Search for: All records

Abstract Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of hair cells and supporting cells. This requires precision in the morphogen signals that set the initial radial compartment boundaries, but this has not been investigated. To measure gradient formation and morphogenetic precision in developing cochlea, we developed a quantitative image analysis procedure measuring SOX2 and pSMAD1/5/9 profiles in mouse embryos at embryonic day (E)12.5, E13.5, and E14.5. Intriguingly, we found that the pSMAD1/5/9 profile forms a linear gradient up to the medial ~ 75% of the PSD from the pSMAD1/5/9 peak in the lateral edge during E12.5 and E13.5. This is a surprising activity readout for a diffusive BMP4 ligand secreted from a tightly constrained lateral region since morphogens typically form exponential or power-law gradient shapes. This is meaningful for gradient interpretation because while linear profiles offer the theoretically highest information content and distributed precision for patterning, a linear morphogen gradient has not yet been observed. Furthermore, this is unique to the cochlear epithelium as the pSMAD1/5/9 gradient is exponential in the surrounding mesenchyme. In addition to the information-optimized linear profile, we found that while pSMAD1/5/9 is stable during this timeframe, an accompanying gradient of SOX2 shifts dynamically. Last, through joint decoding maps of pSMAD1/5/9 and SOX2, we see that there is a high-fidelity mapping between signaling activity and position in the regions that will become Kölliker’s organ and the organ of Corti. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain. 

Embryonic development is a complex phenomenon that integrates genetic regulation and biomechanical cellular behaviors. However, the relative influence of these factors on spatiotemporal morphogen distributions is not well understood. Bone Morphogenetic Proteins (BMPs) are the primary morphogens guiding the dorsal-ventral (DV) patterning of the early zebrafish embryo, and BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however, it is not clear how the source-sink mechanism shapes the morphogen patterns in three-dimensional (3D) space, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo, nor how the patterns are controlled over time. Throughout blastulation and gastrulation, major cell movement, known as epiboly, happens along with the BMP-mediated DV patterning. The layer of epithelial cells begins to thin as they spread toward the vegetal pole of the embryo until it has completely engulfed the yolk cell. This dynamic domain may influence the distributions of BMP network members through advection. We developed a Finite Element Model (FEM) that incorporates all stages of zebrafish embryonic development data and solves the advection-diffusion-reaction Partial Differential Equations (PDE) in a growing domain. We use the model to investigate mechanisms in underlying BMP-driven DV patterning during epiboly. Solving the PDE is computationally expensive for parameter exploration. To overcome this obstacle, we developed a Neural Network (NN) metamodel of the 3D embryo that is accurate and fast and provided a nonlinear map between high-dimensional input and output that replaces the direct numerical simulation of the PDEs. From the modeling and acceleration by the NN metamodels, we identified the impact of advection on patterning and the influence of the dynamic expression level of regulators on the BMP signaling network. 

In response to the growing computational intensity of the healthcare industry, biomedical engineering (BME) undergraduate education is placing increased emphasis on computation. The presence of substantial gender disparities in many computationally intensive disciplines suggests that the adoption of computational instruction approaches that lack intentionality may exacerbate gender disparities. Educational research suggests that the development of an engineering and computational identity is one factor that can support students’ decisions to enter and persist in an engineering major. Discipline-based identity research is used as a lens to understand retention and persistence of students in engineering. Our specific purpose is to apply discipline-based identity research to define and explore the computational identities of undergraduate engineering students who engage in computational environments. This work will inform future studies regarding retention and persistence of students who engage in computational courses. Twenty-eight undergraduate engineering students (20 women, 8 men) from three engineering majors (biomedical engineering, agricultural engineering, and biological engineering) participated in semi-structured interviews. The students discussed their experiences in a computationally-intensive thermodynamics course offered jointly by the Biomedical Engineering and Agricultural & Biological Engineering departments. The transcribed interviews were analyzed through thematic coding. The gender stereotypes associated with computer programming also come part and parcel with computer programming, possibly threatening a student's sense of belonging in engineering. The majority of the participants reported that their computational identity was “in the making.” Students’ responses also suggested that their engineering identity and their computational identity were in congruence, while some incongruence is found between their engineering identity and a creative identity as well as between computational identity and perceived feminine norms. Responses also indicate that students associate specific skills with having a computational identity. This study's findings present an emergent thematic definition of a computational person constructed from student perceptions and experiences. Instructors can support students’ nascent computational identities through intentional mitigation of the gender stereotypes and biases, and by framing assignments to focus on developing specific skills associated with the computational modeling processes.

 

This Work-in-Progress paper in the Research Category uses a retrospective mixed-methods study to better understand the factors that mediate learning of computational modeling by life scientists. Key stakeholders, including leading scientists, universities and funding agencies, have promoted computational modeling to enable life sciences research and improve the translation of genetic and molecular biology high- throughput data into clinical results. Software platforms to facilitate computational modeling by biologists who lack advanced mathematical or programming skills have had some success, but none has achieved widespread use among life scientists. Because computational modeling is a core engineering skill of value to other STEM fields, it is critical for engineering and computer science educators to consider how we help students from across STEM disciplines learn computational modeling. Currently we lack sufficient research on how best to help life scientists learn computational modeling. To address this gap, in 2017, we observed a short-format summer course designed for life scientists to learn computational modeling. The course used a simulation environment designed to lower programming barriers. We used semi-structured interviews to understand students' experiences while taking the course and in applying computational modeling after the course. We conducted interviews with graduate students and post- doctoral researchers who had completed the course. We also interviewed students who took the course between 2010 and 2013. Among these past attendees, we selected equal numbers of interview subjects who had and had not successfully published journal articles that incorporated computational modeling. This Work-in-Progress paper applies social cognitive theory to analyze the motivations of life scientists who seek training in computational modeling and their attitudes towards computational modeling. Additionally, we identify important social and environmental variables that influence successful application of computational modeling after course completion. The findings from this study may therefore help us educate biomedical and biological engineering students more effectively. Although this study focuses on life scientists, its findings can inform engineering and computer science education more broadly. Insights from this study may be especially useful in aiding incoming engineering and computer science students who do not have advanced mathematical or programming skills and in preparing undergraduate engineering students for collaborative work with life scientists. 

This Work-in-Progress paper in the Research Category explores the unique challenges and opportunities of interdisciplinary education in computational modeling for life sciences student researchers at emerging research institutions (ERIs), specifically in predominantly undergraduate institutions (PUIs), and minority serving institutions (MSIs). Engineering approaches such as computational modeling have underappreciated potential for capacity building for the biomedical research enterprises of ERIs. We perform a bibliometric analysis to assess the prevailing use of computational modeling in life sciences research at MSIs, and PUIs. Additionally, we apply Social and Cognitive Theory to identify unique attitudinal, social and structural barriers for student researchers in learning and using computational modeling approaches at each of these types of institutions. Specifically, we use quantitative retrospective pre- and post-survey data and qualitative interviews of students who have attended a short-format computational modeling training course. We supplement these data with qualitative interviews of the students' faculty sponsors. Upon completion, this study will provide deeper understanding of issues related to computer science and engineering education at non-Research I institutions.