cssi/SciSciGPT-SciSciNet huggingface dataset:
Traust: a trust negotiation-based authorization service for open systems

In recent years, trust negotiation (TN) has been proposed as a novel access control solution for use in open system environments in which resources are shared across organizational boundaries. Researchers have shown that TN is indeed a viable solution for these environments by developing a number of policy languages and strategies for TN which have desirable theoretical properties. Further, existing protocols, such as TLS, have been altered to interact with prototype TN systems, thereby illustrating the utility of TN. Unfortunately, modifying existing protocols is often a time-consuming and bureaucratic process which can hinder the adoption of this promising technology.In this paper, we present Traust, a third-party authorization service that leverages the strengths of existing proto-type TN systems. Traust acts as an authorization broker that issues access tokens for resources in an open system after entities use TN to satisfy the appropriate resource access policies. The Traust architecture was designed to allow Traust to be integrated either directly with newer trust-aware applications or indirectly with existing legacy applications; this exibility paves the way for the incremental adoption of TN technologies without requiring widespread software or protocol upgrades. We discuss the design and implementation of Traust, the communication protocol used by the Traust system, and its performance. We also discuss our experiences using Traust to broker access to legacy resources, our proposal for a Traust-aware version of the GridFTP protocol, and Traust's resilience to attack.
A portable runtime interface for multi-level memory hierarchies

We present a platform independent runtime interface for moving data and computation through parallel machines with multi-level memory hierarchies. We show that this interface can be used as a compiler target and can be implemented easily and efficiently on a variety of platforms. The interface design allows us to compose multiple runtimes, achieving portability across machines with multiple memory levels. We demonstrate portability of programs across machines with two memory levels with runtime implementations for multi-core/SMP machines, the STI Cell Broadband Engine, a distributed memory cluster, and disk systems. We also demonstrate portability across machines with multiple memory levels by composing runtimes and running on a cluster of SMP nodes, out-of-core algorithms on a Sony Playstation 3 pulling data from disk, and a cluster of Sony Playstation 3's. With this uniform interface, we achieve good performance for our applications and maximize bandwidth and computational resources on these system configurations.
A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36

The dynamic reversible methylation of lysine residues on histone proteins is central to chromatin biology. Key components are demethylase enzymes, which remove methyl moieties from lysine residues. KDM2A, a member of the Jumonji C domain-containing histone lysine demethylase family, specifically targets lower methylation states of H3K36. Here, structural studies reveal that H3K36 specificity for KDM2A is mediated by the U-shaped threading of the H3K36 peptide through a catalytic groove within KDM2A. The side chain of methylated K36 inserts into the catalytic pocket occupied by Ni(2+) and cofactor, where it is positioned and oriented for demethylation. Key residues contributing to K36me specificity on histone H3 are G33 and G34 (positioned within a narrow channel), P38 (a turn residue), and Y41 (inserts into its own pocket). Given that KDM2A was found to also bind the H3K36me3 peptide, we postulate that steric constraints could prevent α-ketoglutarate from undergoing an "off-line"-to-"in-line" transition necessary for the demethylation reaction. Furthermore, structure-guided substitutions of residues in the KDM2A catalytic pocket abrogate KDM2A-mediated functions important for suppression of cancer cell phenotypes. Together, our results deduce insights into the molecular basis underlying KDM2A regulation of the biologically important methylated H3K36 mark.
Impacts of Fire and Warming on Ecosystem Uptake in the Boreal Forest

Abstract Observations show that the amplitude of the annual atmospheric carbon dioxide cycle has increased. Lagged correlations between carbon dioxide, temperature, and vegetation suggest a modulation by ecosystem response, but the mechanisms remain unclear. Hypotheses include an early season uptake increase and/or winter respiration increase related to climate warming, and increased cycling in cooler conditions caused by disturbances such as fire. The first hypotheses suggest a positive feedback to regional warming, whereas the last suggests a negative feedback. Here it is shown that fire, as it influences species composition, can serve to enhance the increase in early season uptake but that a crucial determinant for the sign of the feedback is the impact of climate change on soil moisture.
Inhibition of mutant KrasG12D-initiated murine pancreatic carcinoma growth by a dual c-Raf and soluble epoxide hydrolase inhibitor t-CUPM.

