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At least 523 records · Page 29

BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice

T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4 + T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. Furthermore, we show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

60 APPLIED LIFE SCIENCES↗

Qualitative and quantitative enhancement of parameter estimation for model-based diagnostics using automatic differentiation with an application to inertial fusion

Parameter estimation using observables is a fundamental concept in the experimental sciences. Mathematical models that represent the physical processes can enable reconstructions of the experimental observables and greatly assist in parameter estimation by turning it into an optimization problem which can be solved by gradient-free or gradient-based methods. In this work, the recent rise in flexible frameworks for developing differentiable scientific computing programs is leveraged in order to dramatically accelerate data analysis of a common experimental diagnostic relevant to laser–plasma and inertial fusion experiments, Thomson scattering. A differentiable Thomson-scattering data analysis tool is developed that uses reverse-mode automatic differentiation (AD) to calculate gradients. By switching from finite differencing to reverse-mode AD, three distinct outcomes are achieved. First, gradient descent is accelerated dramatically to the extent that it enables near real-time usage in laser–plasma experiments. Second, qualitatively novel quantities which require $\mathcal{O}(10^3)$ parameters can now be included in the analysis of data which enables unprecedented measurements of small-scale laser–plasma phenomena. Third, uncertainty estimation approaches that leverage the value of the Hessian become accurate and efficient because reverse-mode AD can be used for calculating the Hessian.

97 MATHEMATICS AND COMPUTING↗

Differentially Private Distributed Sensing

The growth of the Internet of Things (IoT) creates the possibility of decentralized systems of sensing and actuation, potentially on a global scale. IoT devices connected to cloud networks can offer Sensing and Actuation as a Service (SAaaS) enabling networks of sensors to grow to a global scale. But extremely large sensor networks can violate privacy, especially in the case where IoT devices are mobile and connected directly to the behaviors of people. The thesis of this paper is that by adapting differential privacy (adding statistically appropriate noise to query results) to groups of geographically distributed sensors privacy could be maintained without ever sending all values up to a central curator and without compromising the overall accuracy of the data collected. This paper outlines such a scheme and performs an analysis of differential privacy techniques adapted to edge computing in a simulated sensor network where ground truth is known. The positive and negative outcomes of employing differential privacy in distributed networks of devices are discussed and a brief research agenda is presented.

Differential Privacy↗

Fully Polarimetric Differential Intensity W-band Imager

We present a novel architecture based upon a Dicke-switched heterodyne radiometer architecture employing two identical input sections consisting of horn and orthomode transducer to detect the difference between the H and V polarization states of two separate object patches imaged by the radiometer. We have constructed and described previously a fully polarimetric W-band passive millimeter wave imager constructed to study the phenomenology of anomaly detection using polarimetric image exploitation of the Stokes images. The heterodyne radiometer used a PIN diode switch between the input millimeter wave energy and that of a reference load in order to eliminate the effects of component drifts and reduce the effects of 1/f noise. The differential approach differs from our previous work by comparing H and V polarization states detected by each of the two input horns instead of a reference load to form signals delta H and delta V from closely adjacent paired object patches. This novel imaging approach reduces common mode noise and enhances detection of small changes between the H and V polarization states of two object patches, now given as difference terms of the fully polarimetric radiometer. We present the theory of operation, initial proof of concept experimental results, and extension of the differential radiometer to a system with a binocular fore optics that allow adjustment of the convergence or shear of the object patches viewed by the differential polarimetric imager.

