Publications

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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.

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.

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.

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).

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.

The evolution of landscapes, landforms, and other natural structures involves highly interactive physical and chemical processes that often lead to intriguing shapes and recurring motifs. Particularly intricate and fine-scale features characterize the so-called karst morphologies formed by mineral dissolution into water. An archetypal form is the tall, slender, and sharply tipped karst pinnacle or rock spire that appears in multitudes in striking landforms called stone forests, but whose formative mechanisms remain unclear due to complex, fluctuating, and incompletely understood developmental conditions. Here, we demonstrate that exceedingly sharp spires also form under the far-simpler conditions of a solid dissolving into a surrounding liquid. Laboratory experiments on solidified sugars in water show that needlelike pinnacles, as well as bed-of-nails-like arrays of pinnacles, emerge robustly from the dissolution of solids with smooth initial shapes. Although the liquid is initially quiescent and no external flow is imposed, persistent flows are generated along the solid boundary as dense, solute-laden fluid descends under gravity. We use these observations to motivate a mathematical model that links such boundary-layer flows to the shape evolution of the solid. Dissolution induces these natural convective flows that, in turn, enhance dissolution rates, and simulations show that this feedback drives the shape toward a finite-time singularity or blow-up of apex curvature that is cut off once the pinnacle tip reaches microscales. This autogenic mechanism produces ultra-fine structures as an attracting state or natural consequence of the coupled processes at work in the closed solid-fluid system.

One approach to analyzing the dynamics of a physical system is to search for long-lived patterns in its motions. This approach has been particularly successful for molecular dynamics data, where slowly decorrelating patterns can indicate large-scale conformational changes. Detecting such patterns is the central objective of the variational approach to conformational dynamics (VAC), as well as the related methods of time-lagged independent component analysis and Markov state modeling. In VAC, the search for slowly decorrelating patterns is formalized as a variational problem solved by the eigenfunctions of the system’s transition operator. VAC computes solutions to this variational problem by optimizing a linear or nonlinear model of the eigenfunctions using time series data. Here, we build on VAC’s success by addressing two practical limitations. First, VAC can give poor eigenfunction estimates when the lag time parameter is chosen poorly. Second, VAC can overfit when using flexible parametrizations such as artificial neural networks with insufficient regularization. To address these issues, we propose an extension that we call integrated VAC (IVAC). IVAC integrates over multiple lag times before solving the variational problem, making its results more robust and reproducible than VAC’s.

The rotation periods of planet-hosting stars can be used for modeling and mitigating the impact of magnetic activity in radial velocity measurements and can help constrain the high-energy flux environment and space weather of planetary systems. Millions of stars and thousands of planet hosts are observed with the Transiting Exoplanet Survey Satellite (TESS). However, most will only be observed for 27 contiguous days in a year, making it difficult to measure rotation periods with traditional methods. This is especially problematic for field M dwarfs, which are ideal candidates for exoplanet searches, but which tend to have periods in excess of the 27-day observing baseline. We present a new tool, Astraea, for predicting long rotation periods from short-duration light curves combined with stellar parameters from Gaia DR2. Using Astraea, we can predict the rotation periods from Kepler 4-year light curves with 13% uncertainty overall (and a 9% uncertainty for periods > 30 days). By training on 27-day Kepler light curve segments, Astraea can predict rotation periods up to 150 days with 9% uncertainty (5% for periods > 30 days). After training this tool on these 27-day Kepler light curve segments, we applied \texttt{Astraea} to real TESS data. For the 195 stars that were observed by both Kepler and TESS, we were able to predict the rotation periods with 55% uncertainty despite the wild differences in systematics.

Gravitational waves provide a unique tool for observational astronomy. While the first LIGO--Virgo catalogue of gravitational-wave transients (GWTC-1) contains eleven signals from black hole and neutron star binaries, the number of observations is increasing rapidly as detector sensitivity improves. To extract information from the observed signals, it is imperative to have fast, flexible, and scalable inference techniques. In a previous paper, we introduced BILBY: a modular and user-friendly Bayesian inference library adapted to address the needs of gravitational-wave inference. In this work, we demonstrate that BILBY produces reliable results for simulated gravitational-wave signals from compact binary mergers, and verify that it accurately reproduces results reported for the eleven GWTC-1 signals. Additionally, we provide configuration and output files for all analyses to allow for easy reproduction, modification, and future use. This work establishes that BILBY is primed and ready to analyse the rapidly growing population of compact binary coalescence gravitational-wave signals.