Mutant Kras and chronic pancreatitis are the most common pathological events involved in human pancreatic cancer. It has been demonstrated that c-Raf is responsible for transmitting signals from mutant Ras to its downstream signals including MEK-ERK and for initiating carcinogenesis. The soluble epoxide hydrolase (sEH), a pro-inflammatory enzyme, generally inactivates anti-inflammatory and anti-pain epoxyeicosatrienoic acids (EETs). Herein, we have synthesized a novel compound of trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM) via modifying the central phenyl ring of sorafenib and confirmed its dual inhibition of sEH and c-Raf by recombinant kinase activity assay. Pharmacokinetic analysis revealed that oral dosing of t-CUPM resulted in higher blood levels than that of sorafenib throughout the complete time course (48 h). The effect of t-CUPM on the inhibition of mutant Kras(G12D)-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-Kras(G12D)/Pdx1-Cre mice and showed that t-CUPM significantly inhibited this murine pancreatic carcinoma cell growth both in vitro and in mice in vivo. Inhibition of mutant Kras-transmitted phosphorylations of cRAF/MEK/ERK was demonstrated in these pancreatic cancer cells using Western blot assay and immunohistochemical approach. Modulation of oxylipin profile, particularly increased EETs/DHET ratio by sEH inhibition, was observed in mice treated with t-CUPM. These results indicate that t-CUPM is a highly potential agent to treat pancreatic cancer via simultaneously targeting c-Raf and sEH.
Momentum and Energy

Although Newton’s Laws of Motion form the fundamental basis of Newtonian Mechanics, there are several other important concepts that are an integral part of that subject. In this chapter we use Maxima to examine some of these concepts, including linear and angular momentum, center of mass, work, and energy.
Why Metrics Matter: Evaluating Policy Choices for Reactive Nitrogen in the Chesapeake Bay Watershed †

Despite major efforts, the reduction of reactive nitrogen (Nr) using traditional metrics and policy tools for the Chesapeake Bay has slowed in recent years. In this article, we apply the concept of the Nitrogen Cascade to the chemically dynamic nature and multiple sources of Nr to examine the temporal and spatial movement of different forms of Nr through multiple ecosystems and media. We also demonstrate the benefit of using more than the traditional mass fluxes to set criteria for action. The use of multiple metrics provides additional information about where the most effective intervention point might be. Utilizing damage costs or mortality metrics demonstrates that even though the mass fluxes to the atmosphere are lower than direct releases to terrestrial and aquatic ecosystems, total damage costs to all ecosystems and health are higher because of the cascade of Nr and the associated damages, and because they exact a higher human health cost. Abatement costs for reducing Nr releases into the air are al...
Improvements in graphite-furnace atomic-absoption microanalysis with solid sampling

Microanalysis using mechanized solid sampling with graphite-furnace atomic-absorption gives accurate results in the determination of trace elements in different NBS Standard Reference Materials. Analytical conditions are optimized by use of the method of standard additions, and all capabilities of a microcomputer controlled graphite furnace, such as matrix modification by oxygen ashing, temperature ramping and maximum power heating for atomization are used. Direct calibration against acid standards is possible.
Critical Illness in Patients With Asplenia

The critically ill, asplenic patient presents a variety of management challenges. Historically, the focus of the care of the asplenic population has been the prevention and management of infection, including the often-fatal overwhelming postsplenectomy infection with encapsulated organisms such as Streptococcus pneumoniae. Recently, however, there has been increasing recognition of the spleen's function in areas outside of immunity because the asplenic state has been identified as a risk factor for such vascular complications as thrombosis and pulmonary hypertension resulting from dysregulated inflammation and coagulation. Because of the relatively small size of this population and the relative infrequency with which critical illness occurs in it, there are few controlled trials that can serve as a basis for therapeutic maneuvers; thus, optimal management requires an astute clinician with an understanding of the pathogenetic mechanisms underlying the reported consequences of splenectomy. The purpose of this review is to explore the pathophysiology of the asplenic state-impairment in adaptive immunity, loss of blood filtration, endothelial dysfunction, and dysregulated coagulation-and how it leads to infection, thrombosis, and pulmonary hypertension as well as to discuss the implications of these conditions on the management of the critically ill, splenectomized patient.
MEASURING METHOD AND BESIC CHARACTERISTICS OF P-WAVE QUALITY FACTOR OF THE DESERT SURFACE IN XINJIANG

There is not a set of mature and effective method to measure formation quality factor by far. In this paper, a set of instruments and approaches are designed to measure quality factor, which can emulate the situation measured in different buried depth and water saturation condition, and measure the quality factor of unconsolidated sands or clay. Through testing many sands'samples from the Tarim and the Zhungar basin, the stability and the reliability of the instruments and the measuring technique are identified. The research discovers that compression wave quality factor of the sands in desert surface increases as the buried depth and the compression wave velocity's increase. When the relative water content is smaller than a certain value, the quality factor increases as the water content's decrease. After the relative water content reaches this value, the quality factor increases as the water content's increase, which are of importance to the study of seismic wave energy loss and seismic data processing and interpretation.
Considerations on radiation source selection and utilization in vascular brachytherapy.

