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Biology subjects

Getz, M.

Publications and source records attributed to Getz, M..

11 recordsLinked to original sources

Development and evaluation of a low-cost, automated camera trap for surveying bumble bee communities

Widespread declines in insect diversity and abundance underscore an urgent need for standardized, nonlethal monitoring methods for important pollinators such as bumble bees (Bombus spp.). Camera traps are widely used for non-intrusive, continuous surveys of large animals but have not yet been extensively adopted for monitoring insects. An automated camera trap system could improve current insect survey methods, which often rely on lethal traps or in-person observation. We developed an open-source, low-cost camera trap for monitoring wild insects and evaluated its performance relative to established sampling approaches. The system used a low-power microcomputer to collect time-lapse images on colored platforms. We trained whole-image and tiled deep-learning object detection models to detect insects in images captured by the traps. We found that tiled inference models significantly improved detection accuracy and outperformed human review. Bumble bee visitation was highest on platforms featuring a fluorescent bullseye pattern; adding a fluorescent coat to blue platforms increased visitation modestly. With continuous monitoring, the cameras recorded bumble bee visits during all daylight hours. Over 18 days, camera traps recorded six Bombus species, yielding community composition and diversity estimates comparable to those obtained by hand netting and blue vane traps. Using our observed data, we simulated the effect of deploying variable numbers of cameras at sites with distinct levels of diversity. Adding cameras substantially increased sampling completeness, particularly in species-rich communities. Our findings demonstrate that low-cost, automated camera traps paired with deep-learning image analysis can enable scalable, nonlethal studies of bumble bee diversity and behavior. Our work establishes a foundation for monitoring other diurnal insect communities.

ecology↗

V-Cornea:A computational model of corneal epithelium homeostasis, injury, and recovery

PurposeTo develop a computational model that addresses limitations in current ocular irritation assessment methods, particularly regarding long-term effects, and recovery patterns following chemical exposure or trauma to the cornea. MethodsV-Cornea is an agent-based computer simulation implemented in CompuCell3D that models corneal epithelial homeostasis and injury response. The model incorporates biologically-inspired rules governing cell behaviors (proliferation, differentiation, death) and key signaling pathways including Epidermal Growth Factor (EGF), translating cell-level behaviors to tissue-level outcomes (in vitro to in vivo extrapolation, IVIVE). ResultsV-Cornea successfully reproduces corneal epithelial architecture and maintains tissue homeostasis over extended simulated periods. Following simulated trauma or toxicant exposure, the model accurately predicts healing timeframes of 3-5 days for slight and mild injuries. For moderate injuries with basement membrane disruption, the model demonstrates longer recovery times and emergent dynamic structural disorganization that mimics recurrent corneal erosions, providing mechanistic insights into these pathological conditions. ConclusionsV-Corneas modular CompuCell3D implementation is easily extensible to incorporate additional recovery and injury mechanisms. Future versions will include more realistic basement membrane dynamics and explicit representation of stromal tissue and immune response to improve predictivity for moderate injuries. This virtual-tissue approach shows potential not only for toxicological assessments but also for drug discovery and therapy optimization by providing a platform to test interventions and predict outcomes across various injury scenarios.

systems biology↗

Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Memory lymphocytes are durable cells that persist in the absence of antigen, but few human B cell subsets have been characterized in terms of durability. The relative durability of eight non-overlapping human B cell sub-populations covering 100% of all human class-switched B cells was interrogated. Only two long-lived B cell populations persisted in the relative absence of antigen. In addition to canonical germinal center-derived switched-memory B cells with an IgD-CD27+ CXCR5+ phenotype, a second, non-canonical, but distinct memory population of IgD-CD27- CXCR5+ DN1 B cells was also durable, exhibited a unique TP63-linked transcriptional and anti-apoptotic signature, had low levels of somatic hypermutation, but was more clonally expanded than canonical switched-memory B cells. DN1 B cells likely evolved to preserve immunological breadth and may represent the human counterparts of rodent extrafollicular memory B cells that, unlike canonical memory B cells, can enter germinal centers and facilitate B cell and antibody evolution. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/624972v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@169c77forg.highwire.dtl.DTLVardef@1a872f5org.highwire.dtl.DTLVardef@1360cforg.highwire.dtl.DTLVardef@38d7ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Spatiotemporal orchestration of calcium-cAMP oscillations on AKAP/AC nanodomains is governed by an incoherent feedforward loop

