with 119,220,681 confirmed cases as of March 14, 2021. As a result of COVID-19, a significant proportion of patients experienced reduced oxygenation and subsequent hypoxia which have prompted fluctuations in molecular and cell signaling pathways. Recent COVID-19 studies indicate that there is a high cumulative incidence of venous thromboembolism (VTE) in critically ill COVID-19 patients. Due to this prevalence, thrombosis prophylaxis is suggested as the standard of care for VTEs in patients. Thrombosis prophylaxis is instituted if the risk of thrombotic complications is high. However, there have been instances where VTE developed despite the use of thromboprophylaxis. These results highlight that VTE prophylaxis treatment may not be adequate for severe COVID-19 cases. This study will investigate the efficacy of therapeutic anticoagulation after deep vein thrombosis or pulmonary embolism is identified in COVID19 patients in Intensive Care. Data mining approaches and manual chart review were used to retrospectively collect granular clinical data for 1065 adult patients (=18 years) with severe COVID-19 admitted to the University of Michigan. We hope to see a negative association between the administration of therapeutic anticoagulation and the proportions of patients who experienced DVT during their hospital admission versus patients who did not.

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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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Computational Approach to Determining the Properties of Rhodamine-Based pH Sensitive Fluorophores used in Diverse Biomedical Applications

woodbuse

Fluorescent probes are excitable by specific frequencies of light and emit bright visible electromagnetic radiation upon their relaxation to a ground state energy. These probes can be chemically modified to tune their properties and impart specific reactivity. In the biomedical sciences, fluorescent probes are widely used in applications including determining the presence and quantity of a specific protein, determining enzyme activity in real-time assays, determining gene expression, and elucidating physicochemical conditions both intracellularly and extracellularly. However, current probes present a significantly high cost, modest fluorescent intensity, and lack chemical functionality for important uses such as site-specific protein labelling, orthogonal click chemistry, and for use in biomaterial constructs. In this study, we aimed at designing high fluorescent yield, tunable pH-sensitive probes which could be synthesized using inexpensive common reagents to illuminate microenvironmental changes in pH, a critical factor in biologic processes including endosomal uptake, lysosome processing, and extracellular matrix resorption.

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Active for Life with chronic obstructive pulmonary disease (COPD)

vharish

COPD is a chronic lung-based disease that blocks airflow making it harder to breathe. Studies have also shown that muscle strength in people with COPD is lower than that of age-matched individuals without COPD. The decrease in muscle strength can impede individuals from partaking in physical activity (PA) which has been associated with a slower decline in lung function and reduced hospitalization in people with COPD. Traditional interventions for COPD have focused on moderate to vigorous physical activity (MVPA) but the Active For Life: COPD intervention program designed by Dr. Larson is novel in its emphasis on light physical activity (LPA) and decreased sedentary time. Participants were recruited and sorted into control or experimental groups, followed by 10 weeks of training classes for both groups. The experimental group did functional circuit training and learned self-regulation strategies. The control group did chair exercises and guided imagery for relaxation and health education. Both groups came back at 2 months, 3 months, 6 months, and 12 months to have various measures of strength, endurance, and physical activity tested. A study was undertaken to see the impact of this intervention on isometric strength measures through knee flexors and extensors. Due to the study being ongoing and having a partially blind setup in order to minimize bias, blinded group interim analysis will be analyzed. If this intervention is successful, in increasing physical activity and muscle strength it could change general physical activity guidelines for people with COPD shifting away from MVPA and towards LPA.

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Active for Life with chronic obstructive pulmonary disease (COPD): Physical activity and anxiety

malaikap

Individuals with Chronic Obstructive Pulmonary Disease (COPD), tend to live a sedentary life which can increase the risk of mortality and heighten symptoms of COPD. In attempting to prevent this sedentary lifestyle in COPD patients, many exercise programs focus on vigorous physical activity which is not sustainable in the long run. The Principal Investigator of this study, Janet Larson, developed an exercise program, called Active Life. The Active Life program emphasizes light physical activity for patients with COPD. The study conducted is a randomized controlled clinical trial where COPD participants are randomly placed into two groups, the Active for Life intervention and the control intervention. The study is conducted to determine if the Active Life intervention is an effective program in promoting physical activity in COPD patients. The participants in the Active Life intervention complete an exercise program including functional circuit training (FCT), health education, and self-regulation strategies. The participants in the control group complete an exercise program that includes chair exercises, relaxation promotion, and health education. The participants complete 10 weeks of lab-based exercise, then a one-year follow-up which measures activity levels and home-based exercises. Through the data collected from the Active Life study, I decided to look into the effect that physical activity has on anxiety levels in patients with moderate to severe COPD. In the study, data was collected on anxiety levels throughout the study as well as different measurements of physical fitness and activity. I examined the long-term (52-week post-intervention) impact of light physical activity on self-reported anxiety compared to the control group.

