1776 Publications

Cultured Renal Proximal Tubular Epithelial Cells Resemble a Stressed/Damaged Kidney While Supporting BK Virus Infection

Ping An, Maria Teresa Sáenz Robles, R. Sealfon, et al

BK virus (BKV; human polyomavirus 1) infections are asymptomatic in most individuals, and the virus persists throughout life without harm. However, BKV is a threat to transplant patients and those with immunosuppressive disorders. Under these circumstances, the virus can replicate robustly in proximal tubule epithelial cells (PT). Cultured renal proximal tubule epithelial cells (RPTE) are permissive to BKV and have been used extensively to characterize different aspects of BKV infection. Recently, lines of hTERT-immortalized RPTE have become available, and preliminary studies indicate they support BKV infection as well. Our results indicate that BKV infection leads to a similar response in primary and immortalized RPTE. In addition, we examined the patterns of global gene expression of primary and immortalized RPTE and compared them with uncultured PT freshly dissociated from human kidney. As expected, PT isolated from the healthy kidney express a number of differentiation-specific genes that are associated with kidney function. However, the expression of most of these genes is absent or repressed in cultured RPTE. Rather, cultured RPTE exhibit a gene expression profile indicative of a stressed or injured kidney. Inoculation of cultured RPTE with BKV results in the suppression of many genes associated with kidney stress. In summary, this study demonstrated similar global gene expression patterns and responses to BKV infection between primary and immortalized RPTE. Moreover, results from bulk transcriptome sequencing (RNA-seq) and SCT experiments revealed distinct transcriptomic signatures representing cell injury and stress in primary RPTE in contrast to the uncultured, freshly dissociated PT from human kidney.

Show Abstract

Active galactic nucleus jet feedback in hydrostatic haloes

Rainer Weinberger, Kung-Yi Su, Kristian Ehlert, ..., B. Burkart, et. al.

Feedback driven by jets from active galactic nuclei is believed to be responsible for reducing cooling flows in cool-core galaxy clusters. We use simulations to model feedback from hydrodynamic jets in isolated halos. While the jet propagation converges only after the diameter of the jet is well resolved, reliable predictions about the effects these jets have on the cooling time distribution function only require resolutions sufficient to keep the jet-inflated cavities stable. Comparing different model variations, as well as an independent jet model using a different hydrodynamics code, we show that the dominant uncertainties are the choices of jet properties within a given model. Independent of implementation, we find that light, thermal jets with low momentum flux tend to delay the onset of a cooling flow more efficiently on a 50 Myr timescale than heavy, kinetic jets. The delay of the cooling flow originates from a displacement and boost in entropy of the central gas. If the jet kinetic luminosity depends on accretion rate, collimated, light, hydrodynamic jets are able to reduce cooling flows in halos, without a need for jet precession or wide opening angles. Comparing the jet feedback with a `kinetic wind' implementation shows that equal amounts of star formation rate reduction can be achieved by different interactions with the halo gas: the jet has a larger effect on the hot halo gas while leaving the denser, star forming phase in place, while the wind acts more locally on the star forming phase, which manifests itself in different time-variability properties.

Show Abstract

A methylation clock model of mild SARS-CoV-2 infection provides insight into immune dysregulation

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS-CoV-2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow-up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation-based machine learning models that distinguished samples from pre-, during-, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS-CoV-2 infection to the model-defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS-CoV-2 epigenetic landscape we identify is antiprotective.

Show Abstract

A Stochastic Proximal Polyak Step Size

Fabian Schaipp, R. M. Gower, Michael Ulbrich

Recently, the stochastic Polyak step size (SPS) has emerged as a competitive adaptive step size scheme for stochastic gradient descent. Here we develop ProxSPS, a proximal variant of SPS that can handle regularization terms. Developing a proximal variant of SPS is particularly important, since SPS requires a lower bound of the objective function to work well. When the objective function is the sum of a loss and a regularizer, available estimates of a lower bound of the sum can be loose. In contrast, ProxSPS only requires a lower bound for the loss which is often readily available. As a consequence, we show that ProxSPS is easier to tune and more stable in the presence of regularization. Furthermore for image classification tasks, ProxSPS performs as well as AdamW with little to no tuning, and results in a network with smaller weight parameters. We also provide an extensive convergence analysis for ProxSPS that includes the non-smooth, smooth, weakly convex and strongly convex setting.

Show Abstract
May 4, 2023

Finding and Representing Solutions to Transmission Problems for Open Channels

We introduce a layer potential representation for the solution of the transmission problem defined by two dielectric channels, or open waveguides, meeting along the straight-line interface, {x1=0}. The main observation is that the outgoing fundamental solution for the operator Δ+k21+q(x2), acting on functions defined in ℝ2, is easily constructed using the Fourier transform in the x1-variable and the elementary theory of ordinary differential equations. These fundamental solutions can then be used to represent the solution to the transmission problem in half planes. The transmission boundary conditions lead to integral equations along the intersection of the half planes, which, in our normalization, is the x2-axis. We show that, in appropriate Banach spaces, these integral equations are Fredholm equations of second kind, which are therefore generically solvable. We then show that the solutions satisfy an analogue of the Sommerfeld radiation condition that follows from work of Isozaki, Melrose, Vasy, et al. This formulation suggests practicable numerical methods to approximately solve this class of problems.

Show Abstract
April 24, 2023

A 3D View of Orion. I. Barnard’s Loop

Michael M. Foley, Alyssa Goodman, Catherine Zucker, et. al.