The nanoscale organization of enzymes associated with the dynamics of second messengers is critical for ensuring compartmentation and localization of signaling molecules in cells. Specifically, the spatiotemporal orchestration of cAMP and Ca2+ oscillations is critical for many cellular functions. Previous experimental studies have shown that the formation of nanodomains of A-kinase anchoring protein 79/150 (AKAP150) and adenylyl cyclase 8 (AC8) on the surface of pancreatic MIN6 {beta} cells modulates the phase of Ca2+-cAMP oscillations from out-of-phase to in-phase. In this work, we develop computational models of the Ca2+/cAMP pathway and AKAP/AC nanodomain formation that give rise to the two important predictions: instead of an arbitrary phase difference, the out-of-phase Ca2+/cAMP oscillation reaches Ca2+ trough and cAMP peak simultaneously, which is defined as inversely out-of-phase; the in-phase and inversely out-of-phase oscillations associated with Ca2+-cAMP dynamics on and away from the nanodomains can be explained by an incoherent feedforward loop. Factors such as cellular surface-to-volume ratio, compartment size, and distance between nan-odomains do not affect the existence of in-phase or inversely out-of-phase Ca2+/cAMP oscillation, but cellular surface-to-volume ratio and compartment size can affect the time delay for the inversely out-of-phase Ca2+/cAMP oscillation while the distance between two nanodomains does not. Finally, we predict that both the Turing pattern-generated nanodomains and experimentally measured nan-odomains demonstrate the existence of in-phase and inversely out-of-phase Ca2+/cAMP oscillation when the AC8 is at a low level, consistent with the behavior of an incoherent feedforward loop. These findings unveil the key circuit motif that governs cAMP and Ca2+ oscillations and advance our understanding of how nanodomains can lead to spatial compartmentation of second messengers.

systems biology↗

A multiscale model of pulmonary micrometastasis and immune surveillance: towards cancer patient digital twins

Metastasis is the leading cause of death in patients with cancer, driving considerable scientific and clinical interest in immunosurveillance of micrometastases. We investigated this process by creating a multiscale mathematical model to study the interactions between the immune system and the progression of micrometastases in general epithelial tissue. We analyzed the parameter space of the model using high-throughput computing resources to generate over 100,000 virtual patient trajectories. We demonstrated that the model could recapitulate a wide variety of virtual patient trajectories, including uncontrolled growth, partial response, and complete immune response to tumor growth. We classified the virtual patients and identified key patient parameters with the greatest effect on the simulated immunosurveillance. We highlight the lessons derived from this analysis and their impact on the nascent field of cancer patient digital twins (CPDTs). While CPDTs could enable clinicians to systematically dissect the complexity of cancer in each individual patient and inform treatment choices, our work shows that key challenges remain before we can reach this vision. In particular, we show that there remain considerable uncertainties in immune responses, dysfunctional data stratification, and unpredictable personalized treatment. Nonetheless, we also show that in spite of these challenges, patient-specific models suggest strategies to increase control of clinically undetectable micrometastases even without complete parameter certainty.

systems biology↗

Digitize your Biology! Modeling multicellular systems through interpretable cell behavior

Cells are fundamental units of life, constantly interacting and evolving as dynamical systems. While recent spatial multi-omics can quantitate individual cells characteristics and regulatory programs, forecasting their evolution ultimately requires mathematical modeling. We develop a conceptual framework--a cell behavior hypothesis grammar--that uses natural language statements (cell rules) to create mathematical models. This allows us to systematically integrate biological knowledge and multi-omics data to make them computable. We can then perform virtual "thought experiments" that challenge and extend our understanding of multicellular systems, and ultimately generate new testable hypotheses. In this paper, we motivate and describe the grammar, provide a reference implementation, and demonstrate its potential through a series of examples in tumor biology and immunotherapy. Altogether, this approach provides a bridge between biological, clinical, and systems biology researchers for mathematical modeling of biological systems at scale, allowing the community to extrapolate from single-cell characterization to emergent multicellular behavior.

