cssi/SciSciGPT-SciSciNet huggingface dataset:
Bridge Over Troubled Water: Safe Harbor Laws for Sexually Exploited Minors

This Article contributes to the emerging legal scholarship on child sex trafficking by exploring the impact and the potential of recently enacted safe harbor laws. Scholars have already begun to explore the need for new legal responses to domestic child sex trafficking. But, few scholars have explored whether state safe harbor laws are consistent with emerging best practices and model legislation such as the Uniform Act on Prevention of and Remedies for Human Trafficking. Thus, several key questions remain ripe for scholarly debate. For example, do safe harbor laws effectively shift the paradigm from punishment to protection of sexually exploited minors? Do state safe harbor laws represent a new and improved legal approach to child prostitution? Do these safe harbor laws adequately protect sexually exploited children from further exploitation? This Article argues that, while safe harbor laws for prostituted minors have great potential to protect sexually exploited minors in the United States, “prosecution-based models,” such as the New York Safe Harbour for Sexually Exploited Minors Act (“NYSHA”), fail to address some of the key public policy goals behind safe harbor laws. First, because these laws still threaten all minors with prosecution or adjudication as delinquents, they fail to end the age old practice of treating prostituted minors as the main or sole agents of their own commercial sexual exploitation. Safe harbor laws still allow for prosecution or punishment of prostituted minors if the minors fail to meet certain conditions. Second, safe harbor laws that condition rehabilitative services on criminal or juvenile justice adjudication undermine efforts to shift the paradigm. In order to protect minors from commercial sexual exploitation, safe harbor laws must adopt a protective, victim-centered approach.
A Simple Message-Optimal Algorithm for Random Sampling from a Distributed Stream

We present a simple, message-optimal algorithm for maintaining a random sample from a large data stream whose input elements are distributed across multiple sites that communicate via a central coordinator. At any point in time, the set of elements held by the coordinator represent a uniform random sample from the set of all the elements observed so far. When compared with prior work, our algorithms asymptotically improve the total number of messages sent in the system. We present a matching lower bound, showing that our protocol sends the optimal number of messages up to a constant factor with large probability. We also consider the important case when the distribution of elements across different sites is non-uniform, and show that for such inputs, our algorithm significantly outperforms prior solutions.
Myocardial Structural and Functional Response After Long-Term Mechanical Unloading With Continuous Flow Left Ventricular Assist Device: Axial Versus Centrifugal Flow.

Abstract Objectives The aim of this study was to assess the impact of continuous-flow left ventricular assist device (LVAD) type—axial flow (AX) versus centrifugal flow (CR)—on myocardial structural and functional response following mechanical unloading. Background The use of continuous-flow LVADs is increasing steadily as a therapeutic option for patients with end-stage heart failure who are not responsive to medical therapy. Whether the type of mechanical unloading influences the myocardial response is yet to be determined. Methods A total of 133 consecutive patients with end-stage heart failure implanted with continuous-flow LVADs (AX, n = 107 [HeartMate II Thoratec Corporation, Pleasanton, California]; CR, n = 26 [HeartWare, HeartWare International, Framingham, Massachusetts]) were prospectively studied. Echocardiograms were obtained pre-LVAD implantation and then serially at 1, 2, 3, 4, 6, 9, and 12 months post-implantation. Results The 2 pump types led to similar degrees of mechanical unloading as assessed by invasive hemodynamic status and frequency of aortic valve opening. Myocardial structural and functional parameters showed significant improvement post-LVAD in both AX and CR groups. Left ventricular ejection fraction increased significantly from a mean of 18% to 28% and 26% post-LVAD in the AX and CR groups, respectively. Left ventricular end-systolic volume index and left ventricular end-diastolic volume index decreased significantly as early as 30 days post-implantation in the 2 groups. The degree of myocardial structural or functional response between patients in the AX or CR groups appeared to be comparable. Conclusions Long-term mechanical unloading induced by AX and CR LVADs, while operating within their routine clinical range, seems to exert comparable effects on myocardial structural and functional parameters.
A commentary on Zimring and Laqueur (2015): juveniles and co-offending and why the conventional wisdom is often wrong*

AbstractIn a previous study, we found that solo-offending was the primary form of offending among all ages including juveniles. We also observed that the relationship between age and crime, notwithstanding whether it was co-offending or solo-offending, was invariant across sex, race, and offense type. Based on these results, we concluded that group offending was merely incidental in circumstance and thus of little etiological significance. Zimring and Laqueur take exception to our study. Their reanalysis of our data disaggregated by offense type showed that co-offending was the dominant form of offending among juveniles for most serious crimes. However, as we discuss in this commentary, there are a number of problems with Zimring and Laqueur’s offense-specific analysis that invalidates their findings and conclusions.
MO-DE-207B-05: Predicting Gene Mutations in Renal Cell Carcinoma Based On CT Imaging Features: Validation Using TCGA-TCIA Datasets