Differential Millimeter Wave Imager↗

Correspondence between open bosonic systems and stochastic differential equations

Bosonic mean-field theories can approximate the dynamics of systems of $n$ bosons provided that $n \gg 1$. Here, we show that there can also be an exact correspondence at finite $n$ when the bosonic system is generalized to include interactions with the environment and the mean-field theory is replaced by a stochastic differential equation. When the $n \to \infty$ limit is taken, the stochastic terms in this differential equation vanish, and a mean-field theory is recovered. Besides providing insight into the differences between the behavior of finite quantum systems and their classical limits given by $n \to \infty$, the developed mathematics can provide a basis for quantum algorithms that solve some stochastic nonlinear differential equations. We discuss conditions on the efficiency of these quantum algorithms, with a focus on the possibility for the complexity to be polynomial in the log of the stochastic system size. A particular system with the form of a stochastic discrete nonlinear Schrödinger equation is analyzed in more detail.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo

Background: In patients with myelodysplastic syndrome (MDS), bone marrow cells have an increased predisposition to apoptosis, yet MDS cells outcompete normal bone marrow (BM)–suggesting that factors regulating growth potential may be important in MDS. We previously identified v-Erb A related-2 (EAR-2, NR2F6) as a gene involved in control of growth ability. Methods: Bone marrow obtained from C57BL/6 mice was transfected with a retrovirus containing EAR-2-IRES-GFP. Ex vivo transduced cells were flow sorted. In some experiments cells were cultured in vitro, in other experiments cells were injected into lethally irradiated recipients, along with non-transduced bone marrow cells. Short-hairpin RNA silencing EAR-2 was also introduced into bone marrow cells cultured ex vivo. Results: Here, we show that EAR-2 inhibits maturation of normal BM in vitro and in vivo and that EAR-2 transplant chimeras demonstrate key features of MDS. Competitive repopulation of lethally irradiated murine hosts with EAR2-transduced BM cells resulted in increased engraftment and increased colony formation in serial replating experiments. Recipients of EAR-2-transduced grafts had hypercellular BM, erythroid dysplasia, abnormal localization of immature precursors and increased blasts; secondary transplantation resulted in acute leukemia. Animals were cytopenic, having reduced numbers of erythrocytes, monocytes and granulocytes. Suspension culture confirmed that EAR-2 inhibits granulocytic and monocytic differentiation, while knockdown induced granulocytic differentiation. We observed a reduction in the number of BFU-E and CFU-GM colonies and the size of erythroid and myeloid colonies. Serial replating of transduced hematopoietic colonies revealed extended replating potential in EAR-2-overexpressing BM, while knockdown reduced re-plating ability. EAR-2 functions by recruitment of histone deacetylases, and inhibition of differentiation in 32D cells is dependent on the DNA binding domain. Conclusions: This data suggest that NR2F6 inhibits maturation of normal BM in vitro and in vivo and that the NR2F6 transplant chimera system demonstrates key features of MDS, and could provide a mouse model for MDS.

59 BASIC BIOLOGICAL SCIENCES↗

Trehalase Regulates Neuroepithelial Stem Cell Maintenance and Differentiation in the Drosophila Optic Lobe

As one of the major hydrolases in Drosophila, trehalase (Treh) catalyzes the hydrolysis of trehalose into glucose providing energy for flight muscle activity. Treh is highly conserved from bacteria to humans, but little is known about its function during animal development. Here, we analyze the function of Treh in Drosophila optic lobe development. In the optic lobe, neuroepithelial cells (NEs) first divide symmetrically to expand the stem cell pool and then differentiate into neuroblasts, which divide asymmetrically to generate medulla neurons. We find that the knockdown of Treh leads to a loss of the lamina and a smaller medulla. Analyses of Treh RNAi-expressing clones and loss-of-function mutants indicate that the lamina and medulla phenotypes result from neuroepithelial disintegration and premature differentiation into medulla neuroblasts. Although the principal role of Treh is to generate glucose, the Treh loss-of-function phenotype cannot be rescued by exogenous glucose. Thus, our results indicate that in addition to being a hydrolase, Treh plays a role in neuroepithelial stem cell maintenance and differentiation during Drosophila optic lobe development.