systems biology↗

An agent-based modeling approach for lung fibrosis in response to COVID-19

The severity of the COVID-19 pandemic has created an emerging need to investigate the long-term effects of infection on patients. Many individuals are at risk of suffering pulmonary fibrosis due to the pathogenesis of lung injury and impairment in the healing mechanism. Fibroblasts are the central mediators of extracellular matrix (ECM) deposition during tissue regeneration, regulated by anti-inflammatory cytokines including transforming growth factor beta (TGF-{beta}). The TGF-{beta}-dependent accumulation of fibroblasts at the damaged site and excess fibrillar collagen deposition lead to fibrosis. We developed an open-source, multiscale tissue simulator to investigate the role of TGF-{beta} sources in the progression of lung fibrosis after SARS-CoV-2 exposure, intracellular viral replication, infection of epithelial cells, and host immune response. Using the model, we predicted the dynamics of fibroblasts, TGF-{beta}, and collagen deposition for 15 days post-infection in virtual lung tissue. Our results showed variation in collagen area fractions between 2% and 40% depending on the spatial behavior of the sources (stationary or mobile), the rate of activation of TGF-{beta}, and the duration of TGF-{beta} sources. We identified M2 macrophages as primary contributors to higher collagen area fraction. Our simulation results also predicted fibrotic outcomes even with lower collagen area fraction when spatially-localized latent TGF-{beta} sources were active for longer times. We validated our model by comparing simulated dynamics for TGF-{beta}, collagen area fraction, and macrophage cell population with independent experimental data from mouse models. Our results showed that partial removal of TGF-{beta} sources changed the fibrotic patterns; in the presence of persistent TGF-{beta} sources, partial removal of TGF-{beta} from the ECM significantly increased collagen area fraction due to maintenance of chemotactic gradients driving fibroblast movement. The computational findings are consistent with independent experimental and clinical observations of collagen area fractions and cell population dynamics not used in developing the model. These critical insights into the activity of TGF-{beta} sources may find applications in the current clinical trials targeting TGF-{beta} for the resolution of lung fibrosis. Author summaryCOVID-19 survivors are at risk of lung fibrosis as a long-term effect. Lung fibrosis is the excess deposition of tissue materials in the lung that hinder gas exchange and can collapse the whole organ. We identified TGF-{beta} as a critical regulator of fibrosis. We built a model to investigate the mechanisms of TGF-{beta} sources in the process of fibrosis. Our results showed spatial behavior of sources (stationary or mobile) and their activity (activation rate of TGF-{beta}, longer activation of sources) could lead to lung fibrosis. Current clinical trials for fibrosis that target TGF-{beta} need to consider TGF-{beta} sources spatial properties and activity to develop better treatment strategies.

bioengineering↗

DNA-based copy number analysis confirms genomic evolution of PDX models

We previously reported the genomic evolution of the copy number (CN) landscapes of patient-derived xenografts (PDXs) during their engraftment and passaging1. Woo et al. argue that the CN profiles of PDXs are highly conserved, and that the main conclusions of our paper are invalid due to our use of expression-based CN profiles2. Here, we reassess genomic evolution of PDXs using the DNA-based CN profiles reported by Woo et al. We find that the degree of genomic evolution in the DNA-based dataset of Woo et al. is similar to that which we had previously reported. While the overall Pearsons correlation of CN profiles between primary tumors (PTs) and their derived PDXs is high (as reported in our original paper as well), a median of ~10% of the genome is differentially altered between PTs and PDXs across cohorts (range, 0% to 73% across all models). In 24% of the matched PT-PDX samples, over a quarter of the genome is differentially affected by CN alterations. Moreover, in matched analyses of PTs and their derived PDXs at multiple passages, later-passage PDXs are significantly less similar to their parental PTs than earlier-passage PDXs, indicative of genomic divergence. We conclude that genomic evolution of PDX models during model generation and propagation should not be dismissed, and that the phenotypic consequences of this evolution ought to be assessed in order to optimize the application of these valuable cancer models.