Purpose: The goal of this work is to investigate the use of contrast enhanced computed tomographic (CT) features for the prediction of mutations of BAP1, PBRM1, and VHL genes in renal cell carcinoma (RCC). Methods: For this study, we used two patient databases with renal cell carcinoma (RCC). The first one consisted of 33 patients from our institution (UT Southwestern Medical Center, UTSW). The second one consisted of 24 patients from the Cancer Imaging Archive (TCIA), where each patient is connected by a unique identi?er to the tissue samples from the Cancer Genome Atlas (TCGA). From the contrast enhanced CT image of each patient, tumor contour was first delineated by a physician. Geometry, intensity, and texture features were extracted from the delineated tumor. Based on UTSW dataset, we completed feature selection and trained a support vector machine (SVM) classifier to predict mutations of BAP1, PBRM1 and VHL genes. We then used TCIA-TCGA dataset to validate the predictive model build upon UTSW dataset. Results: The prediction accuracy of gene expression of TCIA-TCGA patients was 0.83 (20 of 24), 0.83 (20 of 24), and 0.75 (18 of 24) for BAP1, PBRM1, and VHL respectively. For BAP1 gene, texture feature was the most prominent feature type. For PBRM1 gene, intensity feature was the most prominent. For VHL gene, geometry, intensity, and texture features were all important. Conclusion: Using our feature selection strategy and models, we achieved predictive accuracy over 0.75 for all three genes under the condition of using patient data from one institution for training and data from other institutions for testing. These results suggest that radiogenomics can be used to aid in prognosis and used as convenient surrogates for expensive and time consuming gene assay procedures.
Could trends in time children spend with parents help explain the black–white gap in human capital? Evidence from the American Time Use Survey

ABSTRACTIt is widely believed that the time children spend with parents significantly impacts human capital formation. If time varies significantly between black and white children, this may help explain the large racial gap in test scores and wages. In this study, I use data from the American Time Use Survey to examine the patterns in the time black and white children receive from mothers at each age between birth and age 14 years. I relate patterns in parenting time to trends in human capital formation observed in the literature. I observe that black children spend significantly less time with their mothers than white children in the first years of life. However, differences in parenting time rapidly decline with age and there are never significant differences in teaching time after socioeconomic variables are controlled. My findings suggest that the black–white human capital gap is unlikely to be driven by differences in teaching time or differences in parenting time after children enter school.
Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment

// Cara C. Schafer 1 , Yong Wang 1 , Kenneth P. Hough 1 , Anandi Sawant 2 , Stefan C. Grant 1 , Victor J. Thannickal 1 , Jaroslaw Zmijewski 1 , Selvarangan Ponnazhagan 2 , Jessy S. Deshane 1 1 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 2 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to: Jessy S. Deshane, email: treena@uab.edu Keywords: indoleamine 2,3-dioxygenase, myeloid-derived suppressor cells, lung cancer, metabolism, combination therapy Received: March 01, 2016 Accepted: September 13, 2016 Published: September 26, 2016 ABSTRACT Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8 + memory T cells, and extending survival. Here, we show that combination therapy targets IDO signaling, specifically in MDSCs, tumor cells, and CD8 + T cells infiltrating the TME. Deficiency of IDO caused significant reduction in tumor burden, tumor-infiltrating MDSCs, GM-CSF, MDSC survival and infiltration of programmed death receptor-1 (PD-1)-expressing CD8 + T cells compared to controls. IDO -/- MDSCs downregulated nutrient-sensing AMP-activated protein kinase (AMPK) activity, but IDO -/- CD8 + T cells showed AMPK activation associated with enhanced effector function. Our studies provide proof-of-concept for the efficacy of this combination therapy in inhibiting IDO and T cell exhaustion in a syngeneic model of lung cancer and provide mechanistic insights for IDO-dependent metabolic reprogramming of MDSCs that reduces T cell exhaustion and regulates anti-tumor immunity.
Etiology, Clinical Associations, and the Possibility of Prevention of Childhood Malignancies

Prevention consistently represents the most costeffective, function-preserving, and numerically successful approach to control of a disease. Successful prevention approaches, however, require an intimate knowledge of disease causation. Unlike many adult malignancies where environmental toxins have been shown to be etiologically important, most childhood malignancies appear to be associated with consistent chromosomal abnormalities which place the child at increased risk for specific malignancies. Mulvihill (1992) has urged that the term ecogenetics be used in considering causation of tumors in the young. He argues that cancer in a child or adult is likely the product of many determinants and that to consider only environment or genetics is an oversimplification Mulvihill 1980).
Cross-Talk between Rho GTPases Regulates Actin Cytoskeleton and Chemotaxis of Hematopoietic Progenitor Cell.