Three radiation sources have been approved for commercial use in vascular brachytherapy. The beta sources ( 9 0 Strontium and 3 2 Phosphorous) are more popular because of less radiation protection concerns than gamma sources. Because '°Strontium has a longer half-life than 3 2 Phosphorous, it requires less frequent source exchanges. Also, because 9 0 Strontium is more penetrating, a similar benefit can be achieved with lower delivered doses. Based on these advantages, 9 0 Strontium is the preferred isotope for vascular brachytherapy.
Case Study 1. Practical Considerations with Experimental Design and Interpretation

At some point, anyone with knowledge of drug metabolism and enzyme kinetics started out knowing little about these topics. This chapter was specifically written with the novice in mind. Regardless of the enzyme one is working with or the goal of the experiment itself, there are fundamental components and concepts of every experiment using drug metabolism enzymes. The following case studies provide practical tips, techniques, and answers to questions that may arise in the course of conducting such experiments. Issues ranging from assay design and development to data interpretation are addressed. The goal of this section is to act as a starting point to provide the reader with key questions and guidance while attempting his/her own work.
Relationship of bile acid pool size to biliary lipid excretion and the formation of lithogenic bile in man.

This study was designed to provide additional information on the relationship between a diminished bile acid pool and cholesterol gallstone formation in man. The total bile acid pool and biliary lipid composition were determined in 10 patients with gallstones and 10 patients without gallstones. Bile was obtained from all patients at the same time of day (8 am to 9 am fasting). From these data the amounts of biliary phospholipid and cholesterol secreted during a single total bile acid pool cycle were calculated. In agreement with our earlier findings, patients with cholesterol gallstones (and a lithogenic bile) were found to have a greatly diminished bile acid pool. The bile acid pool was 50% smaller than in patients without gallstones (and a normal bile). Patients with gallstones also had a greatly decreased phospholipid excretion. There was a slight decrease in the excretion of biliary cholesterol in patients with gallstones, but this difference was not significant. There was a high degree of correlation (r = 0.80) between phospholipid excretion and bile acid pool size. There was a lesser degree of correlation (r = 0.61) between bile acid pool size and cholesterol excretion. Phospholipid excretion was considerably more responsive to bile acid pool size than cholesterol. The results of this study suggest that patients with cholesterol .gallstones have a diminished bile acid pool and, as a consequence, a decreased phospholipid excretion and only a slight decrease in cholesterol excretion. This leads to a relative decrease in bile salts and phospholipid in relation to cholesterol and a bile saturated with cholesterol. The breakpoint in bile acid pool size between male patients with and without gallstones was estimated to be in the vicinity of 1.6 to 1.8 g.
Breast cancer biologic and etiologic heterogeneity by young age and menopausal status in the Carolina Breast Cancer Study: a case-control study

Young-onset breast cancer (<40 years) is associated with worse prognosis and higher mortality. Breast cancer risk factors may contribute to distinct tumor biology and distinct age at onset, but understanding of these relationships has been hampered by limited representation of young women in epidemiologic studies and may be confounded by menopausal status. We examined tumor characteristics and epidemiologic risk factors associated with premenopausal women’s and young women’s breast cancer in phases I–III of the Carolina Breast Cancer Study (5309 cases, 2022 control subjects). Unconditional logistic regression was used to assess heterogeneity by age (<40 vs. ≥40 years) and menopausal status. In both premenopausal and postmenopausal strata, younger women had more aggressive disease, including higher stage, hormone receptor-negative, disease as well as increased frequency of basal-like subtypes, lymph node positivity, and larger tumors. Higher waist-to-hip ratio was associated with reduced breast cancer risk among young women but with elevated risk among older women. Parity was associated with increased risk among young women and reduced risk among older women, while breastfeeding was more strongly protective for young women. Longer time since last birth was protective for older women but not for young women. In comparison, when we stratified by age, menopausal status was not associated with distinct risk factor or tumor characteristic profiles, except for progesterone receptor status, which was more commonly positive among premenopausal women. Age is a key predictor of breast cancer biologic and etiologic heterogeneity and may be a stronger determinant of heterogeneity than menopausal status. Young women’s breast cancer appears to be etiologically and biologically distinct from that among older women.
Quantifying differences in cell line population dynamics using CellPD

The increased availability of high-throughput datasets has revealed a need for reproducible and accessible analyses which can quantitatively relate molecular changes to phenotypic behavior. Existing tools for quantitative analysis generally require expert knowledge. CellPD (cell phenotype digitizer) facilitates quantitative phenotype analysis, allowing users to fit mathematical models of cell population dynamics without specialized training. CellPD requires one input (a spreadsheet) and generates multiple outputs including parameter estimation reports, high-quality plots, and minable XML files. We validated CellPD’s estimates by comparing it with a previously published tool (cellGrowth) and with Microsoft Excel’s built-in functions. CellPD correctly estimates the net growth rate of cell cultures and is more robust to data sparsity than cellGrowth. When we tested CellPD’s usability, biologists (without training in computational modeling) ran CellPD correctly on sample data within 30 min. To demonstrate CellPD’s ability to aid in the analysis of high throughput data, we created a synthetic high content screening (HCS) data set, where a simulated cell line is exposed to two hypothetical drug compounds at several doses. CellPD correctly estimates the drug-dependent birth, death, and net growth rates. Furthermore, CellPD’s estimates quantify and distinguish between the cytostatic and cytotoxic effects of both drugs—analyses that cannot readily be performed with spreadsheet software such as Microsoft Excel or without specialized computational expertise and programming environments. CellPD is an open source tool that can be used by scientists (with or without a background in computational or mathematical modeling) to quantify key aspects of cell phenotypes (such as cell cycle and death parameters). Early applications of CellPD may include drug effect quantification, functional analysis of gene knockout experiments, data quality control, minable big data generation, and integration of biological data with computational models.
Optimizing Positioning for In-Office Otology Procedures:

