372 Publications

SARS-CoV-2 RNA concentrations in wastewater foreshadow dynamics and clinical presentation of new COVID-19 cases

Fuqing Wu, Amy Xiao, R. Bonneau, et al.

Current estimates of COVID-19 prevalence are largely based on symptomatic, clinically diagnosed cases. The existence of a large number of undiagnosed infections hampers population-wide investigation of viral circulation. Here, we quantify the SARS-CoV-2 concentration and track its dynamics in wastewater at a major urban wastewater treatment facility in Massachusetts, between early January and May 2020. SARS-CoV-2 was first detected in wastewater on March 3. SARS-CoV-2 RNA concentrations in wastewater correlated with clinically diagnosed new COVID-19 cases, with the trends appearing 4–10 days earlier in wastewater than in clinical data. We inferred viral shedding dynamics by modeling wastewater viral load as a convolution of back-dated new clinical cases with the average population-level viral shedding function. The inferred viral shedding function showed an early peak, likely before symptom onset and clinical diagnosis, consistent with emerging clinical and experimental evidence. This finding suggests that SARS-CoV-2 concentrations in wastewater may be primarily driven by viral shedding early in infection. This work shows that longitudinal wastewater analysis can be used to identify trends in disease transmission in advance of clinical case reporting, and infer early viral shedding dynamics for newly infected individuals, which are difficult to capture in clinical investigations.

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Motile dislocations knead odd crystals into whorls

Ephraim S. Bililign, Florencio Balboa Usabiaga,, M. Shelley, et al.

The competition between thermal fluctuations and potential forces governs the stability of matter in equilibrium, in particular the proliferation and annihilation of topological defects. However, driving matter out of equilibrium allows for a new class of forces that are neither attractive nor repulsive, but rather transverse. The possibility of activating transverse forces raises the question of how they affect basic principles of material self-organization and control. Here we show that transverse forces organize colloidal spinners into odd elastic crystals crisscrossed by motile dislocations. These motile topological defects organize into a polycrystal made of grains with tunable length scale and rotation rate. The self-kneading dynamics drive super-diffusive mass transport, which can be controlled over orders of magnitude by varying the spinning rate. Simulations of both a minimal model and fully resolved hydrodynamics establish the generic nature of this crystal whorl state. Using a continuum theory, we show that both odd and Hall stresses can destabilize odd elastic crystals, giving rise to a generic state of crystalline active matter. Adding rotations to a material’s constituents has far-reaching consequences for continuous control of structures and transport at all scales.

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December 16, 2021

Bidirectional communication in oogenesis: a dynamic conversation in mice and Drosophila

Caroline A. Doherty , Farners Amargant , S. Shvartsman, et al.

In most animals, the oocyte is the largest cell by volume. The oocyte undergoes a period of large-scale growth during its development, prior to fertilization. At first glance, tissues that support the development of the oocyte in different organisms have diverse cellular characteristics that would seem to prohibit functional comparisons. However, these tissues often act with a common goal of establishing dynamic forms of two-way communication with the oocyte. We propose that this bidirectional communication between oocytes and support cells is a universal phenomenon that can be directly compared across species. Specifically, we highlight fruit fly and mouse oogenesis to demonstrate that similarities and differences in these systems should be used to inform and design future experiments in both models.

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December 15, 2021

Shift in MSL1 alternative polyadenylation in response to DNA damage protects cancer cells from chemotherapeutic agent-induced apoptosis

Alexander K. Kunisky , Vivian I. Anyaeche, C. Park, et al.

DNA damage reshapes the cellular transcriptome by modulating RNA transcription and processing. In cancer cells, these changes can alter the expression of genes in the immune surveillance and cell death pathways. Here, we investigate how DNA damage impacts alternative polyadenylation (APA) using the PAPERCLIP technique. We find that APA shifts are a coordinated response for hundreds of genes to DNA damage, and we identify PCF11 as an important contributor of DNA damage-induced APA shifts. One of these APA shifts results in upregulation of the full-length MSL1 mRNA isoform, which protects cells from DNA damage-induced apoptosis and promotes cell survival from DNA-damaging agents. Importantly, blocking MSL1 upregulation enhances cytotoxicity of chemotherapeutic agents even in the absence of p53 and overcomes chemoresistance. Our study demonstrates that characterizing adaptive APA shifts to DNA damage has therapeutic implications and reveals a link between PCF11, the MSL complex, and DNA damage-induced apoptosis.

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October 12, 2021

Collective oscillations of coupled cell cycles

Binglun Shao, Rocky Diegmiller, S. Shvartsman

Problems with networks of coupled oscillators arise in multiple contexts, commonly leading to the question about the dependence of network dynamics on network structure. Previous work has addressed this question in Drosophila oogenesis, where stable cytoplasmic bridges connect the future oocyte to the supporting nurse cells that supply the oocyte with molecules and organelles needed for its development. To increase their biosynthetic capacity, nurse cells enter the endoreplication program, a special form of the cell cycle formed by the iterated repetition of growth and synthesis phases without mitosis. Recent studies have revealed that the oocyte orchestrates nurse cell endoreplication cycles, based on retrograde (oocyte to nurse cells) transport of a cell cycle inhibitor produced by the nurse cells and localized to the oocyte. Furthermore, the joint dynamics of endocycles has been proposed to depend on the intercellular connectivity within the oocyte-nurse cell cluster. We use a computational model to argue that this connectivity guides, but does not uniquely determine the collective dynamics and identify several oscillatory regimes, depending on the time scale of intercellular transport. Our results provide insights into collective dynamics of coupled cell cycles and motivate future quantitative studies of intercellular communication in the germline cell clusters.