Abstract Movement of hematopoietic stem/progenitor cells into (engraftment) and out of (mobilization) the bone marrow involves actin cytoskeleton and chemotaxis. Members of the Rho GTPase family have been well known for their critical roles in morphogenesis and cell migration via regulating actin assembly. Loss of Rac1 and Rac2 alleles leads to defective engraftment and massive mobilization of hematopoietic progenitor cells (HPCs), which are associated with impaired chemotaxis and cortical filamentous (F)-actin polymerization (Gu et al., Science 302: 445–449). RhoH, a hematopoietic-specific member of the RhoE subfamily, negatively regulates HPC engraftment, chemotaxis, F-actin polymerization and Rac activities (Gu et al., Blood 105: 1467–1475). These findings suggest that RhoH may antagonize Rac function in regulating these cellular processes. However, molecular mechanism of the cross-talk between these Rho GTPases is not defined. In this study, we examined the role of RhoH in actin cytoskeleton organization, chemotaxis and Rac membrane translocation in response to stromal-derived factor 1α (SDF-1α) using RhoH-deficient HPCs and retrovirus-mediated expression of EGFP-fusion proteins. RhoH−/− HPCs exhibit increased migration in response to SDF-1α, especially at low concentration, as compared with wild-type (WT) cells [10ng/ml SDF-1α: 3.5 +/− 0.9 vs. 12.3 +/− 1.8; 100ng/ml SDF-1α: 21.4 +/− 1.7 vs. 32.3 +/− 3.4, migrated cells (%), WT vs. RhoH−/−, n=3, p To further address the mechanism by which RhoH cross-talks to affect Rac signaling, we examine the role of RhoH in subcellular localization of EGFP-Rac proteins. SDF-1α induces activation of Rac, leading to translocation to the cell membrane where it co-localizes with lipid rafts and mediates cortical F-actin assembly in HPCs. In contrast, the dominant negative Rac1N17 does not localize to the cell membrane after SDF-1α stimulation. In RhoH−/− HPCs, EGFP-Rac protein presents at the cell membrane in the absence of SDF-1α [cells with membrane-localized EGFP-Rac1 (%): 7.5 +/− 3.9 vs. 44.5 +/− 6.4, WT vs. RhoH−/−, n=2]. In contrast, overexpression of RhoH in HPCs blocks translocation to the cell membrane after SDF-1α stimulation of Rac1, Rac2 and active Rac1V12. Finally, we found that RhoH, a constitutively active, GTP-bound protein, preferentially localizes to the cell membrane even in the absence of SDF-1α. This localization is dependent upon the prenylation site and the c-terminal domains of RhoH. Lack of membrane localization is associated with defective biological function. Together, our data suggest that RhoH is essential for proper cortical F-actin assembly and chemotaxis of HPCs via regulating Rac activation and membrane localization, and implicates a functional cross-talk between RhoH and Rac.
Being “penny-wise but pound foolish” in cancer immunotherapy research: the urgent need for mouse cancer models to reflect human modifying factors

Inbred mice are the mainstay for preclinical cancer assessment of potential therapeutics, especially immune-based approaches. However, the use of young, lean, inbred mice housed under specific-pathogen-free conditions does not mirror the human cancer scenario. This commentary discusses some of the issues in evaluating immunotherapeutics in mice given recent advances.
A Safe, Helpful, and Ubiquitous Place That Requires Further Study

In this article, Bradley Wade Bishop sets forth the unspoken premise that public libraries that offer desired services to their constituents are going to succeed. This article has many specific exa...
Abstract 33: β-Catenin Is Essential for Vascular Smooth Muscle Cell Survival and Artery Formation

Background: The molecular mechanisms required for formation of a competent vessel wall are not fully understood. Although β-catenin (β-ctn) has an essential developmental function in various cell types, its specific contributions to vascular smooth muscle cell (SMC) biology have not been fully determined. In preliminary studies, we found that SMC-selective β-ctn inactivation (KO) in mice was incompatible with postnatal survival. Hypothesis: β-ctn is a key modulator of vascular SMC function during development. Methods: We analyzed mouse embryos from stages E9.5-19.5. β-ctn expression and endothelial and SMC markers were tested by immunohistochemistry. Proliferation and apoptosis were assessed by phospho-histone 3 and TUNEL assays, respectively. In studies of cultured SMCs lacking β-ctn, we followed cell population growth and assessed proliferation and cell cycle by BrdU uptake and FACS analysis. Cell death was induced by serum starvation, hydrogen peroxide, or agonistic anti-Fas antibody, and assessed by LIVE/DEAD assay or FACS. Results: β-ctn inactivation in SMCs caused embryonic lethality by E12.5. Paired and fused dorsal aortae in KO embryos had thinner walls (wall/lumen area ratio 0.38 vs 0.18 in control vs. KO at E11.5, p Conclusion: β-ctn is essential for SMC survival and formation of a competent arterial vessel wall during development, but its survival function in SMCs appears to be stimulus-specific. β-ctn may oppose or promote SMC death depending on specific cellular and environmental conditions and stimuli.
Detection of Genetic Aberrations in the Assessment and Prognosis of Melanoma