ObjectiveSurgeons often report musculoskeletal discomfort in relation to their practice, but few understand optimal ergonomic positioning. This study aims to determine which patient position—sittin...
Distributed Estimation, Guidance, and Control of Formation Flying Spacecraft

Abstract: A three-tiered distributed architecture is proposed in which agents would inde- pendently estimate formation states, determine position assignment, and achieve and hold formation. Simulations of formation flying spacecraft in a low earth orbit are provided to demonstrate a practical case for the proposed three layer structure. Major advantages of such an approach are the relaxation of communication constraints and increased fuel efficiency.
Voltage Regulator Efficiency Aware Power Management

Conventional off-chip voltage regulators are typically bulky and slow, and are inefficient at exploiting system and workload variability using Dynamic Voltage and Frequency Scaling (DVFS). On-die integration of voltage regulators has the potential to increase the energy efficiency of computer systems by enabling power control at a fine granularity in both space and time. The energy conversion efficiency of on-chip regulators, however, is typically much lower than off-chip regulators, which results in significant energy losses. Fine-grained power control and high voltage regulator efficiency are difficult to achieve simultaneously, with either emerging on-chip or conventional off-chip regulators.A voltage conversion framework that relies on a hierarchy of off-chip switching regulators and on-chip linear regulators is proposed to enable fine-grained power control with a regulator efficiency greater than 90%. A DVFS control policy that is based on a reinforcement learning (RL) approach is developed to exploit the proposed framework. Per-core RL agents learn and improve their control policies independently, while retaining the ability to coordinate their actions to accomplish system level power management objectives. When evaluated on a mix of 14 parallel and 13 multiprogrammed workloads, the proposed voltage conversion framework achieves 18% greater energy efficiency than a conventional framework that uses on-chip switching regulators. Moreover, when the RL based DVFS control policy is used to control the proposed voltage conversion framework, the system achieves a 21% higher energy efficiency over a baseline oracle policy with coarse-grained power control capability.
Long-Term Housing and Intimate Partner Violence: Journeys to Healing

For survivors of intimate partner violence (IPV), safe, affordable, long-term housing is a critical aspect of establishing a life free from abuse. New permanent housing models for IPV survivors, wh...
Fractal neuronal firing patterns

Publisher Summary This chapter discusses the discharge pattern of auditory nerve axons. The dead-time-modified Poisson point process model of neuronal firing is successful in describing inter spike-interval histograms and post-stimulus-time histograms, measures that reset at relatively short times and are therefore insensitive to long-time correlations in spike occurrences. The patterns of neuronal firing have been examined in single mammalian neurons at various locations along auditory pathways, including the auditory nerve, the cochlear nucleus, which is the first way station, and the lateral superior olivary complex. The chapter also highlights the several biophysical origins and functional significance of fractal behavior. It also presents the three mathematical models for describing the point process auditory neural firings. The first model is applicable for an arbitrary stationary point process with constant rate, second model is a fractal doubly stochastic Poisson point process, and third model is a generalization of the first that is suitable for a time-varying rate or stimulus.
THE EFFECTS OF oriC-CONTAINTNG PLASMIDS ON HOST CELL GROWTH

ABSTRACT, The extent of growth disturbance of E. coli B/r F44 recA caused by maintenance of plasmids containing either functioning or nonfunctioning chromosome replication origins ( oriC ) was examined. These studies were performed in medium with glucose or glucose plus casamino acids as carbon sources under conditions in which the majority of cells in the populations harbored plasmids. pALl, consisting of a 5.9-MD EcoRI chromo-somal DNA fragment containing oriC and a 4.5-MD frag-ment encoding kanamycin resistance, caused a 2-fold increase in generation times, a 10 to 35% increase in cell mass and DNA content, and little change in DNA/cell mass ratio. pAL2, a deletion derivative of pALl, caused a 20 to 35% increase in generation times and had little effect on other cell properties. pAL3, a composite plasmid consisting of the chromosomal DNA from pAL2 joined to a high copy number cloning vehicle (pACYC184), did not affect exponential phase growth properties of host cells during replication from ori pACYC184. It is most likely that the growth disturbances, where they existed, were consequences of plasmid segregation deficiencies rather than competition between plasmid and chromosomal oriC for rate-limiting factors involved in initiation of chromosome replication.
Cell Culture: Autonomic and Enteric Neurons

