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Generation and characterization of genetically and antigenically diverse infectious clones of dengue virus serotypes 1–4
No full textDengue is caused by four genetically distinct viral serotypes, dengue virus (DENV) 1-4. Following transmission by Aedes mosquitoes, DENV can cause a broad spectrum of clinically apparent disease ranging from febrile illness to dengue hemorrhagic fever and dengue shock syndrome. Progress in the understanding of different dengue serotypes and their impacts on specific host-virus interactions has been hampered by the scarcity of tools that adequately reflect their antigenic and genetic diversity. To bridge this gap, we created and characterized infectious clones of DENV1–4 originating from South America, Africa, and Southeast Asia. Analysis of whole viral genome sequences of five DENV
isolates from each of the four serotypes confirmed their broad genetic and antigenic diversity. Using a modified circular polymerase extension reaction (CPER), we generated de novo viruses from these isolates. The resultant clones replicated robustly in human and insect cells at levels similar to those of the parental strains. To investigate in vivo properties of these genetically diverse isolates, representative viruses from each DENV serotype were administered to NOD Rag1−/−, IL2rg null Flk2−/− (NRGF) mice, engrafted with components of a human immune system. All DENV strains tested resulted in viremia in humanized mice and induced cellular and IgM immune responses. Collectively, we describe here a workflow for rapidly generating de novo infectious clones of DENV – and conceivably other RNA
viruses. The infectious clones described here are a valuable resource for reverse genetic studies and for characterizing host responses to DENV in vitro and in vivo
A decoupled SPH-FEM analysis of hydrodynamic wave pressure on hyperbolic-paraboloid thin-shell coastal armor and corresponding structural response
No full textKinetic Umbrella, an innovative thin-shell structural system, incorporating hyperbolic paraboloid (hypar) geometry, has been proposed for coastal hazard mitigation. Its feasibility against surge and wave loadings has been conceptually validated via a Hurricane Sandy case study. However, the typical hydrodynamic wave pressure on hypar geometries and the rationality of the previously conducted static structural analyses remain unknown. In response, this paper implements a decoupled numerical scheme consisting of smoothed particle hydrodynamics (SPH) and finite element modeling (FEM), investigating the hydrodynamic wave pressure and corresponding structural response via structural dynamic analyses. Furthermore, the accuracy of applying the hydrodynamic wave pressure predicted by the well accepted Goda’s formula to the structural analysis of Kinetic Umbrellas is also evaluated. The results show that the hydrodynamic wave pressure on hypar follows a bilinear like shape along height and increases gradually from the edge of the hypar to the longitudinal spine. The hydrodynamic wave pressure difference between the edge and the longitudinal spine will be intensified by higher warping magnitude of hypar and under breaking waves. For structural response, the maximum displacement and the maximum tensile membrane force of the shell are significantly underestimated by static analyses with Goda’s formula, implying the necessity of implementing the decoupled SPH-FEM scheme with structural dynamic analyses. For other critical demands, the difference is mostly smaller than 20%. The findings reinforce the idea that hypar thin shells are structurally feasible under surge and wave loadings, and ultimately facilitate the employment of
hypar thin shells for coastal defense as a sustainable alternative to traditional coastal structures
Exact quantum scars in the chiral nonlinear Luttinger liquid
No full textWhile the chiral linear Luttinger liquid is integrable via bosonization, its non-linear counterpart does not admit for an analytic solution. In this work, we find a sub-extensive number of exact eigenstates for a large family of density-density interaction terms. These states are embedded in a continuum of strongly-correlated excited states. The real-space entanglement entropy of some exact states scales logarithmically with system size, while that of others has volume-law scaling. We introduce momentum-space entanglement as an unambiguous differentiator between these exact states and the remaining excited states. With regard to momentum space, the exact states behave as bona fide quantum many body scars: they exhibit identically zero momentum-space entanglement, while typical eigenstates behave thermally. We corroborate this finding by a level statistics analysis. Furthermore, we detail the general formalism for systematically finding all interaction terms and associated exact states, and present a number of infinite exact state sequences extending to arbitrarily high energies. Unlike many previous examples of quantum many body scars, the exact states uncovered here do not lie at equidistant energies, and do not follow from a special operator algebra. Instead, they are uniquely enabled by the interplay of Fermi statistics and chirality
Independent determination of the Earth’s orbital parameters with solar neutrinos in Borexino
No full textSince the beginning of 2012, the Borexino collaboration has been reporting precision measurements of the
solar neutrino fluxes, emitted in the proton–proton chain and in the Carbon–Nitrogen–Oxygen cycle. The
experimental sensitivity achieved in Phase-II and Phase-III of the Borexino data taking made it possible to
detect the annual modulation of the solar neutrino interaction rate due to the eccentricity of Earth’s orbit,
with a statistical significance greater than 5. This is the first precise measurement of the Earth’s orbital
parameters based solely on solar neutrinos and an additional signature of the solar origin of the Borexino signal.
