1967 Publications

Apical stress fibers enable a scaling between cell mechanical response and area in epithelial tissue

J. López-Gay, H. Nunley , M. Spencer, F. di Pietro, B. Guriao, F. Bosveld

Tissue development, homeostasis, and repair require cells to sense mechanical forces. Although many molecular actors implicated in cell mechanosensitivity have been extensively studied, the basis by which cells adapt their mechanical responses to their geometry remains poorly defined. López-Gay et al. now identify how two fundamental epithelial structures—stress fibers and tricellular junctions—endow Drosophila cells with an internal ruler to scale their mechanical response with their area. This work explains how cells of different sizes within an epithelial tissue collectively adapt their mechanical response to control tissue shape and proliferation. Scaling of biological properties with size is a core property of other biological systems.

Show Abstract
Science, 370:eabb2169
October 16, 2020

Computational design of mixed chirality peptide macrocycles with internal symmetry

V. Mulligan, C Kang, M Sawaya, S Rettie, X Li, I Antselovich, T Craven, A Watkins, J Labonte, F DiMaio, T Yeates, D Baker

Cyclic symmetry is frequent in protein and peptide homo‐oligomers, but extremely rare within a single chain, as it is not compatible with free N‐ and C‐termini. Here we describe the computational design of mixed‐chirality peptide macrocycles with rigid structures that feature internal cyclic symmetries or improper rotational symmetries inaccessible to natural proteins. Crystal structures of three C2‐ and C3‐symmetric macrocycles, and of six diverse S2‐symmetric macrocycles, match the computationally‐designed models with backbone heavy‐atom RMSD values of 1 Å or better. Crystal structures of an S4‐symmetric macrocycle (consisting of a sequence and structure segment mirrored at each of three successive repeats) designed to bind zinc reveal a large‐scale zinc‐driven conformational change from an S4‐symmetric apo‐state to a nearly inverted S4‐symmetric holo‐state almost identical to the design model. These symmetric structures provide promising starting points for applications ranging from design of cyclic peptide based metal organic frameworks to creation of high affinity binders of symmetric protein homo‐oligomers. More generally, this work demonstrates the power of computational design for exploring symmetries and structures not found in nature, and for creating synthetic switchable systems.

Show Abstract

SARS-CoV-2 receptor networks in diabetic and COVID-19 associated kidney disease

R Menon, E Otto, R. Sealfon, V Nair, A. Wong, C Theesfeld, X. Chen, Y Wang, A Boppana, J Luo, Y Yang, P Kasson, J Schaub, C Berthier, S Eddy , C Lienczewski , B Godfrey, S Dagenais , R Sohaney, J Hartman, D Fermin, L Subramanian, H Looker , J Harder, L Mariani, J Hodgin, J Sexton, C Wobus , A Naik, R Nelson, O. Troyanskaya, M Kretzler

COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cell-specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2–infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19–related kidney damage.

Show Abstract

The CAMELS project: Cosmology and Astrophysics with MachinE Learning Simulations

F. Villaescusa-Navarro, D. Angles-Alcazar, S. Genel, D. Spergel, Rachel S. Somerville, Romeel Dave, Annalisa Pillepich, Lars Hernquist, Dylan Nelson, Paul Torrey, Desika Narayanan, Y. Li, Oliver Philcox, Valentina La Torre, A. M. Delgado, S. Ho, S. Hassan, B. Burkart, Digvijay Wadekar, Nicholas Battaglia, G. Contardo

We present the Cosmology and Astrophysics with MachinE Learning Simulations --CAMELS-- project. CAMELS is a suite of 4,233 cosmological simulations of $(25~h^{-1}{\rm Mpc})^3$ volume each: 2,184 state-of-the-art (magneto-)hydrodynamic simulations run with the AREPO and GIZMO codes, employing the same baryonic subgrid physics as the IllustrisTNG and SIMBA simulations, and 2,049 N-body simulations. The goal of the CAMELS project is to provide theory predictions for different observables as a function of cosmology and astrophysics, and it is the largest suite of cosmological (magneto-)hydrodynamic simulations designed to train machine learning algorithms. CAMELS contains thousands of different cosmological and astrophysical models by way of varying $\Omega_m$, $\sigma_8$, and four parameters controlling stellar and AGN feedback, following the evolution of more than 100 billion particles and fluid elements over a combined volume of $(400~h^{-1}{\rm Mpc})^3$. We describe the simulations in detail and characterize the large range of conditions represented in terms of the matter power spectrum, cosmic star formation rate density, galaxy stellar mass function, halo baryon fractions, and several galaxy scaling relations. We show that the IllustrisTNG and SIMBA suites produce roughly similar distributions of galaxy properties over the full parameter space but significantly different halo baryon fractions and baryonic effects on the matter power spectrum. This emphasizes the need for marginalizing over baryonic effects to extract the maximum amount of information from cosmological surveys. We illustrate the unique potential of CAMELS using several machine learning applications, including non-linear interpolation, parameter estimation, symbolic regression, data generation with Generative Adversarial Networks (GANs), dimensionality reduction, and anomaly detection.

Show Abstract
arXiv e-prints
October 1, 2020

Regional Embedding Enables High-Level Quantum Chemistry for Surface Science

Bryan T. G. Lau, Gerald Knizia, Timothy C. Berkelbach

Compared to common density functionals, ab initio wave function methods can provide greater reliability and accuracy, which could prove useful when modeling adsorbates or defects of otherwise periodic systems. However, the breaking of translational symmetry necessitates large supercells that are often prohibitive for correlated wave function methods. As an alternative, we introduce the regional embedding approach, which enables correlated wave function treatments of only a target fragment of interest through small, fragment-localized orbital spaces constructed using a simple overlap criterion. Applications to the adsorption of water on lithium hydride, hexagonal boron nitride, and graphene substrates show that regional embedding combined with focal point corrections can provide converged CCSD(T) (coupled cluster) adsorption energies with very small fragment sizes.