Sympathetic neuronal culture is widely used in mechanistic studies of neuronal development, plasticity, and neurotransmission. Other than chick ciliary ganglia, parasympathetic and enteric cultures have not been widely used, with most studies focusing on electrophysiological and pharmacological properties of these cells. Recent advances in isolating, maintaining, and manipulating gene expression in autonomic and enteric cultures will increase the power of these culture models for addressing significant gaps in our understanding of the cell biology of these neurons, the impact of which is underscored by the importance of autonomic and enteric nervous systems in regulating all major organ systems in vertebrates.
State Variable Methods

The system analysis methods considered in previous chapters involved primarily linear, time-invariant, single-input-single-output (SISO) systems. To find the step response of a continuous system described by its differential equation, we used classical and Laplace transform methods. Similarly, to analyze a discrete system represented by its difference equation, we employed classical and Ƶ transform techniques.
Safe Food Handling for Successful Pregnancy Outcomes

Pregnancy is one of the vital phases of a woman’s life during which hormonal changes such as increased progesterone levels downregulate immune function to prevent the death of the fetus. These hormonal changes make pregnant women vulnerable to food-borne illnesses by microbial pathogens (Listeria monocytogenes, Toxoplasma gondii, Salmonella, and others) and chemical contaminants (methyl mercury from seafood). Subsequent illnesses may lead to serious health consequences such as miscarriage, stillbirth, premature delivery, or serious infection of the newborn, neonatal sepsis, chorioamnionitis, meningitis, mental retardation, and harsh neurological effects for the fetus, mother, and/or the newborn.
A Catalog of Redshift Estimates for 1366 BATSE Long-Duration Gamma-Ray Bursts: Evidence for Strong Selection Effects on the Phenomenological Prompt Gamma-Ray Correlations

We present a catalog of the redshift estimates and probability distributions for 1366 individual Long-duration Gamma-Ray Bursts (LGRBs) detected by the Burst And Transient Source Experiment (BATSE). This result is based on a careful classification and modeling of the population distribution of BATSE LGRBs in the 5-dimensional space of redshift as well as intrinsic prompt gamma-ray emission properties: peak luminosity, total isotropic emission, the spectral peak energy, and the intrinsic duration, while taking into account the detection mechanism of BATSE and sample incompleteness. The underlying assumption in our modeling approach is that LGRBs trace the Cosmic Star Formation Rate and that the joint 4-dimensional distribution of the aforementioned prompt gamma-ray emission properties follows a multivariate log-normal distribution. Our modeling approach enables us to constrain the redshifts of BATSE LGRBs to average uncertainty ranges of $0.7$ and $1.7$ at $50\%$ and $90\%$ confidence levels, respectively. Our predictions are almost entirely at odds with the previous estimates of BATSE redshifts based on the phenomenological high-energy correlations, in particular with the estimates derived from the lag-luminosity and the variability-luminosity relations. There is, however, a weak but significant correlation of strength $\sim0.26$ between our predicted redshift estimates and those derived from the hardness-brightness relations. The discrepancies between the estimates can be explained by the strong influence of sample incompleteness in shaping the phenomenologically proposed high-energy correlations in the literature. The presented catalog here can be useful for demographic studies of LGRBs and studies of individual BATSE events.
Efficacy and Safety of Nasal High-Flow Therapy for Neonatal Transport.

Abstract Objective Noninvasive ventilation, including nasal high-flow therapy (nHFT), provides effective neonatal respiratory support. There are limited data on nHFT use during neonatal transport. Our objective was to assess the efficacy and safety of nHFT during neonatal transport. Methods One hundred ninety-five neonates transported on nHFT via a Neo-Pod “T” system (Westmed Inc, Tucson, AZ) were identified from Life Flight transport data. Data included demographics, transport location, distance, indication, and mode as well as pretransport and intratransport respiratory support data. We compared neonates who successfully tolerated nHFT transport with those who required support escalation (defined as increase in flow ≥2 L/min or fraction of inspired oxygen [FiO2] ≥20%). Results Eighty-seven percent of neonates (170/195) were effectively transported on nHFT. Infants requiring escalation of nHFT support had a significantly higher pretransport FiO2 (median = 0.60 [interquartile range, 0.36-1.00] vs. 0.36 [0.23-0.56]; P Conclusion Nasal HFT can be an effective mode of respiratory support in the transport of selected neonates. FiO2 at the time of transport may be a key parameter to aid in determining neonates who can be safely transported on nHFT.
Chemical Synthesis of Staphyloferrin A (I) and Its Application for Staphylococcus aureus Detection.

The title compound synthesized in six steps with 79% overall yield, shows excellent capacity to bind S.
Clinical and Therapeutic Implications of Cancer Stem Cells.