The complete periodogram of the time series of the Borexino solar neutrino detection rate is also reported,
exploring frequencies between one cycle/year and one cycle/day. No other significant modulation frequencies
are found. The present results were uniquely made possible by Borexino’s decade-long high-precision solar
neutrino detection
Recent advances and limitations in the application of kahalalides for the control of cancer
No full textSince the discovery of the kahalalide family of marine depsipeptides in 1993, considerable work
has been done to develop these compounds as new and biologically distinct anti-cancer agents.
Clinical trials and laboratory research have yielded a wealth of data that indicates tolerance of
kahalalides in healthy cells and selective activity against diseased cells. Currently, two molecules
have attracted the greates level of attention, kahalalide F (KF) and isokahalalide F (isoKF, Irvalec,
PM 02734, elisidepsin). Both compounds were originally isolated from the sarcoglossan mollusk
Elysia rufescens but due to distinct structural characteristics it has been hypothesized and recently
shown that the ultimate origin of the molecules is microbial. The search for their true source has
been a subject of considerable research in the anticipation of finding new analogs and a culturable
expression system that can produce sufficient material through fermentation to be industrially
relevant
An Invariance Principle for the Multi-slice, with Applications
No full textGiven an alphabet size m∈N thought of as a constant, and k⃗ =(k1,…,km) whose entries sum of up n , the k⃗ -multi-slice is the set of vectors x∈[m]n in which each symbol i∈[m] appears precisely ki times. We show an invariance principle for low-degree functions over the multi-slice, to functions over the product space ( [m]n,μn ) in which μ(i)=ki/n . This answers a question raised by [21]. As applications of the invariance principle, we show: 1)An analogue of the “dictatorship test implies computational hardness” paradigm for problems with perfect completeness, for a certain class of dictatorship tests. Our computational hardness is proved assuming a recent strengthening of the Unique-Games Conjecture, called the Rich 2-to-1 Games Conjecture. Using this analogue, we show that assuming the Rich 2-to-1 Games Conjecture, (a) there is an r -ary CSP Pr for which it is NP-hard to distinguish satisfiable instances of the CSP and instances that are at most 2r+12r+o(1) satisfiable, and (b) hardness of distinguishing 3-colorable graphs, and graphs that do not contain an independent set of size o(1) . 2)A reduction of the problem of studying expectations of products of functions on the multi-slice to studying expectations of products of functions on correlated, product spaces. In particular, we are able to deduce analogues of the Gaussian bounds from [38] for the multi-slice. 3)In a companion paper, we show further applications of our invariance principle in extremal combinatorics, and more specifically to proving removal lemmas of a wide family of hypergraphs H called ζ -forests, which is a natural extension of the well-studied case of matchings
FlexiBERT: Are Current Transformer Architectures too Homogeneous and Rigid?