The assessment of melanoma by light microscopy with hematoxylin-eosin staining remains an often subjective process. However, there are additional diagnostic measures that may be of utility, such as immunohistochemical staining and genetic evaluation. Adjunctive genetic assessment to augment the diagnosis of melanoma includes comparative genomic hybridization or fluorescent in situ hybridization to assess for gains or losses in genetic material, or gene expression profiling in some form, to ascertain the expression of genes associated with malignancy. Although these techniques may bolster the dermatopathologic assessment of melanoma, none of them, at the present time, are singularly diagnostic. Additional developments in the genetic assessment and prognostication of melanoma are anticipated.
Fundamental Field Equations

The fundamental field equations for electromagnetic fields are Maxwell's equations. This chapter reviews differential and integral forms of these equations and discusses boundary conditions, energy relations, Poynting's theorem, the uniqueness theorem, and the reciprocity theorem. Vector and scalar potentials and Hertz vectors are discussed, as they give alternative and often simpler formulations of the problem. Although electromagnetic waves are vector fields, they can sometimes be represented or approximated by scalar fields. The chapter presents formulations for scalar acoustic waves as examples of scalar fields. The wave at a single frequency is often called a time‐harmonic or monochromatic wave and is most conveniently described by the real part of the phasor field. The chapter considers Maxwell's equations for time‐harmonic electromagnetic fields and the general time‐varying electromagnetic fields satisfying Maxwell's equations. The complete mathematical description of the electromagnetic problem includes Maxwell's equations, boundary conditions, the radiation condition, and the edge condition.
Measurements and Modelling of Flow in Gas Sparged, Agitated Vessels

Effects of poor gas distribution, liquid mixing, and rates of interphase mass transfer continue to be important issues in the design and scaleup of gas-liquid, gas-liquid-solid, slurry catalyzed gas-liquid, and biologicalgrowth reactors. Most studies of mass transfer rates, which directly affect reaction rates and yield, have been done on a volume-averaged basis, although some measurements of bubble size and bubble surface area have been done to determine local variations. Preliminary work is reported in this paper on measurements and simulation of local bubble dynamics and effects on liquid hydrodynamics (flow patterns). Laser-Doppler anemometry (LDA) was used to measure liquid velocities with and without sparged gas. It was necessary to maintain low relative gas rates and high impeller rates in order to maintain a regime where LDA gave useful results. Air was sparged into tap water giving bubble sizes which were estimated to be 1 to 5mm. Simulations done with the code FLUENT gave results with close similarity to the experimental measurements and showed aspects of bubble dynamics that are very difficult to see visually. Importantly, most of the gas, even under highly dispersed conditions, channels upward along the upstream sides of the baffles. Also the higher the gas loading at a given impeller rotation rate, the greater is the channelling tendency and the poorer is gas distribution. Preliminary mass transfer rate computations gave promising results and will lead to more studies.
Pernicious Plants: Imitation and Uncanny Ecocritical Thought in Gustav Meyrink's “Die Pflanzen des Dr. Cinderella”

This article examines Gustav Meyrink's “Die Pflanzen des Dr. Cinderella” (1905), a fantastical tale about plant-animal-human hybrids born of experimental human intervention. I argue that this short story translates scientific hypotheses from the nineteenth century—Charles Darwin's botanical and zoological writings, for example—into the genre of the grotesque. Given the historical and geographic contexts in which Meyrink was writing, it is safe to say that his literature responds to an environmentally charged fear ubiquitous among industrialized or technologically advanced societies. “Die Pflanzen des Dr. Cinderella” demonstrates that Meyrink was concerned with the potential sentient nature of all living things and also with the agency of objects that many would consider dead matter. Thus, I will take an anachronistic leap to consider how this text can be brought into dialogue with twenty-first-century theories on political ecology and posthuman perspectives.
Responding to Bad Press: How CEO Temporal Focus Influences the Sensitivity to Media Coverage

Strategy scholars have demonstrated that media coverage is an important influence on how stakeholders and managers perceive a firm and that media coverage about a firm can influence strategic decis...
Mitochondria Export Sulfur Species Required for Cytosolic tRNA Thiolation.

