Engineering synthetic phosphorylation signaling networks in human cells.

Protein phosphorylation signaling networks have a central role in how cells sense and respond to their environment. We engineered artificial phosphorylation networks in which reversible enzymatic phosphorylation cycles were assembled from modular protein domain parts and wired together to create synthetic phosphorylation circuits in human cells. Our design scheme enabled model-guided tuning of circuit function and the ability to make diverse network connections; synthetic phosphorylation circuits can be coupled to upstream cell surface receptors to enable fast-timescale sensing of extracellular ligands, and downstream connections can regulate gene expression.

A universal niche geometry governs the response of ecosystems to environmental perturbations.

How ecosystems respond to environmental perturbations is a fundamental question in ecology, made especially challenging due to the strong coupling between species and their environment. Here, we introduce a theoretical framework for calculating the steady-state response of ecosystems to environmental perturbations in generalized consumer-resource. Our construction is applicable to a wide class of systems, including models with non-reciprocal interactions, cross-feeding, and non-linear growth/consumption rates.

A single-center retrospective chart review of percutaneous PNS for treatment of chronic shoulder pain.

Objective: The present IRB-approved retrospective chart review describes the use of a 60-day PNS treatment for shoulder pain at a single center in 60 total consecutive patients.

Background: Chronic shoulder pain affects an increasing number of patients per year and is especially prevalent in elderly populations. Percutaneous peripheral nerve stimulation (PNS) treatment targeting the nerves of the shoulder has been shown to reduce pain in prospective clinical studies and in analysis of real-world data.

A differentiable Gillespie algorithm for simulating chemical kinetics, parameter estimation, and designing synthetic biological circuits.

The Gillespie algorithm is commonly used to simulate and analyze complex chemical reaction networks. Here, we leverage recent breakthroughs in deep learning to develop a fully differentiable variant of the Gillespie algorithm. The differentiable Gillespie algorithm (DGA) approximates discontinuous operations in the exact Gillespie algorithm using smooth functions, allowing for the calculation of gradients using backpropagation.

Integrating local energetics into Maxwell-Calladine constraint counting to design mechanical metamaterials.

The Maxwell-Calladine index theorem plays a central role in our current understanding of the mechanical rigidity of discrete materials. By considering the geometric constraints each material component imposes on a set of underlying degrees of freedom, the theorem relates the emergence of rigidity to constraint counting arguments. However, the Maxwell-Calladine paradigm is significantly limited-its exclusive reliance on the geometric relationships between constraints and degrees of freedom completely neglects the actual energetic costs of deforming individual components.

A differentiable Gillespie algorithm for simulating chemical kinetics, parameter estimation, and designing synthetic biological circuits.

The Gillespie algorithm is commonly used to simulate and analyze complex chemical reaction networks. Here, we leverage recent breakthroughs in deep learning to develop a fully differentiable variant of the Gillespie algorithm. The differentiable Gillespie algorithm (DGA) approximates dis-continuous operations in the exact Gillespie algorithm using smooth functions, allowing for the calculation of gradients using backpropagation.

Generation of human alveolar epithelial type I cells from pluripotent stem cells.

Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human in vitro AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells.

Phase Transition to Chaos in Complex Ecosystems with Nonreciprocal Species-Resource Interactions.

Nonreciprocal interactions between microscopic constituents can profoundly shape the large-scale properties of complex systems. Here, we investigate the effects of nonreciprocity in the context of theoretical ecology by analyzing a generalization of MacArthur's consumer-resource model with asymmetric interactions between species and resources. Using a mixture of analytic cavity calculations and numerical simulations, we show that such ecosystems generically undergo a phase transition to chaotic dynamics as the amount of nonreciprocity is increased.

A universal niche geometry governs the response of ecosystems to environmental perturbations.

How ecosystems respond to environmental perturbations is a fundamental question in ecology, made especially challenging due to the strong coupling between species and their environment. Here, we introduce a theoretical framework for calculating the linear response of ecosystems to environmental perturbations in generalized consumer-resource models. Our construction is applicable to a wide class of systems, including models with non-reciprocal interactions, cross-feeding, and non-linear growth/consumption rates.

Les Houches Lectures on Community Ecology: From Niche Theory to Statistical Mechanics.

Ecosystems are among the most interesting and well-studied examples of self-organized complex systems. Community ecology, the study of how species interact with each other and the environment, has a rich tradition. Over the last few years, there has been a growing theoretical and experimental interest in these problems from the physics and quantitative biology communities.

Phase transition to chaos in complex ecosystems with non-reciprocal species-resource interactions.

Non-reciprocal interactions between microscopic constituents can profoundly shape the large-scale properties of complex systems. Here, we investigate the effects of non-reciprocity in the context of theoretical ecology by analyzing a generalization of MacArthur's consumer-resource model with asymmetric interactions between species and resources. Using a mixture of analytic cavity calculations and numerical simulations, we show that such ecosystems generically undergo a phase transition to chaotic dynamics as the amount of non-reciprocity is increased.