Cancer Stem Cells Cancers arise in tissues that can replicate and self-renew. Like normal tissues, cancers can replenish themselves, grow, and metastasize because of stem cells that are similar to ...
Lipid management beyond the guidelines

Abstract The 2018 AHA/ACC cholesterol guideline builds on the 2013 ACC/AHA cholesterol guideline statin recommendations to provide more detailed recommendations for the use of nonstatin therapy risk stratification for primary prevention statin use. New information has become available after the development of the 2018 AHA/ACC cholesterol guideline that can further inform clinical practice. Proprotein convertase subtilisin kexin type-9 (PCSK9) monoclonal antibodies are now a reasonable or even good value following over 60% reductions in their acquisition price, and the identification of high risk patient groups most likely to benefit from further low-density lipoprotein cholesterol (LDL-C) lowering. Meta-analyses and clinical trial data now show that patients with LDL-C ≥ 100 mg/dl are more likely to experience progressively greater reductions in the risk of cardiovascular and total mortality and coronary heart disease events for progressively higher LDL-C levels. Icosapent ethyl, a highly concentrated form of modified EPA has been shown to reduce cardiovascular events in high risk patients with moderate hypertriglyceridemia on statin therapy. Comparisons with other statin guidelines revealed that statin initiation for those with ≥7.5% 10-year atherosclerotic cardiovascular disease (ASCVD) risk is the most effective strategy for reducing the most ASCVD events for the proportion of the population treated. Data from younger populations finally became available for coronary artery calcium (CAC) scoring (mean age of 51 years) which confirmed the value of CAC > 0 for identifying individuals at increased ASCVD risk most likely to benefit from statin initiation. This analysis also found that statins could keep CAC = 0 in those with risk factors. Epidemiologic pooling studies now clearly show that LDL-C and non-high-density lipoprotein cholesterol levels in young adulthood confer excess risk for ASCVD later in life. Accumulating data support earlier risk factor intervention trials as the next research priority.
Prevalence and Knowledge of Potential Interactions Between Over-the-Counter Products and Apixaban

Background Direct-acting oral anticoagulants (DOACs), such as apixaban, are the most commonly prescribed anticoagulants, with advantages in that they do not require routine monitoring. However, less frequent contact with healthcare professionals may contribute to poor patient knowledge about potential interactions between over-the-counter (OTC) products and DOACs. Objective Determine the prevalence of use of OTC products (OTC medications and dietary supplements) with potentially serious apixaban interactions and assess patient knowledge of potential interactions. Design Cross-sectional survey. Setting Academic-affiliated outpatient medical practices in northern and southern California. Participants A total of 791 English- or Spanish-speaking patients prescribed apixaban. Measurements Use and knowledge of OTC medications and dietary supplements with potentially serious apixaban interactions. Results Almost all respondents (n = 771; 97.5%) reported OTC product use. Of respondents, 33% (n = 266) took at least one OTC product with potentially serious apixaban interactions daily/most days and 53 (6.7%) took multiple products (mean = 2.6 [SD = 2.6]). Aspirin was taken daily by 116 (14.7%; of which 75 [64.7%] also consumed other potentially interacting OTC products), and some days/as needed by an additional 82 (10.4%). Ibuprofen and naproxen were taken daily/most days by 14 (1.8%) and occasionally by 225 (28.5%). Dietary supplements with potentially serious interactions were taken daily/most days by 160 (20.2%). Approximately 66% of respondents were either uncertain or incorrect about the potential for increased bleeding from combining nonsteroidal anti-inflammatory drugs and apixaban. Less knowledge about OTC products with potentially serious interactions was associated with greater OTC product use (odds ratio = 0.54; 95% confidence interval = 0.35-0.85). Conclusion Significant numbers of patients take OTC products (particularly dietary supplements) with potentially serious interactions with the DOAC apixaban and appear to lack knowledge about potentially harmful interactions. Interventions are needed to educate patients and healthcare providers about potential dangers of taking interacting OTC products in combination with apixaban, and data are needed on outcomes associated with concomitant apixaban-OTC product use. J Am Geriatr Soc 68:155-162, 2019.
Low Incidence of FIP1L1-PDGFRA in Eosinophilic Patients and Long-Term Experience with Imatinib Therapy.

Background : The FIP1L1-PDGFRA fusion, an imatinib-sensitive molecular target, is detected in a subset of cases with moderate-to-severe eosinophilia (eosinophil count ≥1500/μL). Using 2 FISH strategies to detect loss of the CHIC2 locus as a surrogate marker of the FIP1L1-PDGFRA fusion, we previously found 14% of cases to be CHIC2 -deleted when studying bone marrow smears from 81 adult patients with moderate-to-severe, non-reactive eosinophilia at our institution ( Blood 2004, 104:3038–3045 ). Since then, the FISH test has been made available for routine clinical use both within our institution, and to external physicians as a mail-in test, for the workup of patients with eosinophilic disorders, including systemic mast cell disease (SMCD). Study design : FISH data, subsequent to the test’s introduction into routine clinical practice (from Nov. 2003), were retrospectively analyzed for CHIC2 -deletion. Data from the initial pilot study of 81 patients was not used in this analysis (Table). The imatinib treatment analysis, however, included all CHIC2 -deleted patients treated at our institution, including those from the pilot study (Table). Results : A total of 741 patients were studied in the post-pilot phase. Of these, 20 cases were found to be CHIC2 -deleted, with an overall prevalence of 2.7% (Table). Of the 219 patients seen at our institution, 13 (all male) were found to be CHIC2 -deleted (Table) (prevalence=5.9%), and of these, 10 have been treated with imatinib (100 mg/day starting dose) to date. Nine patients are evaluable for response - all achieved a complete clinical and histological remission (7 patients were tested by FISH post-treatment - all achieved cytogenetic remission). One patient received concomitant corticosteroids for co-morbidities and could not be evaluated for response. After a median follow-up of 24 months (range 17 to 39 months), all 9 patients continue to be in remission, with a normal eosinophil count. At last follow-up, one patient had discontinued imatinib and the others were on maintenance therapy at the following dose: 100mg/wk (n=1), 100mg BIW (n=1), 100mg TIW (n=2), 50mg QOD (n=1), and 100 mg/day (n=3). Conclusions : FIP1L1-PDGFRA prevalence in non-selected patients with eosinophilia is lower than anticipated from prior studies. Patients with FIP1L1-PDGFRA exhibit durable responses to imatinib therapy. It may be feasible to maintain some patients in remission on an empirically derived, intermittent schedule of low-dose imatinib.
Metabolic Labeling for the Visualization and Identification of Potentially O‐GlcNAc‐Modified Proteins