Summary In eukaryotes, mitochondria have been hypothesized to generate sulfur species required for tRNA thiolation in the cytosol, although no direct evidence thus far exists. Here we have detected these sulfur species, making use of our observation that isolated yeast cytosol alone is unable to thiolate tRNAs but can do so upon addition of mitochondria. Mitochondria were found to utilize the cysteine desulfurase Nfs1 to produce sulfur-containing species with masses ranging from 700 to 1,100 Da. Mitochondria exported these species via the Atm1 transporter in the inner membrane. Once exported to the cytosol, these sulfur species promoted cytosolic tRNA thiolation with no further requirement of mitochondria. Furthermore, we found that the Isu1/2 scaffolds but not the Ssq1 chaperone of the mitochondrial iron-sulfur cluster machinery were required for cytosolic tRNA thiolation, and thus the sulfur utilization pathway bifurcates at the Isu1/2 site for intra-organellar use in mitochondria or export to the cytosol.
Trust of, in, and among adaptive systems

Adaptation brings with it challenges related to trust. Mission critical and safety related systems usually require very predictable and repeatable behavior in order to be deployed. However, adaptation can satisfy many of the newer requirements of these systems. Service oriented architectures that adapt can enhance robustness, yet they bring the issue of choosing which of several services to trust for a particular need. Some adaptive systems require human interaction or must observe their human users in order to effect the adaptation. Users must develop trust for these systems so that they feel their time and energy are not wasted and that the system will in fact yield increased efficiency and effectiveness. This paper discusses these challenges and suggests some solutions for ensuring trust in adaptive systems.
Hollow fiber adsorbents for CO2 capture: Kinetic sorption performance

Abstract We describe a CO 2 capture platform based on hollow polymeric fibers with sorbent particles embedded in the porous fiber wall for post-combustion CO 2 capture. These fibers are intended for use in a rapid temperature swing adsorption (RTSA) process. The RTSA system utilizes the hollow fiber morphology by flowing cooling water on the bore-side of the fibers during sorption to prevent temperature rise associated with the sorption enthalpy. Steam or hot water is flowed through the bores during desorption to desorb CO 2 rapidly. To minimize material transfer between the bore and the fiber wall, a dense Neoprene ® lumen layer is cast on the bore-side of the fiber wall. In this paper, the key sorption step and associated kinetic resistances for the uncooled fibers are examined and evaluated for this portion of the RTSA process. Chopped fibers in a packed bed, as well as fibers assembled into a parallel flow module, have been tested in a simulated flue gas stream. Kinetic limitations in the hollow fiber modules are largely overcome by increasing the superficial gas velocity and the fiber packing in the module—indicating that film diffusion is the controlling mass transfer limitation in the fiber system. The un-cooled fiber modules lose apparent capacity as superficial velocities are increased, likely indicating non-isothermal operation, whereas the actively-cooled fibers in the packed bed maintain apparent capacity at all flowrates studied.
Can measuring the ankle-brachial index improve public health?

Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis, with a prevalence ranging from 4% in the healthy U.S. adult population over the age of 40 years, to 29% in patients screened in primary care offices, with diabetes, cigarette smoking, and age as risk factors ([1,2
Paper trail: slavery and governance in the Spanish Empire

This article explores the role of the Spanish legal ecology in maintaining social cohesion, bolstering the popular legitimacy of the imperial project, and setting the boundaries of economic develop...
External field electromagnetic measurement of blood flow. An alternative approach to the solution of the baseline problem.

An electromagnetic intravascular rate of volume flow meter of minimal dimensions is described. It is activated by an extracorporeal magnetic field. The location at the apex of the aortic arch minimizes ECG artifacts and circumvents the problem of securing a zero-flow baseline which is given by the lowest mid-diastolic flow level. The magnetic field at the electrodes is maximized by placing the subject axially into the magnetic coil. The flow transducer also offers a means of measuring the artery diameter and its pulsations. The electromagnetic flow measurements of cardiac output agree within about 20% with dyedilution technique determinations.
The uncanny valley: No need for any further judgments when an avatar looks eerie

Abstract Considering that a 3D scanning technology allows to create avatars that embody more authentic and rich information about its users, it could be expected that enhancing avatar realism will increase the accuracy of thin-slice judgments of the person represented by the avatar. However, previous studies suggest that the objective realism of avatars may not always lead to positive outcomes, and the activation of negative affect and the aversive motivational system through the uncanny valley effects may rather harm the accuracy of thin-slice judgments by making people distance themselves from available information in avatars. To validate this speculation, a 2 (Realism: Cartoonish vs. Hyper-realistic) x 2 (Animacy: Still vs. Animate) between-subjects experiment (N = 134) was conducted. In support of our prediction, results from an online experiment confirmed that hyper-realistic and animate avatars can induce a greater feeling of eeriness as compared to cartoonish and still avatars. This feeling of eeriness, evoked by the uncanny valley effects, suppressed the amount of information processing oriented for thin-slice judgments, and subsequently decreased the accuracy of extraversion and agreeableness judgments. Further theoretical implications of the findings are discussed.
Decoding without the cipher

A new method introduces ubiquitin or ubiquitin-like proteins at specific sites in any protein without the requirement of the cellular ubiquitylation machinery. This will help decipher the code by which these modifications control cellular processes.
Stabilizing Off-Policy Q-Learning via Bootstrapping Error Reduction

