gebhart/patrepeval huggingface dataset:
CDC25 Inhibitors as Anticancer Agents Are Moving Forward (2008)

The identification of a CDC25 inhibitor to arrest the cell cycle closely followed the discovery of CDC25 by Russell and Nurse in 1986. Recent advances at the preclinical and clinical stages reinforce the rationale to consider CDC25 as a relevant target for a cancer treatment. Here, in order to exemplify recent drug discovery efforts, we present our own experience with various chemical series of CDC25 inhibitors. We discuss how we have progressed and how we are considering the next steps to define the clinical entry points and hopefully complete this target validation to generate a new class of therapeutic agents.
Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to <i>Caenorhabditis elegans</i> (2016)

Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1. The nsy-1(gf) allele caused hyperinduction of p38 MAPK PMK-1-dependent immune effectors, had greater levels of phosphorylated p38 MAPK, and was more resistant to killing by the bacterial pathogen Pseudomonas aeruginosa compared to wild-type controls. In addition, the nsy-1(gf) mutation was toxic to developing animals. Together, these data suggest that the activity of the MAPKKK NSY-1 is tightly regulated as part of a physiological mechanism to control p38 MAPK-mediated innate immune hyperactivation, and ensure cellular homeostasis in C. elegans.
Objective and Automated Detection of Diffuse White Matter Abnormality in Preterm Infants Using Deep Convolutional Neural Networks (2019)

Diffuse white matter abnormality (DWMA), or diffuse excessive high signal intensity is observed in 50-80% of very preterm infants at term-equivalent age. It is subjectively defined as higher than normal signal intensity in periventricular and subcortical white matter in comparison to normal unmyelinated white matter on T<sub>2</sub>-weighted MRI images. Despite the well-documented presence of DWMA, it remains debatable whether DWMA represents pathological tissue injury or a transient developmental phenomenon. Manual tracing of DWMA exhibits poor reliability and reproducibility and unduly increases image processing time. Thus, objective and ideally automatic assessment is critical to accurately elucidate the biologic nature of DWMA. We propose a deep learning approach to automatically identify DWMA regions on T<sub>2</sub>-weighted MRI images. Specifically, we formulated DWMA detection as an image voxel classification task; that is, the voxels on T<sub>2</sub>-weighted images are treated as samples and exclusively assigned as DWMA or normal white matter voxel classes. To utilize the spatial information of individual voxels, small image patches centered on the given voxels are retrieved. A deep convolutional neural networks (CNN) model was developed to differentiate DWMA and normal voxels. We tested our deep CNN in multiple validation experiments. First, we examined DWMA detection accuracy of our CNN model using computer simulations. This was followed by <i>in vivo</i> assessments in a cohort of very preterm infants (<i>N</i> = 95) using cross-validation and holdout validation. Finally, we tested our approach on an <i>independent</i> preterm cohort (<i>N</i> = 28) to externally validate our model. Our deep CNN model achieved Dice similarity index values ranging from 0.85 to 0.99 for DWMA detection in the aforementioned validation experiments. Our proposed deep CNN model exhibited significantly better performance than other popular machine learning models. We present an objective and automated approach for accurately identifying DWMA that may facilitate the clinical diagnosis of DWMA in very preterm infants.
Biological approaches to generating cardiac biopacemaker for bradycardia. (2007)

Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sinoatrial (SA) node which locates in the right atrium. SA node dysfunction or atrial-ventricular (AV) conduction block causes improper heart rate (bradycardia). Such dysfunction, if severe enough, is currently treated by implanting an electronic pacemaker which has been well established technically, but there are some limitations and inadequacies. Recently, progress in developing engineered cardiac biopacemakers with use of genes or cells has been made in experimental animal models. The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel (pacemaker channel) modulates cardiac automaticity via the hyperpolarization-activated cation current (I(f)). HCN genes have been delivered to animal myocardium via viral vectors or HCN-transferred cells for recreating biological pacemakers. Approaches with non-HCN genes or transplantation of beating cells are also novel and have been investigated for generating cardiac biopacers. This article summarizes the progresses in research on recreation of cardiac biopacemakers. Genetically engineered biological pacemaker holds great promise to potentially cure severe bradycardia if critical issues, such as their stability and longevity, are properly solved.
Protein Arginine Deiminase 4:  Evidence for a Reverse Protonation Mechanism (2007)