O-GlcNAcylation is a posttranslational modification involving the addition of the single monosaccharide N-acetylglucosamine (GlcNAc) onto serine and threonine residues of intracellular proteins. Though O-GlcNAc is found on ∼1000 proteins in mammals, its specific function on individual substrates remains largely a mystery. To overcome this shortcoming, work has been put toward developing metabolic chemical reporters (MCRs) to label O-GlcNAcylated proteins for subsequent biochemical analysis. Typically, these MCRs are GlcNAc or GalNAc analogs functionalized with azide or alkyne handles. These unnatural sugar moieties can be metabolically incorporated directly on to protein substrates. The protocols outlined in this article describe how to use MCRs as tools for visualizing and identifying potentially O-GlcNAc modified proteins via in-gel fluorescence, Western blotting, and mass spectrometry. Taken together, MCR labeling provides a powerful tool to discover where and when substrates are O-GlcNAc modified. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Treatment of cells and CuAAC Basic Protocol 2: In-gel fluorescence of labeled cell lysates (1 mg scale) Basic Protocol 3: Enrichment of labeled proteins, trypsinolysis, and collection of peptides for proteomics Basic Protocol 4: Proteomic identification of labeled proteins.
Ultraviolet Raman spectroscopy for understanding structure and formation mechanism of amyloid fibrils

Abstract Ultraviolet resonance Raman (UVRR) is a powerful tool for the study of biomolecular structure and dynamics including the secondary structure conformational analysis at the level of individual peptide bonds in large proteins. Deep ultraviolet resonance Raman (DUVRR) is uniquely suitable for structural characterization of proteins at all stages of amyloid fibril formation because it avoids interference from fluorescence, and selectively enhances the peptide backbone, making it suitable for the study of biological studies. The combination of hydrogen–deuterium exchange with DUVRR spectroscopy allows for probing the variations in cross-β core structure of fibril polymorphs. The application of advanced statistics, chemometrics, and two-dimensional correlation spectroscopy in particular for DUVRR spectra analysis significantly increases the quality and amount of information on protein structure and dynamics. This approach is especially useful for establishing the kinetic mechanisms of amyloid fibrillation, which is associated with numerous human diseases.
Effects of H2A.B incorporation on nucleosome structures and dynamics.

Abstract The H2A.B histone variant is an epigenetic regulator involved in transcriptional upregulation, DNA synthesis, and splicing that functions by replacing the canonical H2A histone in the nucleosome core particle. Introduction of H2A.B results in less compact nucleosome states with increased DNA unwinding and accessibility at the nucleosomal entry and exit sites. Despite being well characterized experimentally, the molecular mechanisms by which H2A.B incorporation alters nucleosome stability and dynamics remain poorly understood. To study the molecular mechanisms of H2A.B, we have performed a series of conventional and enhanced sampling molecular dynamics simulation of H2A.B- and canonical H2A-containing nucleosomes. Results of conventional simulations show that H2A.B weakens protein-protein and protein-DNA interactions at specific locations throughout the nucleosome. These weakened interactions result in significantly more DNA opening from both the entry and exit sites in enhanced sampling simulations. Furthermore, free energy profiles show that H2A.B-containing nucleosomes have significantly broader free wells and that H2A.B allows for sampling of states with increased DNA breathing, which are shown to be stable on the hundreds of nanoseconds timescale with further conventional simulations. Together, our results show the molecular mechanisms by which H2A.B creates less compacted nucleosome states as a means of increasing genetic accessibility and gene transcription.
10399 DNA-PK(cs) Regulates Stability of Egr1 During T Cell Activation