Off-policy reinforcement learning aims to leverage experience collected from prior policies for sample-efficient learning. However, in practice, commonly used off-policy approximate dynamic programming methods based on Q-learning and actor-critic methods are highly sensitive to the data distribution, and can make only limited progress without collecting additional on-policy data. As a step towards more robust off-policy algorithms, we study the setting where the off-policy experience is fixed and there is no further interaction with the environment. We identify bootstrapping error as a key source of instability in current methods. Bootstrapping error is due to bootstrapping from actions that lie outside of the training data distribution, and it accumulates via the Bellman backup operator. We theoretically analyze bootstrapping error, and demonstrate how carefully constraining action selection in the backup can mitigate it. Based on our analysis, we propose a practical algorithm, bootstrapping error accumulation reduction (BEAR). We demonstrate that BEAR is able to learn robustly from different off-policy distributions, including random and suboptimal demonstrations, on a range of continuous control tasks.
Predicting the Potential for Cannabinoids to Precipitate Pharmacokinetic Drug Interactions via Reversible Inhibition or Inactivation of Major Cytochromes P450.

Cannabis is used for both recreational and medicinal purposes. The most abundant constituents are the cannabinoids - cannabidiol (CBD, nonpsychoactive) and (−)-trans-Δ9-tetrahydrocannabinol (THC, psychoactive). Both have been reported to reversibly inhibit or inactivate cytochrome P450 (CYPs) enzymes. However, the low aqueous solubility, microsomal protein binding, and nonspecific binding to labware were not considered, potentially leading to an underestimation of CYPs inhibition potency. Therefore, the binding-corrected reversible (IC50,u) and irreversible (KI,u) inhibition potency of each cannabinoid toward major CYPs were determined. The fraction unbound of CBD and THC in the incubation mixture was 0.12 ± 0.04 and 0.05 ± 0.02, respectively. The IC50,u for CBD toward CYP1A2, 2C9, 2C19, 2D6, and 3A was 0.45 ± 0.17, 0.17 ± 0.03, 0.30 ± 0.06, 0.95 ± 0.50, and 0.38 ± 0.11 µM, respectively; the IC50,u for THC was 0.06 ± 0.02, 0.012 ± 0.001, 0.57 ± 0.22, 1.28 ± 0.25, and 1.30 ± 0.34 µM, respectively. Only CBD showed time-dependent inactivation (TDI) of CYP1A2, 2C19, and CYP3A, with inactivation efficiencies (kinact/KI,u) of 0.70 ± 0.34, 0.11 ± 0.06, and 0.14 ± 0.04 minutes−1 µM−1, respectively. A combined (reversible inhibition and TDI) mechanistic static model populated with these data predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2/2C9/2C19/2D6/3A and between orally administered THC and drugs extensively metabolized by CYP1A2/2C9/3A. These predictions will be extended to a dynamic model using physiologically based pharmacokinetic modeling and simulation and verified with a well-designed clinical cannabinoid-drug interaction study. SIGNIFICANCE STATEMENT This study is the first to consider the impact of limited aqueous solubility, nonspecific binding to labware, or extensive binding to incubation protein shown by cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) on their true cytochrome P450 inhibitory potency. A combined mechanistic static model predicted a moderate to strong pharmacokinetic interaction risk between orally administered CBD and drugs extensively metabolized by CYP1A2, 2C9, 2C19, 2D6, or 3A and between orally administered THC and drugs extensively metabolized by CYP1A2, 2C9, or 3A.
Multiple pools of Protein Phosphatase 2A-B56 function to antagonize spindle assembly, promote kinetochore attachments and maintain cohesion in Drosophila Oocytes

Meiosis in female oocytes lack centrosomes, the major microtubule-organizing center, which makes them especially vulnerable to aneuploidy. In the acentrosomal oocytes of Drosophila, meiotic spindle assembly depends on the chromosomal passenger complex (CPC). Aurora B is the catalytic component of the CPC while the remaining subunits regulate its localization. Using an inhibitor of Aurora B activity, Binucleine 2, we found that continuous Aurora B activity is required to maintain the oocyte spindle during meiosis I, and this activity is antagonized by phosphatases acting on spindle associated proteins such as kinesins. Protein Phosphatase 2A (PP2A) exists in two varieties, B55 and B56. While both antagonize Aurora B, B55 has only minor roles in meiosis I spindle function. The B56 subunit is encoded by two partially redundant paralogs in the Drosophila genome, wdb and wrd. Knocking down both paralogs showed that the B56 subunit is critical for maintaining sister chromatid cohesion, establishing end-on microtubule attachments, and the metaphase I arrest in oocytes. We found that WDB recruitment to the centromeres depends on BUBR1, MEI-S332, and kinetochore protein SPC105R. While BUBR1 has been shown previously to stabilize microtubule attachments in Drosophila oocytes, only SPC105R is required for cohesion maintenance during meiosis I. We propose that SPC105R promotes cohesion maintenance by recruiting two proteins that recruit PP2A, MEI-S332, and the Soronin homolog Dalmatian.
Apolipoprotein CIII and Angiopoietin-like Protein 8 are Elevated in Lipodystrophy and Decrease after Metreleptin.