The presumed role of an overactive protein arginine deiminase 4 (PAD4) in the pathophysiology of rheumatoid arthritis (RA) suggests that PAD4 inhibitors could be used to treat an underlying cause of RA, potentially offering a mechanism to stop further disease progression. Thus, the development of such inhibitors is of paramount importance. Toward the goal of developing such inhibitors, we initiated efforts to characterize the catalytic mechanism of PAD4 and thereby identify important mechanistic features that can be exploited for inhibitor development. Herein we report the results of mutagenesis studies as well as our efforts to characterize the initial steps of the PAD4 reaction, in particular, the protonation status of Cys645 and His471 prior to substrate binding. The results indicate that Cys645, the active site nucleophile, exists as the thiolate in the active form of the free enzyme. pH studies on PAD4 further suggest that this enzyme utilizes a reverse protonation mechanism.
Atomic Layer Deposition of AlF<sub>3</sub> Thin Films Using Halide Precursors (2014)

Aluminum fluoride thin films have potential in both optic and lithium-ion battery applications. AlF3 thin films have mostly been deposited using physical vapor deposition methods. In this study, we present a new atomic layer deposition process for AlF3. Our method makes use of a halide–halide exchange reaction with AlCl3 and TiF4 as the precursors. With this new chemistry, thin films of AlF3 can be deposited at a temperature range of 160–340 °C. The films have been studied by UV–vis spectroscopy, field emission scanning electron microscopy, X-ray diffraction, X-ray reflectance, atomic force microscopy, time-of-flight elastic recoil detection analysis (ToF-ERDA), energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. At 220 °C, the growth rate of the films is approximately 1.1 Å per cycle, and the refractive index is 1.36 (at 580 nm). The films show only small amounts of Cl and Ti impurities when deposited at high temperatures, as determined by ToF-ERDA. Surface oxidation of the films due to moisture in ambient air is observed.
Microwave response measurement and modeling of high-temperature superconducting thin-film detectors (1994)

We report here a model of a high temperature superconducting detector response to microwaves. The goal of the model is to approximate, based on microscopic theoretical results, the measured response of a superconducting detector to microwave frequency over a wide temperature range (from zero up to the critical temperature of the superconductor, T<SUB>c</SUB>). In this work, the nonbolometric response is emphasized because its detector performance is better than the bolometric response. The nonbolometric response model is based on microwave enhancement of a thermal fluctuation voltage occurring in the networks of inherent Josephson junctions. Modeling the film as a distribution of granular connections with varying critical currents and temperatures yields results similar to those observed in microwave response measurements in granular Bi-Sr-Ca-Cu-O thin films. We also report here initial measurements and modeling of the microwave (9 GHz) response of a bi-epitaxial thin film showing the simultaneous presence of bolometric and nonbolometric response peaks in the same sample. The response in this Y-Ba-Cu-O thin films gives further evidence of microwave detection in the networks of inherent Josephson junctions presented at the grain boundaries of two epitaxial layers.
Abstract PR02: Identification of ERK1/2 mutations that confer resistance to MAPK pathway inhibitors (2015)

Abstract Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increased progression free survival by many months. However, resistance to these targeted agents is a common occurrence, with relapse occurring in almost every case. Many of the alterations that confer clinical resistance to RAF and MEK inhibitors in BRAF mutant melanoma reactivate the MAPK pathway, but remain sensitive to ERK inhibition in vitro. Prospectively determining mechanisms of resistance to MAPK pathway inhibitors, such as an ERK inhibitor, before clinical trials begin may inform which patients will respond to therapy, potential markers of resistance, or best therapy combinations. Previous studies have shown that in vitro random mutagenesis screens can select specific alleles seen in resistant patient populations. Since ERK inhibitors are entering clinical trials, we wanted to determine mutations in ERK1 and ERK2 that could confer resistance to ERK or RAF/MEK inhibition. Therefore, we expressed dox-inducible ERK1 or ERK2 mutant libraries in A375 cells, which were then treated with MAPK inhibitor(s) and doxycycline until resistant cells emerged. Exogenous ERK1 or ERK2 was analyzed in resistant cells by massively parallel DNA sequencing. We validated 15 alleles that conferred resistance to the ERK inhibitor, VX-11e, and 11 alleles that conferred resistance to RAF, MEK, or RAF+MEK inhibition (dabrafenib and trametinib). Some resistance alleles were analogous between ERK1 and ERK2, while others were specific to ERK1 or ERK2. ERK inhibitor resistant alleles were localized to areas surrounding the ATP/drug binding site, including the glycine-rich loop, c-helix, and activation loop. These alleles were also cross-resistant to another ERK inhibitor, SCH-772984, albeit some only at lower concentrations. The RAF/MEK inhibitor resistant residues were located in the c-helix, activation loop, and common docking domain. Only a single ERK1 allele was found to confer resistance to RAF + MEK and ERK inhibition, suggesting that resistance mutations in ERK might be suppressed if RAF, MEK, and ERK inhibitors are given in combination. In addition, an ERK mutation arising in a patient treated with an ERK inhibitor would still be sensitive to RAF/MEK inhibition and vice versa. Screening for these alleles before administering therapy or after relapse may help inform patient treatment. Citation Format: Eva M. Goetz, Mahmoud Ghandi, Daniel Treacy, Nikhil Wagle, Levi A. Garraway. Identification of ERK1/2 mutations that confer resistance to MAPK pathway inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR02.
A novel tunable optical add/drop multiplexer with liquid crystal as the active layer (2004)