Barnard's Loop is a famous arc of Hα emission located in the Orion star-forming region. Here, we provide evidence of a possible formation mechanism for Barnard's Loop and compare our results with recent work suggesting a major feedback event occurred in the region around 6 Myr ago. We present a 3D model of the large-scale Orion region, indicating coherent, radial, 3D expansion of the OBP-Near/Briceño-1 (OBP-B1) cluster in the middle of a large dust cavity. The large-scale gas in the region also appears to be expanding from a central point, originally proposed to be Orion X. OBP-B1 appears to serve as another possible center, and we evaluate whether Orion X or OBP-B1 is more likely to be the cause of the expansion. We find that neither cluster served as the single expansion center, but rather a combination of feedback from both likely propelled the expansion. Recent 3D dust maps are used to characterize the 3D topology of the entire region, which shows Barnard's Loop's correspondence with a large dust cavity around the OPB-B1 cluster. The molecular clouds Orion A, Orion B, and Orion λ reside on the shell of this cavity. Simple estimates of gravitational effects from both stars and gas indicate that the expansion of this asymmetric cavity likely induced anisotropy in the kinematics of OBP-B1. We conclude that feedback from OBP-B1 has affected the structure of the Orion A, Orion B, and Orion λ molecular clouds and may have played a major role in the formation of Barnard's Loop.

Show Abstract

A fast, accurate and easy to implement Kapur — Rokhlin quadrature scheme for singular integrals in axisymmetric geometries

Evan Toler, A.J. Cerfon, D. Malhotra

Many applications in magnetic confinement fusion require the efficient calculation of surface integrals with singular integrands. The singularity subtraction approaches typically used to handle such singularities are complicated to implement and low-order accurate. In contrast, we demonstrate that the Kapur–Rokhlin quadrature scheme is well-suited for the logarithmically singular integrals encountered for a toroidally axisymmetric confinement system, is easy to implement and is high-order accurate. As an illustration, we show how to apply this quadrature scheme for the efficient and accurate calculation of the normal component of the magnetic field due to the plasma current on the plasma boundary, via the virtual-casing principle.

Show Abstract

Dissipation and energy propagation across scales in an active cytoskeletal material

Peter J. Foster , and Jinhye Bae, D. Needleman

Living systems are intrinsically nonequilibrium: They use metabolically derived chemical energy to power their emergent dynamics and self-organization. A crucial driver of these dynamics is the cellular cytoskeleton, a defining example of an active material where the energy injected by molecular motors cascades across length scales, allowing the material to break the constraints of thermodynamic equilibrium and display emergent nonequilibrium dynamics only possible due to the constant influx of energy. Notwithstanding recent experimental advances in the use of local probes to quantify entropy production and the breaking of detailed balance, little is known about the energetics of active materials or how energy propagates from the molecular to emergent length scales. Here, we use a recently developed picowatt calorimeter to experimentally measure the energetics of an active microtubule gel that displays emergent large-scale flows. We find that only approximately one-billionth of the system’s total energy consumption contributes to these emergent flows. We develop a chemical kinetics model that quantitatively captures how the system’s total thermal dissipation varies with ATP and microtubule concentrations but that breaks down at high motor concentration, signaling an interference between motors. Finally, we estimate how energy losses accumulate across scales. Taken together, these results highlight energetic efficiency as a key consideration for the engineering of active materials and are a powerful step toward developing a nonequilibrium thermodynamics of living systems.

Show Abstract

Automatic, high-order, and adaptive algorithms for Brillouin zone integration

J. Kaye, Sophie Beck, A. Barnett, Lorenzo Van Muñoz, Olivier Parcollet

We present efficient methods for Brillouin zone integration with a non-zero but possibly very small broadening factor η, focusing on cases in which downfolded Hamiltonians can be evaluated efficiently using Wannier interpolation. We describe robust, high-order accurate algorithms automating convergence to a user-specified error tolerance ε, emphasizing an efficient computational scaling with respect to η. After analyzing the standard equispaced integration method, applicable in the case of large broadening, we describe a simple iterated adaptive integration algorithm effective in the small η regime. Its computational cost scales as \(\)(log3(η−1)) as η→0+ in three dimensions, as opposed to \(\)(η−3) for equispaced integration. We argue that, by contrast, tree-based adaptive integration methods scale only as \(\)(log(η−1)/η2) for typical Brillouin zone integrals. In addition to its favorable scaling, the iterated adaptive algorithm is straightforward to implement, particularly for integration on the irreducible Brillouin zone, for which it avoids the tetrahedral meshes required for tree-based schemes. We illustrate the algorithms by calculating the spectral function of SrVO3 with broadening on the meV scale.

Show Abstract

Docking cholesterol to integral membrane proteins with Rosetta

Brennica Marlow, Georg Kuenze, Jens Meiler, J. Koehler

Lipid molecules such as cholesterol interact with the surface of integral membrane proteins (IMP) in a mode different from drug-like molecules in a protein binding pocket. These differences are due to the lipid molecule’s shape, the membrane’s hydrophobic environment, and the lipid’s orientation in the membrane. We can use the recent increase in experimental structures in complex with cholesterol to understand protein-cholesterol interactions. We developed the RosettaCholesterol protocol consisting of (1) a prediction phase using an energy grid to sample and score native-like binding poses and (2) a specificity filter to calculate the likelihood that a cholesterol interaction site may be specific. We used a multi-pronged benchmark (self-dock, flip-dock, cross-dock, and global-dock) of protein-cholesterol complexes to validate our method. RosettaCholesterol improved sampling and scoring of native poses over the standard RosettaLigand baseline method in 91% of cases and performs better regardless of benchmark complexity. On the β2AR, our method found one likely-specific site, which is described in the literature. The RosettaCholesterol protocol quantifies cholesterol binding site specificity. Our approach provides a starting point for high-throughput modeling and prediction of cholesterol binding sites for further experimental validation.

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