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October 5, 2021

Genetic and epigenetic coordination of cortical interneuron development

Kathryn C. Allaway, M. Gabitto, R. Bonneau, et al.

One of the hallmarks of the cerebral cortex is the extreme diversity of interneurons. The two largest subtypes of cortical interneurons, parvalbumin- and somatostatin-positive cells, are morphologically and functionally distinct in adulthood but arise from common lineages within the medial ganglionic eminence.This makes them an attractive model for studying the generation of cell diversity. Here we examine how developmental changes in transcription and chromatin structure enable these cells to acquire distinct identities in the mouse cortex. Generic interneuron features are first detected upon cell cycle exit through the opening of chromatin at distal elements. By constructing cell-type-specific gene regulatory networks, we observed that parvalbumin- and somatostatin-positive cells initiate distinct programs upon settling within the cortex. We used these networks to model the differential transcriptional requirement of a shared regulator, Mef2c, and confirmed the accuracy of our predictions through experimental loss-of-function experiments. We therefore reveal how a common molecular program diverges to enable these neuronal subtypes to acquire highly specialized properties by adulthood. Our methods provide a framework for examining the emergence of cellular diversity, as well as for quantifying and predicting the effect of candidate genes on cell-type-specific development.

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September 22, 2021

Quadrature by fundamental solutions: kernel-independent layer potential evaluation for large collections of simple objects

Well-conditioned boundary integral methods for the solution of elliptic boundary value problems (BVPs) are powerful tools for static and dynamic physical simulations. When there are many close-to-touching boundaries (eg, in complex fluids) or when the solution is needed in the bulk, nearly-singular integrals must be evaluated at many targets. We show that precomputing a linear map from surface density to an effective source representation renders this task highly efficient, in the common case where each object is "simple", ie, its smooth boundary needs only moderately many nodes. We present a kernel-independent method needing only an upsampled smooth surface quadrature, and one dense factorization, for each distinct shape. No (near-)singular quadrature rules are needed. The resulting effective sources are drop-in compatible with fast algorithms, with no local corrections nor bookkeeping. Our extensive numerical tests include 2D FMM-based Helmholtz and Stokes BVPs with up to 1000 objects (281000 unknowns), and a 3D Laplace BVP with 10 ellipsoids separated by 1/30 of a diameter. We include a rigorous analysis for analytic data in 2D and 3D.

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September 18, 2021

aLENS: towards the cellular-scale simulation of motor-driven cytoskeletal assemblies

W. Yan, Saad Ansari, A. Lamson, Matthew A. Glaser, Meredith Betterton, M. Shelley

The cytoskeleton -- a collection of polymeric filaments, molecular motors, and crosslinkers -- is a foundational example of active matter, and in the cell assembles into organelles that guide basic biological functions. Simulation of cytoskeletal assemblies is an important tool for modeling cellular processes and understanding their surprising material properties. Here we present aLENS, a novel computational framework to surmount the limits of conventional simulation methods. We model molecular motors with crosslinking kinetics that adhere to a thermodynamic energy landscape, and integrate the system dynamics while efficiently and stably enforcing hard-body repulsion between filaments -- molecular potentials are entirely avoided in imposing steric constraints. Utilizing parallel computing, we simulate different mixtures of tens to hundreds of thousands of cytoskeletal filaments and crosslinking motors, recapitulating self-emergent phenomena such as bundle formation and buckling, and elucidating how motor type, thermal fluctuations, internal stresses, and confinement determine the evolution of active matter aggregates.

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September 16, 2021

Attenuated activation of pulmonary immune cells in mRNA-1273–vaccinated hamsters after SARS-CoV-2 infection

Michelle Meyer, X. Chen, O. Troyanskaya, et al.

The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and nonhuman primates, low-level virus replication in mRNA-1273–vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high-resolution analysis that is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a 2-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.

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Topological braiding and virtual particles on the cell membrane

Jinghui Liu, Jan F. Totz, P. Miller

Braiding of topological structures in complex matter fields provides a robust framework for encoding and processing information, and it has been extensively studied in the context of topological quantum computation. In living systems, topological defects are crucial for the localization and organization of biochemical signaling waves, but their braiding dynamics remain unexplored. Here, we show that the spiral wave cores, which organize the Rho-GTP protein signaling dynamics and force generation on the membrane of starfish egg cells, undergo spontaneous braiding dynamics. Experimentally measured world line braiding exponents and topological entropy correlate with cellular activity and agree with predictions from a generic field theory. Our analysis further reveals the creation and annihilation of virtual quasi-particle excitations during defect scattering events, suggesting phenomenological parallels between quantum and living matter.

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