In this talk, we propose a novel tunable optical add/drop multiplexer (OADM), based on Asymmetric Bragg Coupler (ABC) and the liquid crystal as the active layer material. The asymmetric Bragg coupler is made of OG series polymer ridged waveguide. The liquid crystal is filled to cover the waveguide structure, which sandwiches between upper and bottom electrodes. When the external voltage applied, the index of liquid crystal changes to adjust effective index of coupler and inherently tunes the transmission spectrum of the device precisely. The transmission bandwidth is about 32.5GHz, and the tunable range is about 250GHz centered at 1.55nm.
Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics (2020)

The development of targeted medicine has greatly expanded treatment options and spurred new research avenues in cancer therapeutics, with monoclonal antibodies (mAbs) emerging as a prevalent treatment in recent years. With mixed clinical success, mAbs still hold significant shortcomings, as they possess limited tumor penetration, high manufacturing costs, and the potential to develop therapeutic resistance. However, the recent discovery of "nanobodies," the smallest-known functional antibody fragment, has demonstrated significant translational potential in preclinical and clinical studies. This review highlights their various applications in cancer and analyzes their trajectory toward their translation into the clinic.
Automated <i>In Vivo</i> Sub-Hertz Analysis of Viscoelasticity (SAVE) for Evaluation of Breast Lesions (2017)

We present an automated method for acquiring images and contrast parameters based on mechanical properties of breast lesions and surrounding tissue at load frequencies less than 1 Hz. The method called sub-Hertz analysis of viscoelasticity (SAVE) uses a compression device integrated with ultrasound imaging to perform in vivo ramp-and-hold uniaxial creep-like test on human breast in vivo. It models the internal deformations of tissues under constant surface stress as a linear viscoelastic response. We first discuss different aspects of our unique measurement approach and the expected variability of the viscoelastic parameters estimated based on a simplified one-dimensional reconstruction model. Finite-element numerical analysis is used to justify the advantages of using imaging contrast over viscoelasticity values. We then present the results of SAVE applied to a group of patients with breast masses undergoing biopsy.
Method for in situ heating hydrocarbonaceous formations. [Radio frequency heating] (1986)

A method for extracting valuable constituents from underground hydrocarbonaceous deposits such as heavy crude, tar sands and oil shale is disclosed. Initially, a stratum containing a rich deposit is hydraulically fractured to form a horizontally extending fracture plane. A conducting liquid and proppant are then injected into the fracture plane to form a conducting plate. Electrical excitations are then introduced into the stratum adjacent the conducting plate to retort the rich stratum along the conducting plate. The valuable constituents from the stratum adjacent the conducting plate are then recovered. Subsequently, the remainder of the deposit is also combustion retorted to further recover valuable constituents from the deposit. Various rf heating systems are also disclosed for use in the present invention. 5 figs.
Elliptic constellations for optimal coverage of selected geographical areas (1996)

Elliptical satellite constellations can provide more intensive coverage of selected geographical areas (i.e., higher redundancy, higher elevation angles, and longer dwell times) than can circular LEO constellations, with fewer satellites at a lower total system cost. It has been shown that total continuous global coverage can be obtained with only four elliptic satellites (but cannot be obtained with four circular satellites). The use of elliptic orbits has been proven very effective in covering specified latitudinal zones (e.g., the Russian Molniya system). The authors have developed and have patents pending on elliptic constellations, or arrays, lying in the equatorial plane, and at the two critical inclinations for elliptic orbits (63.435 and 116.565 deg). These arrays are designed to concentrate coverage with respect to both longitude and latitude positions, and also to time of day. Longitudinal coverage is concentrated on equally spaced meridians; this spacing is a function of satellite mean motion. Latitudinal coverage and time-of-day coverage is optimized through proper orientation of the ellipse in either of the critically inclined planes through selection of suitable eccentricity and argument of perigee. (Author)
Total Chemical Synthesis of Di‐ubiquitin Chains (2010)