Emergent competition shapes top-down versus bottom-up control in multi-trophic ecosystems.

Ecosystems are commonly organized into trophic levels-organisms that occupy the same level in a food chain (e.g., plants, herbivores, carnivores).

Posterior Lateral Arthrodesis as a Treatment Option for Lumbar Spinal Stenosis: Safety and Early Clinical Outcomes.

Introduction: Lumbar spinal stenosis (LSS) is a common condition caused by degenerative changes in the lumbar spine with age. LSS is caused by a variety of factors, including degenerative spondylosis and spondylolisthesis. People suffering with LSS experience neurogenic claudication, which causes severe physical limitations, discomfort, and a decrease in quality of life.

Geometry of ecological coexistence and niche differentiation.

A fundamental problem in ecology is to understand how competition shapes biodiversity and species coexistence. Historically, one important approach for addressing this question has been to analyze consumer resource models using geometric arguments. This has led to broadly applicable principles such as Tilman's R^{*} and species coexistence cones.

Metabolic similarity and the predictability of microbial community assembly.

When microbial communities form, their composition is shaped by selective pressures imposed by the environment. Can we predict which communities will assemble under different environmental conditions? Here, we hypothesize that quantitative similarities in metabolic traits across metabolically similar environments lead to predictable similarities in community composition. To that end, we measured the growth rate and by-product profile of a library of proteobacterial strains in a large number of single nutrient environments.

scTOP: physics-inspired order parameters for cellular identification and visualization.

Advances in single-cell RNA sequencing provide an unprecedented window into cellular identity. The abundance of data requires new theoretical and computational frameworks to analyze the dynamics of differentiation and integrate knowledge from cell atlases. We present 'single-cell Type Order Parameters' (scTOP): a statistical, physics-inspired approach for quantifying cell identity given a reference basis of cell types.

Engineering synthetic phosphorylation signaling networks in human cells.

Protein phosphorylation signaling networks play a central role in how cells sense and respond to their environment. Here, we describe the engineering of artificial phosphorylation networks in which "push-pull" motifs-reversible enzymatic phosphorylation cycles consisting of opposing kinase and phosphatase activities-are assembled from modular protein domain parts and then wired together to create synthetic phosphorylation circuits in human cells. We demonstrate that the composability of our design scheme enables model-guided tuning of circuit function and the ability to make diverse network connections; synthetic phosphorylation circuits can be coupled to upstream cell surface receptors to enable fast-timescale sensing of extracellular ligands, while downstream connections can regulate gene expression.

Phase transition to chaos in complex ecosystems with non-reciprocal species-resource interactions.

Non-reciprocal interactions between microscopic constituents can profoundly shape the large-scale properties of complex systems. Here, we investigate the effects of non-reciprocity in the context of theoretical ecology by analyzing a generalization of MacArthur's consumer-resource model with asymmetric interactions between species and resources. Using a mixture of analytic cavity calculations and numerical simulations, we show that such ecosystems generically undergo a phase transition to chaotic dynamics as the amount of non-reciprocity is increased.

Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice.

Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. After transplantation, these progenitors mature in the distal lung, assuming the molecular phenotypes of alveolar type 2 (AT2) and type 1 (AT1) cells.

Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis.

Transient, tissue-specific, embryonic progenitors are important cell populations in vertebrate development. In the course of respiratory system development, multipotent mesenchymal and epithelial progenitors drive the diversification of fates that results to the plethora of cell types that compose the airways and alveolar space of the adult lungs. Use of mouse genetic models, including lineage tracing and loss-of-function studies, has elucidated signaling pathways that guide proliferation and differentiation of embryonic lung progenitors as well as transcription factors that underlie lung progenitor identity.

Geometry of ecological coexistence and niche differentiation.

A fundamental problem in ecology is to understand how competition shapes biodiversity and species coexistence. Historically, one important approach for addressing this question has been to analyze consumer resource models using geometric arguments. This has led to broadly applicable principles such as Tilman's and species coexistence cones.

Geometry of ecological coexistence and niche differentiation.

A fundamental problem in ecology is to understand how competition shapes biodiversity and species coexistence. Historically, one important approach for addressing this question has been to analyze Consumer Resource Models (CRMs) using geometric arguments. This has led to broadly applicable principles such as Tilman's * and species coexistence cones.

Catastrophic Antiphospholipid Syndrome: A Case Series.

Catastrophic antiphospholipid syndrome (CAPS) is the rare but most severe form of antiphospholipid syndrome with multiple organ ischemia developing over a short period of time. CAPS should be considered when imaging suggests an acute and concurrent multiorgan ischemia, associated with positive antiphospholipid antibodies. As CAPS can have fulminant irreversible complications, its early recognition is important to initiate the treatment promptly.