Context Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. Objective Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Methods Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. Results Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 (P < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma (P < .0001), which did not change after metreleptin. Conclusion Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.
Wicked Problems in Pharmacy Education

Wicked problems are unstructured, cross-cutting, and relentless. While problem-solving is an expected outcome of pharmacy education programs, are we, as pharmacy educators, acknowledging the wicked problems we have in the Academy? This commentary will provide examples of wicked problems in pharmacy practice and education and provide suggestions for engaging with wicked problems in an effort to solve them. Pharmacy educators must hold a Summit on Wicked Problems in Pharmacy Education in order to address the complex problems we are currently facing in order to shape the profession for the future.
One change, different effects: the impacts of reducing clerkship length.

Medical school curricula are constantly evolving and change has potential positive and negative effects. At East Tennessee State University Quillen College of Medicine, a broader understanding of the effects of a curriculum change (reduction in clerkship length for one transitional year) was explored. A broad, system-wide evaluation was used to evaluate impacts on all stakeholders. Curriculum management data, including qualitative and quantitative data and short-term and follow-up perspectives of stakeholders, were used for evaluation. Students evaluated the change positively. Academic performance in the transitional year was similar to the prior year. Differences in students’ clerkship evaluations were not statistically significant. Clerkship directors were concerned that students’ clinical experience suffered and noted that implementing changes was time consuming but recognized the benefits for students. Administrators dedicated a significant amount of time to planning the transitional year; however, the additional weeks at the beginning of fourth year made the scheduling process easier. This article demonstrates an overall positive result with this tool for curriculum change but also indicates the impacts differed across stakeholders. Knowledge gained from this experience can help other schools successfully anticipate challenges and prepare for a variety of outcomes in implementing necessary curriculum change.
Optical constants of Al0.85Ga0.15As0.56Sb0.44 and Al0.79In0.21As0.74Sb0.26

Digital alloy Al0.85Ga0.15As0.56Sb0.44 and random alloy Al0.79In0.21As0.74Sb0.26 avalanche photodiodes with a 1-μm multiplication layer exhibit low excess noise under 543-nm laser illumination comparable to Si avalanche photodiodes. This has motivated a study of the optical characteristics of these materials. The absorption coefficients and complex refractive indices were extracted via variable-angle spectroscopic ellipsometry. Features of three semiconductor layer fitting approaches are compared, and a Kramers–Kronig-consistent basis spline function was chosen due to its flexibility and accuracy of approximating optical constants of quaternary materials. The external quantum efficiency has been calculated based on the extracted absorption coefficients and is shown to agree well with the measured external quantum efficiency.
DANTE: Predicting Insider Threat using LSTM on system logs

Insider threat is one of the most pernicious threat vectors to information and communication technologies (ICT)across the world due to the elevated level of trust and access that an insider is afforded. This type of threat can stem from both malicious users with a motive as well as negligent users who inadvertently reveal details about trade secrets, company information, or even access information to malignant players. In this paper, we propose a novel approach that uses system logs to detect insider behavior using a special recurrent neural network (RNN) model. Ground truth is established using DANTE and used as the baseline for identifying anomalous behavior. For this, system logs are modeled as a natural language sequence and patterns are extracted from these sequences. We create workflows of sequences of actions that follow a natural language logic and control flow. These flows are assigned various categories of behaviors - malignant or benign. Any deviation from these sequences indicates the presence of a threat. We further classify threats into one of the five categories provided in the CERT insider threat dataset. Through experimental evaluation, we show that the proposed model can achieve 99% prediction accuracy.
State, Energy and Power

If at any instant of time the system dynamics is fully determined by a finite number of variables x1,…,xN, we call them state variables of the system. The time instantaneous values of these variables give information on the present state of the system as well as on its past. Thus the state is represented by a state vector \(\bar{X}\left( t \right) = {{\left( {{{X}_{1}}\left( t \right),...,{{X}_{N}}\left( t \right)} \right)}^{T}}\) corresponding to a variable point in the state space ℝ N that describes the motion of the system. There t is the independent time variable t ≥ t0, \(\rlap{--}{V}{{t}_{0}} \in \mathbb{R}\), where as before t0 is the initial instant. We let Δ be a given bounded set (or its closure) in ℝN, representing the formal (mathematical) and physical constraints imposed upon the state \(\bar X\left( t \right)\). It will often be called a set of admissible states. The motion may proceed indefinitely in Δ, i.e. for t ∈ ℝ+,, ℝ+ = [t°,∞), or it may terminate at the finite instant The latter is either arbitrary or stipulated. Correspondingly \({{\bar{x}}^{0}}\underline{\underline \vartriangle } \bar{x}\left( {{{t}_{0}}} \right),{{\bar{x}}^{f}}\underline{\underline \vartriangle } \bar{x}\left( {{{t}^{f}}} \right)\) denote the initial and terminal states.
Methodology for the Conceptual Design Process of Morphing Configurations