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Mitochondrial trafficking is altered in insulin receptor knockout dorsal root ganglion sensory neurons

ecbersch

Diabetes is a global epidemic that affects 463 million individuals. Approximately 50% of diabetic patients develop a serious complication called diabetic neuropathy (DN) that can also develop in patients with pre-diabetes and obesity. DN is characterized by tingling or burning, sharp pains, and eventual loss of sensation in the hands or feet that results from significant nerve damage. Despite the severity of DN, there are no disease-modifying treatments for DN associated with type 2 diabetes, prediabetes, or obesity. Recent studies indicate that dyslipidemia correlates with DN, suggesting that fatty acids may contribute to DN onset or progression. Dorsal root ganglion (DRG) neurons are a cluster of primary sensory neurons located just outside the spinal cord that extend axons into the nerves and transmit sensory information from the peripheral nervous system to the central nervous system. DRG neurons depend on mitochondrial trafficking and function to produce ATP in the axons, and it has been reported that insulin signaling regulates mitochondrial function. In this study, we sought to determine whether the presence of the insulin receptor regulates axonal mitochondrial trafficking in fatty acid-treated DRG neurons. DRG neurons from insulin receptor knockout mice (IRKO) were given six different treatments to explore the effect of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) on axonal mitochondrial trafficking. A kymographing analysis was used to analyze mitochondrial transport in individual DRG axons and identify the percent of mitochondria that were stationary or motile. Interestingly, we found significantly fewer motile mitochondria in the IRKO DRG axons compared to wild type DRG axons. The SFA treatments impaired mitochondrial trafficking, while the addition of MUFAs prevented the reduction in mitochondrial trafficking in both wild type and IRKO DRG neurons. This study suggests that the loss of the insulin receptor reduces basal mitochondrial trafficking in DRG neurons but does not contribute to fatty acid-induced alterations in mitochondrial trafficking.

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Effect of aging on human induced pluripotent stem cell generation

juratli

Coronary stents are used to relieve patient symptoms of angina, or chest pain, due to obstruction of blood flow in coronary arteries. After stents are implanted, endothelial cells grow over the stents. Before that occurs, patients are at risk for developing a clot, or thrombus, inside of the stent. We are seeking to find novel ways to accelerate the coronary stent endothelialization process. We aim to understand if human-induced pluripotent stem cells (hiPSC-ECs) are a viable option for pre-endothelializing stents prior to implantation. In addition to aiming to determine stent growth properties on coronary stents, we aim to discover if there is a phenotypic difference between the endothelial cells created from hiPSC-ECs taken from younger and older patients by using a sample of their mononuclear blood cells. We are currently taking blood samples from older subjects having a procedure in the cardiac catheterization lab. After obtaining consent for the patient, approximately 8 mL of the patient’s blood is drawn from the patient’s IV into a vial with an anticoagulant. The vial is centrifuged for 30 minutes at 1800 RCF in order to isolate the mononuclear blood cells. Afterward, the sample is transported to the Cardiovascular Regeneration Core Laboratory, where the cells are converted to hiPSC-ECs and placed on commercially-available coronary artery stents to observe their growth. Thus far, one blood sample has been recently collected, with results from the cardiovascular regeneration core lab pending. Separately, subjects in the young age group will be recruited through the www.UMHealthResearch.org website. In total, we aim to test cells from blood samples acquired from 20 different patients over the course of the year. Potentially, hiPSC-ECs from older patients can be reprogrammed to more closely resemble cells from younger patients.

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Physiological Reactions to Emotional Images in Individuals with PTSD and Stress-Related Disorders

romohan

Individuals with post-traumatic stress disorder (PTSD) have impairments in fear modulation, the ability to change fear responses when an unsafe situation becomes safe or vice versa. Fear modulation deficits can be shown by an overreaction during extinction recall and fear renewal, where we measure patients’ reactivity to the previously presented extinction and fear learning context, respectively. Research has shown that the fear modulation deficits common in PTSD patients also occur in patients with fibromyalgia (FM), which is often comorbid with PTSD. This study aims to examine group differences in their response to extinction recall and fear renewal. We hypothesize that PTSD and FM groups will demonstrate significantly greater skin conductance response (SCR) during extinction recall and fear renewal phases. Participants ranging from 18 to 45 years old have been recruited for each subject group-PTSD, FM, and healthy controls. They went through fear conditioning and extinction learning on Day 1 where an unconditioned stimulus (electrical current) was paired with a conditioned stimulus (e.g., blue light) in a certain context (office vs. bookshelf). They then learned that the same conditioned stimulus is not dangerous in a different context (extinction learning). We have not reached our target sample size and are currently collecting data. We hope that the results of the current study will help us understand these disorders to eventually create a better-suited treatment option targeting the improvement of their fear modulation deficits.

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