Show Abstract
October 1, 2020

Identification of new therapeutic targets in CRLF2-overexpressing B-ALL through discovery of TF-gene regulatory interactions

S. Badri, B. Carella, P. Lhoumaud, D. Castro, C. Skok Gibbs, R. Raviram, S. Narang, N. Evensen, A. Watters, W. Carroll, R. Bonneau, J. Skok

Although genetic alterations are initial drivers of disease, aberrantly activated transcriptional regulatory programs are often responsible for the maintenance and progression of cancer. CRLF2-overexpression in B-ALL patients leads to activation of JAK-STAT, PI3K and ERK/MAPK signaling pathways and is associated with poor outcome. Although inhibitors of these pathways are available, there remains the issue of treatment-associated toxicities, thus it is important to identify new therapeutic targets. Using a network inference approach, we reconstructed a B-ALL specific transcriptional regulatory network to evaluate the impact of CRLF2-overexpression on downstream regulatory interactions.

Comparing RNA-seq from CRLF2-High and other B-ALL patients (CRLF2-Low), we defined a CRLF2-High gene signature. Patient-specific chromatin accessibility was interrogated to identify altered putative regulatory elements that could be linked to transcriptional changes. To delineate these regulatory interactions, a B-ALL cancer-specific regulatory network was inferred using 868 B-ALL patient samples from the NCI TARGET database coupled with priors generated from ATAC-seq peak TF-motif analysis. CRISPRi, siRNA knockdown and ChIP-seq of nine TFs involved in the inferred network were analyzed to validate predicted TF-gene regulatory interactions.

In this study, a B-ALL specific regulatory network was constructed using ATAC-seq derived priors. Inferred interactions were used to identify differential patient-specific transcription factor activities predicted to control CRLF2-High deregulated genes, thereby enabling identification of new potential therapeutic targets.

Show Abstract
September 26, 2020

Stoichiometric interactions explain spindle dynamics and scaling across 100 million years of nematode evolution

R. Farhadifar, C-H. Yu, G. Fabig, H-Y. Wu, D. Stein, M. Rockman, T. Müller-Reichert, M. Shelley, D. Needleman

The spindle shows remarkable diversity, and changes in an integrated fashion, as cells vary over evolution. Here, we provide a mechanistic explanation for variations in the first mitotic spindle in nematodes. We used a combination of quantitative genetics and biophysics to rule out broad classes of models of the regulation of spindle length and dynamics, and to establish the
importance of a balance of cortical pulling forces acting in different directions. These experiments led us to construct a model of cortical pulling forces in which the stoichiometric interactions of microtubules and force generators (each force generator can bind only one microtubule), is key to\ explaining the dynamics of spindle positioning and elongation, and spindle final length and scaling with cell size. This model accounts for variations in all the spindle traits we studied here, both within species and across nematode species spanning over 100 million years of evolution.

Show Abstract
September 23, 2020

Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies

R Dannenfelser, G Allen, B VanderSluis, A Koegel, S Levinson, S Stark, V Yao, A Tadych, O. Troyanskaya, W Lim

Precise discrimination of tumor from normal tissues remains a major roadblock for therapeutic efficacy of chimeric antigen receptor (CAR) T cells. Here, we perform a comprehensive in silico screen to identify multi-antigen signatures that improve tumor discrimination by CAR T cells engineered to integrate multiple antigen inputs via Boolean logic, e.g., AND and NOT. We screen >2.5 million dual antigens and ∼60 million triple antigens across 33 tumor types and 34 normal tissues. We find that dual antigens significantly outperform the best single clinically investigated CAR targets and confirm key predictions experimentally. Further, we identify antigen triplets that are predicted to show close to ideal tumor-versus-normal tissue discrimination for several tumor types. This work demonstrates the potential of 2- to 3-antigen Boolean logic gates for improving tumor discrimination by CAR T cell therapies. Our predictions are available on an interactive web server resource (antigen.princeton.edu).

Show Abstract

Stripes, Antiferromagnetism, and the Pseudogap in the Doped Hubbard Model at Finite Temperature

The interplay between thermal and quantum fluctuations controls the competition between phases of matter in strongly correlated electron systems. We study finite-temperature properties of the strongly coupled two-dimensional doped Hubbard model using the minimally-entangled typical thermal states (METTS) method on width 4 cylinders. We discover that a novel phase characterized by commensurate short-range antiferromagnetic correlations and no charge ordering occurs at temperatures above the half-filled stripe phase extending to zero temperature. The transition from the antiferromagnetic phase to the stripe phase takes place at temperature T/t≈0.05 and is accompanied by a step-like feature of the specific heat. We find the single-particle gap to be smallest close to the nodal point at k=(π/2,π/2) and detect a maximum in the magnetic susceptibility. These features bear a strong resemblance to the pseudogap phase of high-temperature cuprate superconductors. The simulations are verified using a variety of different unbiased numerical methods in the three limiting cases of zero temperature, small lattice sizes, and half-filling.

Show Abstract
  • Previous Page
  • Viewing
  • Next Page
Advancing Research in Basic Science and MathematicsSubscribe to Flatiron Institute announcements and other foundation updates