59 BASIC BIOLOGICAL SCIENCES↗

Fast Computational Algorithms for Partial Differential Equations and Uncertainty Quantifications

This project concerned the construction, testing and analysis of computational algorithms for solving parameterized and stochastic partial differential equations. The study and understanding of equations of this type is of fundamental importance in numerous engineering and scientific applications. Examples include simulation of plasma dynamics in models of electric propulsion and nuclear fusion, simulation of multiphase flows, such as the flow of water, gas and oil in reservoirs, and structural analysis of the dependence of structures on materials. Parametrization is used in such settings when properties of the models such as viscosity of fluids or electric resistivity of materials are not precisely understood and instead are treated as random variables. The resulting solutions are themselves random, and having such solutions will enable engineers to use probabilistic methods to assess the likelihood of events, for example, whether a pollutant in a liquid will exceed a limit, and to use such analyses to develop ways to ensure positive outcomes. Construction of accurate (high resolution) computational solutions is expensive, requiring significant computer time and computational resources, and there is need to reduce computational cost to make simulation useful and effective. The aim of the project was to construct algorithms to efficiently compute surrogate solutions to parameterized problems to allow for efficient and accurate simulation. The technical approach used focused on two related strategies, based on rank-reduction methods and reduced-order models. These methods construct surrogate solutions of parameter-dependent models by projection or interpolation into low-dimensional approximation spaces. Cost savings are achieved if the low-dimensional spaces can be identified and constructed efficiently and if the resulting low-dimensional algebraic systems can be solved cheaply. Accomplishments include: Theoretical and empirical demonstration of the effectiveness of fast multigrid solution strategies for computing low-rank representations of parameter-dependent solutions to discrete partial differential equations, including the first proof establishing so-called textbook convergence properties for low-rank methods. Development of efficient solution algorithms for solving nonlinear parameter-dependent partial differential equations used in models of fluid dynamics. Developent of efficient algorithms for low-rank representation of solutions of time-dependent simulations of fluid dynamics using multi-dimensional tensor representations of solutions.

97 MATHEMATICS AND COMPUTING↗

Top differential cross section measurements (Tevatron)

Differential cross sections in the top quark sector measured at the Fermilab Tevatron collider are presented. CDF used 2.7 fb{sup -1} of data and measured the differential cross section as a function of the invariant mass of the t{bar t} system. The measurement shows good agreement with the standard model and furthermore is used to derive limits on the ratio {kappa}/M{sub Pl} for gravitons which decay to top quarks in the Randall-Sundrum model. D0 used 1.0 fb{sup -1} of data to measure the differential cross section as a function of the transverse momentum of the top-quark. The measurement shows a good agreement to the next-to-leading order perturbative QCD prediction and various other standard model predictions.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

A Unified Differential Evolution Algorithm for Global Optimization

Abstract?In this paper, we propose a new unified differential evolution (uDE) algorithm for single objective global optimization. Instead of selecting among multiple mutation strategies as in the conventional differential evolution algorithm, this algorithm employs a single equation as the mutation strategy. It has the virtue of mathematical simplicity and also provides users the flexbility for broader exploration of different mutation strategies. Numerical tests using twelve basic unimodal and multimodal functions show promising performance of the proposed algorithm in comparison to convential differential evolution algorithms.

43 PARTICLE ACCELERATORS↗

An Adaptive Unified Differential Evolution Algorithm for Global Optimization

In this paper, we propose a new adaptive unified differential evolution algorithm for single-objective global optimization. Instead of the multiple mutation strate- gies proposed in conventional differential evolution algorithms, this algorithm employs a single equation unifying multiple strategies into one expression. It has the virtue of mathematical simplicity and also provides users the flexibility for broader exploration of the space of mutation operators. By making all control parameters in the proposed algorithm self-adaptively evolve during the process of optimization, it frees the application users from the burden of choosing appro- priate control parameters and also improves the performance of the algorithm. In numerical tests using thirteen basic unimodal and multimodal functions, the proposed adaptive unified algorithm shows promising performance in compari- son to several conventional differential evolution algorithms.