No full textThe existence of a plethora of language models makes the problem of selecting the best one for a custom task challenging. Most state-of-the-art methods leverage transformer-based models (e.g., BERT) or their variants. Training such models and exploring their hyperparameter space, however, is computationally expensive. Prior work proposes several neural architecture search (NAS) methods that employ performance predictors (e.g., surrogate models) to address this issue; however, analysis has been limited to homogeneous models that use fixed dimensionality throughout the network. This leads to sub-optimal architectures. To address this limitation, we propose a suite of heterogeneous and flexible models, namely FlexiBERT, that have varied encoder layers with a diverse set of possible operations and different hidden dimensions. For better-posed surrogate modeling in this expanded design space, we propose a new graph-similarity-based embedding scheme. We also propose a novel NAS policy, called BOSHNAS, that leverages this new scheme, Bayesian modeling, and second-order optimization, to quickly train and use a neural surrogate model to converge to the optimal architecture. A comprehensive set of experiments shows that
the proposed policy, when applied to the FlexiBERT design space, pushes the performance frontier upwards compared to traditional models. FlexiBERT-Mini, one of our proposed models, has 3% fewer parameters than BERT-Mini and achieves 8.9% higher GLUE score. A FlexiBERT model with equivalent performance as the best homogeneous model achieves 2.6× smaller size. FlexiBERT-Large, another proposed model, achieves state-of-the-art results, outperforming the baseline models by at least 5.7% on the GLUE benchmark
Nanoscale covariance magnetometry with diamond quantum sensors
No full textNitrogen vacancy (NV) centers in diamond are atom-scale defects that can be used to sense magnetic fields with high sensitivity and spatial resolution. Typically, the magnetic field is measured by averaging sequential measurements of single NV centers, or by spatial averaging over ensembles of many NV centers, which provides mean values that contain no nonlocal information about the relationship between two points separated in space or time. Here, we propose and implement a sensing modality whereby two or more NV centers are measured simultaneously, and we extract temporal and spatial correlations in their signals that would otherwise be inaccessible. We demonstrate measurements of correlated applied noise using spin-to-charge readout of two NV centers and implement a spectral reconstruction protocol for disentangling local and nonlocal noise sources
SHARP: Shielding-Aware Robust Planning for Safe and Efficient Human-Robot Interaction
No full textJointly achieving safety and efficiency in human-robot interaction settings is a challenging problem, as the robot’s planning objectives may be at odds with the human’s own intent and expectations. Recent approaches ensure safe robot operation in uncertain environments through a supervisory control scheme, sometimes called “shielding,” which overrides the robot’s nominal plan with a safety fallback strategy when a safety-critical event is imminent. These reactive “last-resort” strategies (typically in the form of aggressive emergency maneuvers) focus on preserving safety without efficiency considerations; when the nominal planner is unaware of possible safety overrides, shielding can be activated more frequently than necessary, leading to degraded performance. In this letter, we propose a new shielding-based planning approach that allows the robot to plan efficiently by explicitly accounting for possible future shielding events. Leveraging recent work on Bayesian human motion prediction, the resulting robot policy proactively balances nominal performance with the risk of high-cost emergency maneuvers triggered by low-probability human behaviors. We formalize Shielding-Aware Robust Planning (SHARP) as a stochastic optimal control problem and propose a computationally efficient framework for finding tractable approximate solutions at runtime. Our method outperforms the shielding-agnostic motion planning baseline (equipped with the same human intent inference scheme) on simulated driving examples with human trajectories taken from the recently released Waymo Open Motion Dataset
Structure of Water Adsorbed on Nanocrystalline Calcium Silicate Hydrate Determined from Neutron Scattering and Molecular Dynamics Simulations
No full textCalcium silicate hydrate (C-S-H) is a disordered, nanocrystalline material that acts as a primary binding phase in Portland cement. Thin films of water are present on the surfaces and in nanopores of C-S-H, impacting many of its chemical and mechanical properties, such as ion transport, creep, or thermal behavior. Despite decades of research, a full understanding of the structural details of adsorbed, confined, and bulk water in C-S-H remains elusive. In this work, we applied a multi47 technique study involving molecular dynamics (MD) simulations validated by neutron diffraction with an isotopic substitution (NDIS) and X-ray scattering methods to investigate the structure of water in C49 S-H and C-A-S-H (an Al-bearing, low-CO2 C-S-H substitute). Direct comparison of NDIS data with the MD results reveals that the structure of confined and interfacial water differs significantly from the bulk water and exhibits a larger degree of mesoscale ordering for more hydrated C-S-H structures. This observation suggests an important role of water as a stabilizer of the atomistic-level structure of C-S-H