Optimal performance objectives in the highly conserved bone morphogenetic protein signaling pathway.

Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in determining cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant.

Optimal Performance Objectives in the Highly Conserved Bone Morphogenetic Protein Signaling Pathway.

Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in these cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant.

Atypical peripheral actin band formation via overactivation of RhoA and nonmuscle myosin II in mitofusin 2-deficient cells.

Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophil-like cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization.

Early radial positional information in the cochlea is optimized by a precise linear BMP gradient and enhanced by SOX2.

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.

Computational modeling of TGF-β2:TβRI:TβRII receptor complex assembly as mediated by the TGF-β coreceptor betaglycan.

Transforming growth factor-β1, -β2, and -β3 (TGF-β1, -β2, and -β3) are secreted signaling ligands that play essential roles in tissue development, tissue maintenance, immune response, and wound healing. TGF-β ligands form homodimers and signal by assembling a heterotetrameric receptor complex comprised of two type I receptor (TβRI):type II receptor (TβRII) pairs. TGF-β1 and TGF-β3 ligands signal with high potency due to their high affinity for TβRII, which engenders high-affinity binding of TβRI through a composite TGF-β:TβRII binding interface.

PDE-constrained shape registration to characterize biological growth and morphogenesis from imaging data.

We propose a PDE-constrained shape registration algorithm that captures the deformation and growth of biological tissue from imaging data. Shape registration is the process of evaluating optimum alignment between pairs of geometries through a spatial transformation function. We start from our previously reported work, which uses 3D tensor product B-spline basis functions to interpolate 3D space.

"I Think I Am Getting There" Understanding the Computational Identity of Engineering Students Participating in a Computationally Intensive Thermodynamics Course.

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.

Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling.

Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present.

Automatic wavelet-based 3D nuclei segmentation and analysis for multicellular embryo quantification.

Identification of individual cells in tissues, organs, and in various developing systems is a well-studied problem because it is an essential part of objectively analyzing quantitative images in numerous biological contexts. We developed a size-dependent wavelet-based segmentation method that provides robust segmentation without any preprocessing, filtering or fine-tuning steps, and is robust to the signal-to-noise ratio. The wavelet-based method achieves robust segmentation results with respect to True Positive rate, Precision, and segmentation accuracy compared with other commonly used methods.

Acceleration of PDE-Based Biological Simulation Through the Development of Neural Network Metamodels.

Purpose Of Review: Partial differential equation (PDE) mathematical models of biological systems and the simulation approaches used to solve them are widely used to test hypotheses and infer regulatory interactions based on optimization of the PDE model against the observed data. In this review, we discuss the ability of powerful machine learning methods to accelerate the parametric screening of biophysical informed- PDE systems.

Recent Findings: A major shortcoming in more broad adaptation of PDE-based models is the high computational complexity required to solve and optimize the models and it requires many simulations to traverse the very high-dimensional parameter spaces during model calibration and inference tasks.

Diversity and robustness of bone morphogenetic protein pattern formation.

Pattern formation by bone morphogenetic proteins (BMPs) demonstrates remarkable plasticity and utility in several contexts, such as early embryonic development, tissue patterning and the maintenance of stem cell niches. BMPs pattern tissues over many temporal and spatial scales: BMP gradients as short as 1-2 cell diameters maintain the stem cell niche of the germarium over a 24-h cycle, and BMP gradients of several hundred microns establish dorsal-ventral tissue specification in , zebrafish and embryos in timescales between 30 min and several hours. The mechanisms that shape BMP signaling gradients are also incredibly diverse.

Proteolytic Restriction of Chordin Range Underlies BMP Gradient Formation.

A fundamental question in developmental biology is how morphogens, such as bone morphogenetic protein (BMP), form precise signaling gradients to impart positional and functional identity to the cells of the early embryo. We combine rigorous mutant analyses with quantitative immunofluorescence to determine that the proteases Bmp1a and Tolloid spatially restrict the BMP antagonist Chordin in dorsoventral (DV) axial patterning of the early zebrafish gastrula. We show that maternally deposited Bmp1a plays an unexpected and non-redundant role in establishing the BMP signaling gradient, while the Bmp1a/Tolloid antagonist Sizzled is surprisingly dispensable.

Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton.

Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (MFN2) regulates neutrophil homeostasis and chemotaxis -deficient neutrophils are released from the hematopoietic tissue, trapped in the vasculature in zebrafish embryos, and not capable of chemotaxis.

Evaluation of BMP-mediated patterning in a 3D mathematical model of the zebrafish blastula embryo.