43 PARTICLE ACCELERATORS↗

Differentiation of Microbial Species and Strains in Coculture Biofilms by Multivariate Analysis of Laser Desorption Postionization Mass Spectra

7.87 to 10.5 eV vacuum ultraviolet (VUV) photon energies were used in laser desorption postionization mass spectrometry (LDPI-MS) to analyze biofilms comprised of binary cultures of interacting microorganisms. The effect of photon energy was examined using both tunable synchrotron and laser sources of VUV radiation. Principal components analysis (PCA) was applied to the MS data to differentiate species in Escherichia coli-Saccharomyces cerevisiae coculture biofilms. PCA of LDPI-MS also differentiated individual E. coli strains in a biofilm comprised of two interacting gene deletion strains, even though these strains differed from the wild type K-12 strain by no more than four gene deletions each out of approximately 2000 genes. PCA treatment of 7.87 eV LDPI-MS data separated the E. coli strains into three distinct groups two ?pure? groups and a mixed region. Furthermore, the ?pure? regions of the E. coli cocultures showed greater variance by PCA when analyzed by 7.87 eV photon energies than by 10.5 eV radiation. Comparison of the 7.87 and 10.5 eV data is consistent with the expectation that the lower photon energy selects a subset of low ionization energy analytes while 10.5 eV is more inclusive, detecting a wider range of analytes. These two VUV photon energies therefore give different spreads via PCA and their respective use in LDPI-MS constitute an additional experimental parameter to differentiate strains and species.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

SUNDIALS time integrators for exascale applications with many independent systems of ordinary differential equations

Many complex systems can be accurately modeled as a set of coupled time-dependent partial differential equations (PDEs). However, solving such equations can be prohibitively expensive, easily taxing the world’s largest supercomputers. One pragmatic strategy for attacking such problems is to split the PDEs into components that can more easily be solved in isolation. This operator splitting approach is used ubiquitously across scientific domains, and in many cases leads to a set of ordinary differential equations (ODEs) that need to be solved as part of a larger “outer-loop” time-stepping approach. The SUNDIALS library provides a plethora of robust time integration algorithms for solving ODEs, and the U.S. Department of Energy Exascale Computing Project (ECP) has supported its extension to applications on exascale-capable computing hardware. In this paper, we highlight some SUNDIALS capabilities and its deployment in combustion and cosmology application codes (Pele and Nyx, respectively) where operator splitting gives rise to numerous, small ODE systems that must be solved concurrently.

97 MATHEMATICS AND COMPUTING↗

Single Bimodular Sensor for Differentiated Detection of Multiple Oxidative Gases

Semiconductive metal-oxide sensors suffer from cross-sensitivities under mixed chemical condition, specifically upon mixture of multiple oxidative or reductive gases. Herein, a single bimodular sensor is demonstrated for smart differentiation of multiple oxidative analytes by relating the resistance-metric mode to impedance-metric mode. The sensor construct based on ZnO nanorods readily outputs three response datasets upon exposure of oxidative-gas mixture including O 2 , SO 2 , and NO 2 , the resistance, real part impedance, and imaginary part impedance. The differentiative and correlated nature between these response signals allows such a single sensor platform to differentiate these oxidative gases accurately and robustly. Linear and non-linear decision boundaries are established over a large gas-concentration range from 2 ppm to 3% through a combination of principal component analysis and artificial neural network training. A facile user interface is demonstrated for recognition and measurement of unknown gas analytes, with the error of the predicted analyte-concentration as low as 2%.

36 MATERIALS SCIENCE↗

SPIO‐Au core–shell nanoparticles for promoting osteogenic differentiation of MC3T3‐E1 cells: Concentration‐dependence study

Abstract This work aims to explore the concentration‐dependence of SPIO‐Au core–shell nanoscale particles (NPs) (17.3 ± 1.2 nm in diameter) on biocompatibility and osteogenic differentiation of preosteoblast MC3T3‐E1 cells. The stability of NPs was first investigated by UV–vis absorption spectra and zeta potential measurement. Then concentration effects of NPs (1–80 μg/mL) were evaluated on viability, morphology, proliferation, cellular uptake, and alkaline phosphate (ALP) activity levels. Results have shown strong stability and no acute toxicity (viability > 93%) or morphological difference at all concentration levels of NPs. The proliferation results indicated that the concentration of NPs below 40 μg/mL does not affect the cell proliferation for 7 days of incubation. Transmission electron microscopy images revealed the successful internalization of NPs into MC3T3‐E1 cells and the dose‐dependent accumulation of NPs inside the cytoplasm. The ALP level of MC3T3‐E1 cells was improved by 49% (of control) after treated with NPs at 10 μg/mL for 10 days, indicating their positive effect on early osteogenic differentiation. This study confirmed the excellent biocompatibility of SPIO‐Au NPs and their great potential for promoting osteogenic differentiation and promised the future application for these NPs in bone engineering including drug delivery, cell labeling, and activity tracking within scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3350–3359, 2017.