ABSTRACT IMPACT: This work provides supporting evidence for the development of a novel immunosuppression therapy for transplant patients. OBJECTIVES/GOALS: Our laboratory reported that inhibition of the kinase DNA-PK(cs) in mice delays allogeneic graft rejection in part by mitigating the induction of certain cytokines. We hypothesized that this was due to an inhibition of intracellular signaling programs in T cells and designed studies to identify the mechanism(s) by which this occurs. METHODS/STUDY POPULATION: The immortalized Jurkat T cell line was used to evaluate the effect of the DNA-PK(cs) inhibitor NU7441 on T cell activation by PMA/Ionomycin or PMA/PHA. Mouse primary splenocytes also were used to demonstrate the universality and reproducibility of our observations. Initially, protein mass spectrometry of lysates from untreated and NU7441-treated Jurkat cells identified proteins of interest regulated by DNA-PK(cs) that play a role in T cell activation and cytokine production. CRISPR genome editing was used to validate a potential downstream target of DNA-PK(cs). Western blot, ELISA, and flow cytometry were used to document changes in protein levels with respect to treatments. RESULTS/ANTICIPATED RESULTS: We observed that expression of the transcription factor Egr1 was highly induced after activation but attenuated after treatment with NU7441 in both Jurkat T cells and mouse splenocytes. Phosphorylated serine 301 of Egr1 was identified by mass spectrometry in stimulated cells and fits the kinase consensus sequence for DNA-PK(cs). Both an endogenous CRISPR-generated serine 301 to alanine mutant and expression of a plasmid-based S301A mutant resulted in an unstable form of Egr1 that was barely detectable. In contrast, expression of either a S301 to D or E phospho-mimetic mutant resulted in a stable form of the protein detectable by Western blot. Further evaluation of these mutants and Egr1 phosphorylation is underway to determine the mechanism by which DNA-PK(cs) kinase regulates protein stability. DISCUSSION/SIGNIFICANCE OF FINDINGS: We previously reported a role for DNA-PK(cs) in immunomodulation. We now have evidence that this occurs in part through stabilization of Egr1. We believe this novel finding will lead to uncovering a broader role for DNA-PK(cs) as a mediator of protein stability in T cells and provide support for targeting DNA-PK(cs) in immunosuppression therapy.
Clinical Use of Surface Electromyography to Track Acute Upper Extremity Muscle Recovery after Stroke: A Descriptive Case Study of a Single Patient.

Arm recovery varies greatly among stroke survivors. Wearable surface electromyography (sEMG) sensors have been used to track recovery in research; however, sEMG is rarely used within acute and subacute clinical settings. The purpose of this case study was to describe the use of wireless sEMG sensors to examine changes in muscle activity during acute and subacute phases of stroke recovery, and understand the participant’s perceptions of sEMG monitoring. Beginning three days post-stroke, one stroke survivor wore five wireless sEMG sensors on his involved arm for three to four hours, every one to three days. Muscle activity was tracked during routine care in the acute setting through discharge from inpatient rehabilitation. Three- and eight-month follow-up sessions were completed in the community. Activity logs were completed each session, and a semi-structured interview occurred at the final session. The longitudinal monitoring of muscle and movement recovery in the clinic and community was feasible using sEMG sensors. The participant and medical team felt monitoring was unobtrusive, interesting, and motivating for recovery, but desired greater in-session feedback to inform rehabilitation. While barriers in equipment and signal quality still exist, capitalizing on wearable sensing technology in the clinic holds promise for enabling personalized stroke recovery.
A Full bridge type series connected Modular Multilevel Converters for Medium Voltage Drive

This paper proposes a new MMC topology, in which, a "full-bridge" with four arms of cascaded full-bridge modules is applied for each phase and three phase legs are series connected in vertical direction to support the DC-link. The major advantages of proposed topology are as follows: (1) The total number of required submodules are reduced to 2/3 compared with traditional MMC topology. As a result, the volume of the converter shrinks significantly. Regarding the reduced voltage amplitude, an AC transformer is used to bring the voltage back into the normal amplitude in a three-phase Y-connection manner. (2) The second order harmonic is eliminated in the proposed unique configuration. Thus, the capacitor size is reduced and no more circulating current control loop is required. A detailed 20 MW simulation has been conducted and the related results of proposed topology have been presented. What’s more, The SM prototype and preliminary experiments are also demonstrated and analyzed.
Contesting Immigration Policy in Court: Legal Activism and its Radiating Effects in the United States and France

What difference does law make in immigration policymaking? Since the 1970s, networks of progressive attorneys in both the US and France have attempted to use litigation to assert rights for non-citizens. Yet judicial engagement - while numerically voluminous - remains doctrinally curtailed. This study offers new insights into the constitutive role of law in immigration policymaking by focusing on the legal frames, narratives, and performances forged through action in court. Challenging the conventional wisdom that 'cause litigation' has little long-term impact on policymaking unless it produces broad rights-protective principles, this book shows that legal contestation can have important radiating effects on policy by reshaping how political actors approach immigration issues. Based on extensive fieldwork in the United States and France, this book explores the paths by which litigation has effected policy change in two paradigmatically different national contexts.