Building the chains: A general and effective approach for the total chemical synthesis of all the di-ubiquitin chains (see picture) is presented. The behavior of the synthetic chains in the presence of isopeptidase T, an enzyme responsible for the disassembly of the majority of unanchored polyubiquitin in vivo, was examined. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Magnetic-Characteristic-Free High-Speed Position-Sensorless Control of Switched Reluctance Motor Drives With Quadrature Flux Estimators (2021)

High-speed position-sensorless control of switched reluctance motor (SRM) drives is often realized by searching <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">a priori</i> flux linkage lookup table. However, obtaining the nonlinear flux linkage characteristic requires time-consuming offline measurement and occupies large memory storage. To deal with this problem, this article proposes a new position estimation scheme for SRM drives without using any magnetic characteristics. This feature is achieved by using a quadrature flux estimator (QFE) that can extract the fundamental flux and its quadrature signal from the real-time calculated flux linkage. The flux bias and flux harmonics can also be suppressed by the QFE’s adaptive bandpass capability. Therefore, the proposed method can reduce the nonlinearity in SRM flux linkage and derive simple sine–cos position signals. Afterward, the rotor position and speed can be estimated from the orthogonal flux signals using a three-phase phase-locked loop. To baseline the advantages, comparative experimental validation with the conventional method is conducted on a three-phase 12/8 SRM test bench. The results show that the proposed scheme can achieve the same estimation accuracy as the conventional method even though no magnetic characteristics are used.
A Humanized Anti-Tumor Necrosis Factor-α Monoclonal Antibody That Acts as a Partial, Competitive Antagonist of the Template Antibody (1994)

We have constructed several humanized versions of a monoclonal antibody (MAb78) against human tumor necrosis factor-alpha (huTNF-alpha) retaining the complementarity-determining regions (CDR) of the original mouse MAb with or without a variable number of original framework region (FR) residues. All versions, except one, showed a loss of binding affinity and neutralizing potency of at least 10-fold compared to the original mouse MAb or its chimeric equivalent. In some cases, however, the decrease in neutralizing potency was significantly greater than the decrease in binding affinity. Two humanized versions showing the greatest dissociation between these two parameters were studied for their capacity to inhibit the neutralizing activity of chimeric or murine MAb78 when used at concentrations that bound but only partially neutralized huTNF-alpha. One humanized version (MAb78D) was indeed able to do so, whereas the other (MAb78C) was not found to exert any inhibitory activity at all concentrations tested. The antagonistic effect of MAb78D was concentration dependent and could be overcome by increasing the concentrations of chimeric or murine MAb78. Two different models of MAb78-huTNF-alpha interaction that may help explain the antagonist activity of humanized MAb78D are discussed.
Adaptive Soft Detection for Flash Memory (2019)

To provide reliability of flash memory, error-correcting codes are usually used which can be further enhanced by moving on from hard-decision to soft-decision decoders. This requires multiple readings to obtain a reliability measure of the stored data, which is complicated by the fact that a posteriori probability distributions change as the memory ages through retention and wear-out. The existing methods for reading a flash memory either assume knowledge of these distributions or require a large number of readings for accurate estimation. In this letter, we propose a low-complexity algorithm that tracks the soft-decision boundaries and estimates the corresponding log-likelihood ratios (LLRs). It does not require any additional readings and only involves simple calculations using already available variables. The efficacy is verified through the simulations and is shown to provide near-optimal performance.
Coupled Inductors in Interleaved Multiphase Three-Level DC–DC Converter for High-Power Applications (2015)

This paper investigates and evaluates coupled inductors (CIs) in the interleaved multiphase three-level dc-dc converter. If non-CIs are used in the multiphase three-level dc-dc converter, interleaving operation of the converter will increase inductor current ripple, although the overall output current ripple and common-mode (CM) voltage will become smaller. To reduce inductor current ripple, inverse-CIs are employed. The current ripple in the CI is analyzed in detail. The benefits of the three-level dc-dc converter with CIs under interleaving operation are evaluated. By adding CIs and working under interleaving operation, smaller inductor current ripple, smaller overall output current ripple, and smaller CM voltage can be achieved simultaneously compared with the noninterleaving case. The analysis results are verified by simulations and 10 kW scale-down experiments.
Improved Mechanical Seals For Tubes (1996)

Improved tube-to-fitting seals made by application of soft metal pieces to either ends of tubes or to interior of fittings. Metal silver, gold, platinum, tin, or other easily malleable metal selected to be inert with fluid of use. Metal plated, evaporated, or sputter-deposited. Coat of soft metal thin, so no changes required in design or tolerances of standard fittings. Technique suitable for hydraulic or other fluid systems in which leakage from mechanically joined sections of tubes occur.