cancer biology↗

Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit

Signaling networks are spatiotemporally organized in order to sense diverse inputs, process information, and carry out specific cellular tasks. In pancreatic {beta} cells, Ca2+, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback, which allows for specific signaling controls based on the oscillation frequencies. Here, we describe a novel mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca2+. We show that nanodomain clustering of Ca2+-sensitive adenylyl cyclases drives oscillations of local cAMP levels to be precisely in-phase with Ca2+ oscillations, whereas Ca2+-sensitive phosphodiesterases maintain out-of-phase oscillations outside of the nanodomain, representing a striking example and novel mechanism of cAMP compartmentation. Disruption of this precise in-phase relationship perturbs Ca2+ oscillations, suggesting that the relative phase within an oscillatory circuit can encode specific functional information. This example of a signaling nanodomain utilized for localized tuning of an oscillatory circuit has broad implications for the spatiotemporal regulation of signaling networks.

cell biology↗

STABILITY ANALYSIS OF A BULK-SURFACE REACTION MODEL FOR MEMBRANE-PROTEIN CLUSTERING

Protein aggregation on the plasma membrane (PM) is of critical importance to many cellular processes such as cell adhesion, endocytosis, fibrillar conformation, and vesicle transport. Lateral diffusion of protein aggregates or clusters on the surface of the PM plays an important role in governing their heterogeneous surface distribution. However, the stability behavior of the surface distribution of protein aggregates remains poorly understood. Therefore, understanding the spatial patterns that can emerge on the PM solely through protein-protein interaction, lateral diffusion, and feedback is an important step towards a complete description of the mechanisms behind protein clustering on the cell surface. In this work, we investigate the pattern formation of a reaction-diffusion model that describes the dynamics of a system of ligand-receptor complexes. The purely diffusive ligand in the cytosol can bind receptors in the PM, and the resultant ligand-receptor complexes not only diffuse laterally but can also form clusters resulting in different oligomers. Finally, the largest oligomers recruit ligands from the cytosol in a positive feedback. From a methodological viewpoint, we provide theoretical estimates for diffusion-driven instabilities of the protein aggregates based on the Turing mechanism. Our main result is a threshold phenomenon, in which a sufficiently high recruitment of ligands promotes the input of new monomeric components and consequently drives the formation of a single-patch spatially heterogeneous steady-state.

cell biology↗

Guanine-nucleotide Exchange Modulator, GIV/Girdin, Serves as a Tunable Valve for Growth Factor-Stimulated Cyclic AMP Signals

Cellular levels of the versatile second messenger, cyclic-(c)AMP are regulated by the antagonistic actions of the canonical G protein[->]adenylyl cyclase pathway that is initiated by G-protein-coupled receptors (GPCRs) and by phosphodiesterases (PDEs); dysregulated cAMP signaling drives many diseases, including cancers. Recently, an alternative paradigm for cAMP signaling has emerged, in which growth factor-receptor tyrosine kinases (RTKs; e.g., EGFR) access and modulate G proteins via cytosolic guanine-nucleotide exchange modulator (GEM), GIV/Girdin; dysregulation of this pathway is frequently encountered in cancers. Here we present a comprehensive network-based compartmental model for the paradigm of GEM-dependent signaling that reveals unforeseen crosstalk and network dynamics between upstream events and the various feedback-loops that fine-tune the GEM action of GIV, and captures the experimentally determined dynamics of cAMP. The model also reveals that GIV acts a tunable control-valve within the RTK[->]cAMP pathway; hence, it modulates cAMP via mechanisms distinct from the two most-often targeted classes of cAMP modulators, GPCRs and PDEs.

systems biology↗