Traditional historical-data based design processes are clearly inappropriate for morphing vehicles. There are no historical data for these type of configurations, the appropriate mission for this class of vehicles is unknown, and there are many unique aspects of a morphing vehicle that are dependent on the specific concept chosen. The design process proposed in this paper attempts to account for these difficulties in a flexible and transparent manner while leveraging existing tools and processes wherever possible.
An overview of the Tokamak Physics Experiment vacuum vessel preliminary design

The mission of the Tokamak Physics Experiment (TPX) Project is to develop the scientific basis for a compact and continuously operating tokamak fusion reactor. The vacuum vessel, which consists of a double walled torus, ports and supports, is a major element of the TPX machine. This paper provides an overview of the vacuum vessel preliminary design work. The design of the vacuum vessel is being carried out by an industrial team under subcontract to the Princeton Plasma Physics Laboratory. The respective work scopes of this team are discussed. The role of concurrent engineering is presented in the context of this design-build subcontract. A discussion of the engineering requirements, material selection rationale and vacuum vessel configuration is provided. Titanium 6AL-4V will be used to fabricate the vacuum vessel. Significant material concerns were identified with the use of titanium; hydrogen embrittlement and the effects of borated water were the major issues. A research and development (R&D) program was established to resolve these material issues as well as to develop the vessel weld details. A comprehensive analytical effort was established to perform the structural and thermal analysis of the vessel. Design details of the vessel, supports, ports, and flanges are presented.
Market Power in the Cheese Industry: Further Evidence

The recent public disclosure of proprietary information providesinsights into the pricing conduct and performance of leadingcheese marketers. Most important, the evidence supports thehypotheses that following its acquisition by Philip Morris in1988, Kraft became particularly aggressive strategically,both byselling on the NCE to drive bulk cheese prices lower and byincreasing the selling prices and gross profit margins on theirfinished cheese. The result was significantly higher prices toconsumers and lower prices to suppliers of bulk cheese, as Kraft'sgross profit margins rose from an estimated $880 million in1989 to $1020 million in 1991.
Testing the Effects of a Role-Playing Simulation

In this paper, I test whether a blog-based role-playing simulation is associated with improved academic performance among students in an introductory international relations course. Previously I compared student performance in a 2009 non-honors class that participated in the simulation to a 2008 honors class that did not participate in it. The 2008 honors students generally performed better than the 2009 non-honors students, but it was unclear what if any effect was associated with the simulation. In the Fall 2011 semester, I taught an honors section of the same course and used the simulation again. Average scores on exams and papers in the 2009 and 2011 classes were nearly identical, suggesting that the simulation had no effect on student learning.
Chapter 5 Theoretical and computational approaches for identifying and optimizing novel thermoelectric materials

Publisher Summary Electronic structures and lattice dynamics are of particular importance to thermoelectric materials. The goal in thermoelectrics research is to find new materials for application. This means finding materials with low-cost, favorable mechanical, thermal, electrical interfacial, and other properties. However, the sine qua non is finding a material with high figure of merit, ZT, in the intended temperature range. This defines the maximum possible performance of a material in a device. The chapter focuses on ZT. The use of modern ab initio band structure techniques to understand thermoelectric materials is illustrated and the results of calculations in relation to experimental measurements are discussed in the chapter. The emphasis of the chapter is on novel thermoelectrics, especially skutterdites, as they have been the most extensively studied using first principles methods, although certainly useful information is still being obtained about standard materials such as bismuth telluride.
A New Structure of Linear Recursive Estimator

A new structure of linear recursive estimator which minimizes the mean square error is derived for a system with a multiplicative noise included in the measurement model. The signal is modeled in the same way as in the Kalman filter. The conventional form of a recursive estimator (the new estimate is the linear combination of the new data and the previous estimate) is not appropriate for the above system. In contrast, according to our new form of estimator, the new estimate is the linear combination of the previous estimate and the new innovation which is recursively obtained by a linear combination of the new data, the previous data, and the previous innovation. The new recursive form of the innovation process gives the new form of a linear MMSE estimator. Not only is the on-line estimation recursive, but also the off-line computation of the coefficients (which are the counterparts of the Kalman gain) is recursive. A constraint on the system matrices should be satisfied and its limitation is justified. A physical interpretation of this constraint is also given.
Conventional Surgical Management of Primary Hyperparathyroidism

Primary hyperparathyroidism is the most common form of hyperparathyroidism (HPTH) and is the most frequent explanation for hypercalcemia in the outpatient setting. Population-based estimates reveal an overall incidence of approximately 25 per 100,000 in the general population, with 50,000 new annual cases. The peak incidence is in the fifth and sixth decades of life, with a female to male ratio of 3:1. Some studies have estimated the overall prevalence of HPTH in the elderly at 2–3%, with approximately 200 cases/100,000 population.