Yuan, Muzhaozi↗

Differential Higgs production at N 3 LO beyond threshold

We present several key steps towards the computation of differential Higgs boson cross sections at N 3 LO in perturbative QCD. Specifically, we work in the framework of Higgs-differential cross sections that allows to compute precise predictions for realistic LHC observables. We demonstrate how to perform an expansion of the analytic N 3 LO coefficient functions around the production threshold of the Higgs boson. Our framework allows us to compute to arbitrarily high order in the threshold expansion and we explicitly obtain the first two expansion coefficients in analytic form. Furthermore, we assess the phenomenological viability of threshold expansions for differential distributions. We find that while a few terms in the threshold expansion are sufficient to approximate the exact rapidity distribution well, transverse momentum distributions require a signficantly higher number of terms in the expansion to be adequately described. We find that to improve state of the art predictions for the rapidity distribution beyond NNLO even more sub-leading terms in the threshold expansion than presented in this article are required. In addition, we report on an interesting obstacle for the computation of N 3 LO corrections with LHAPDF parton distribution functions and our solution. We provide files containing the analytic expressions for the partonic cross sections as supplementary material attached to this paper.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Measurement of inclusive and differential cross sections of single top quark production in association with a W boson in proton-proton collisions at $\sqrt{s}$ = 13.6 TeV

The first measurement of the inclusive and normalised differential cross sections of single top quark production in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13.6 TeV is presented. The data were recorded with the CMS detector at the LHC in 2022, and correspond to an integrated luminosity of 34.7 fb −1 . The analysed events contain one muon and one electron in the final state. For the inclusive measurement, multivariate discriminants exploiting the kinematic properties of the events are used to separate the signal from the dominant top quark-antiquark production background. A cross section of $82.3\pm 2.1{\left(\textrm{stat}\right)}_{-9.7}^{+9.9}\left(\textrm{syst}\right)\pm 3.3\left(\textrm{lumi}\right)$ pb is obtained, consistent with the predictions of the standard model. A fiducial region is defined according to the detector acceptance to perform the differential measurements. The resulting differential distributions are unfolded to particle level and show good agreement with the predictions at next-to-leading order in perturbative quantum chromodynamics.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Measurements of $ \mathrm{t}\overline{\mathrm{t}} $ differential cross sections in proton-proton collisions at $ \sqrt{\mathrm{s}}=13 $ TeV using events containing two leptons

Measurements of differential top quark pair $\mathrm{t\overline{t}}$ cross sections using events produced in proton-proton collisions at a centre-of-mass energy of 13 TeV containing two oppositely charged leptons are presented. The data were recorded by the CMS experiment at the CERN LHC in 2016 and correspond to an integrated luminosity of 35.9 fb$^{-1}$. The differential cross sections are presented as functions of kinematic observables of the top quarks and their decay products, the $\mathrm{t\overline{t}}$ system, and the total number of jets in the event. The differential cross sections are defined both with particle-level objects in a fiducial phase space close to that of the detector acceptance and with parton-level top quarks in the full phase space. All results are compared with standard model predictions from Monte Carlo simulations with next-to-leading-order (NLO) accuracy in quantum chromodynamics (QCD) at matrix-element level interfaced to parton-shower simulations. Where possible, parton-level results are compared to calculations with beyond-NLO precision in QCD. Significant disagreement is observed between data and all predictions for several observables. As a result, the measurements are used to constrain the top quark chromomagnetic dipole moment in an effective field theory framework at NLO in QCD and to extract $\mathrm{t\overline{t}}$ and leptonic charge asymmetries.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