Bone Morphogenetic Proteins (BMPs) play an important role in dorsal-ventral (DV) patterning of the early zebrafish embryo. 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 patterns in 3D, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo.

Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration.

Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those, decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells.

Scale invariance of BMP signaling gradients in zebrafish.

In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk.

Interplay Between the Persistent Random Walk and the Contact Inhibition of Locomotion Leads to Collective Cell Behaviors.

Cell migration plays an important role in physiology and pathophysiology. It was observed in the experiments that cells, such as fibroblast, leukocytes, and cancer cells, exhibit a wide variety of migratory behaviors, such as persistent random walk, contact inhibition of locomotion, and ordered behaviors. To identify biophysical mechanisms for these cellular behaviors, we developed a rigorous computational model of cell migration on a two-dimensional non-deformable substrate.

Imaging and Quantification of P-Smad1/5 in Zebrafish Blastula and Gastrula Embryos.

Spatiotemporal patterns of morphogen activity drive differential gene expression with a high degree of precision within a developing embryo and reproducibly between embryos. Understanding the formation and function of a morphogen gradient during development requires quantitative measurement of morphogen activity throughout an individual embryo and also between embryos within a population. Quantification of morphogen gradients in to presents unique challenges in imaging and image processing to minimize error and maximize the quality of the data so it may be used in computational models of development and in statistically testing hypotheses.

Mechanisms and Measurements of Scale Invariance of Morphogen Gradients.

Morphogen gradients provide positional information to underlying cells that translate the information into differential gene expression and eventually different cell fates. Scale invariance is the property where the gradients of the morphogen adjust proportionately to the size of the domain. Scale invariance of morphogen gradients or patterns of differentiation is a common phenomenon observed between individuals within the same species and between homologous tissues or structures in different species.

An automated workflow for quantifying RNA transcripts in individual cells in large data-sets.

Advanced molecular probing techniques such as single molecule fluorescence in situ hybridization (smFISH) or RNAscope can be used to assess the quantity and spatial location of mRNA transcripts within cells. Quantifying mRNA expression in large image sets usually involves automated counting of fluorescent spots. Though conventional spot counting algorithms may suffice, they often lack high-throughput capacity and accuracy in cases of crowded signal or excessive noise.

An Integrative multi-lineage model of variation in leukopoiesis and acute myelogenous leukemia.

Background: Acute myelogenous leukemia (AML) progresses uniquely in each patient. However, patients are typically treated with the same types of chemotherapy, despite biological differences that lead to differential responses to treatment.

Results: Here we present a multi-lineage multi-compartment model of the hematopoietic system that captures patient-to-patient variation in both the concentration and rates of change of hematopoietic cell populations.

Systems biology derived source-sink mechanism of BMP gradient formation.

A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral embryonic axis of vertebrates and invertebrates. The prevailing view in vertebrates for BMP gradient formation is through a counter-gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels. To delineate the mechanism in zebrafish, we precisely quantified the BMP activity gradient in wild-type and mutant embryos and combined these data with a mathematical model-based computational screen to test hypotheses for gradient formation.

Fluorescent imaging of protein myristoylation during cellular differentiation and development.

Protein post-translational modifications (PTMs) serve to give proteins new cellular functions and can influence spatial distribution and enzymatic activity, greatly enriching the complexity of the proteome. Lipidation is a PTM that regulates protein stability, function, and subcellular localization. To complement advances in proteomic identification of lipidated proteins, we have developed a method to image the spatial distribution of proteins that have been co- and post-translationally modified via the addition of myristic acid (Myr) to the N terminus.

LobeFinder: A Convex Hull-Based Method for Quantitative Boundary Analyses of Lobed Plant Cells.

Dicot leaves are composed of a heterogeneous mosaic of jigsaw puzzle piece-shaped pavement cells that vary greatly in size and the complexity of their shape. Given the importance of the epidermis and this particular cell type for leaf expansion, there is a strong need to understand how pavement cells morph from a simple polyhedral shape into highly lobed and interdigitated cells. At present, it is still unclear how and when the patterns of lobing are initiated in pavement cells, and one major technological bottleneck to addressing the problem is the lack of a robust and objective methodology to identify and track lobing events during the transition from simple cell geometry to lobed cells.

The role of mathematical models in understanding pattern formation in developmental biology.

In a Wall Street Journal article published on April 5, 2013, E. O. Wilson attempted to make the case that biologists do not really need to learn any mathematics-whenever they run into difficulty with numerical issues, they can find a technician (aka mathematician) to help them out of their difficulty.