cssi/SciSciGPT-SciSciNet huggingface dataset:
OP0264 Upregulation of Cytokines in Juvenile Idiopathic Arthritis is Mediated Tcr-Independent Activation of T Cells

Background JIA is a heterogenous group of rheumatic conditions characterized by local inflammation and destruction of the joint space. Pro-inflammatory cytokines derived from T cells are considered culprits of disease. We have recently shown that some of these cytokines directly come from a distinct subset of T cells expressing CD31, an adhesion molecule normally expressed by granulocytes and endothelial cells. Objectives In the present work, we examined whether the array of cytokines in blood and synovial fluid of patients are the same array produced by CD8+ T cells activation through CD31 ligation independent of the TCR. We propose that CD31-driven cytokine production by T cells is a self-perpetuating mechanism of local and systemic inflammation in JIA. Methods Following informed consent/assent, blood and/or synovial fluid were collected from children with oligoarticular and polyarticular JIA. Similar blood samples were also collected from healthy subjects. Cytokine composition of the plasma and/or fluid was determined by multiplex analysis. Phenotypes of mononuclear cells in blood and synovial fluid were examined by multicolor flow cytometry. Drawing from the results of the multiplex assay, receptor crosslinking bioassays for cytokine production were performed using CD31+ primary T cells, and T lymphoid cell lines. Results As expected, the overall cytokine signature of JIA is characterized by the dominance of IL-6, IL-10 and TNFα. Patients with oligoarticular disease showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular disease. Both types of patients however showed a similar cellular signature characterized by T cells deficient in CD4, CD8, and CD28, but expressing CD31. Results of CD31 cross-linking bioassays, using either specific antibody or its recombinant ligand CD38, showed high levels of induction of IL-2, IL-17, and IFNγ. Specificity of CD31-driven, TCR-independent cytokine production was verified by similar bioassays using somatic T cell line mutants deficient in TCR or in TCR/CD3 complex, but are both CD31+. The observed cytokine production was associated with phosphorylation of classical T cell-signaling substrates indicating CD31 ligation effectively pass the TCR-driven route of activation. Conclusions Our data show that the cytokine profile of oligoarticular JIA is distinct with the dominance of IFNγ and IL17. CD31-driven induction of these cytokines in a TCR-independent manner indicates maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity/clinical outcomes, and the CD31 signaling cascade will pave way to innovations in immunotherapy in JIA. Acknowledgements This work is supported by grants from the Nancy Taylor Foundation for Chronic Diseases, and the National Institutes of Health (T32 AR052282). Authors have no financial conflicts of interest. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5501
Establishment of Oxysterol Biomarkers in a Mouse Model of Smith-Lemli-Opitz Syndrome and the Effect of Antioxidant Supplementation

Establishment of Oxysterol Biomarkers in a Mouse Model of Smith-Lemli-Opitz Syndrome and the Effect of Antioxidant Supplementation Libin Xu, Zeljka Korade, Karoly Mirnics, and Ned A. Porter Vanderbilt University Levels of 7-dehydrocholesterol (7-DHC) are greatly elevated in patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding the last enzyme in cholesterol biosynthesis, 7-DHC reductase (DHCR7). SLOS is characterized by multiple congenital malformation and developmental disabilities (including autism). 7-DHC was found to be the most reactive lipid molecule toward free radical peroxidation, leading to over a dozen biologically active oxidation products (i.e., oxysterols). Here we demonstrated that in Neuro2a cells and human fibroblasts, the primary 7-DHC-derived oxysterols were readily metabolized to more stable oxysterols, including 3 ,5 -dihydroxycholest-7-en-6-one, 3 ,5 ,9 -trihydroxycholest-7-en-6-one, and 3 ,5 -dihydroxy-cholesta7,9(11)-dien-6-one. These three novel oxysterol biomarkers were also successfully identified in brain and liver tissues of a Dhcr7null mouse model of SLOS by HPLC-MS. In an attempt to develop novel therapy to SLOS, we fed Dhcr7-heterozygous mice with diets that are enriched with vitamin-E (400 IU vitamin-E/kg diet) during pregnancy. We found that levels of the oxysterol biomarkers in both brain and liver tissues of the newborn Dhcr7null pups were significantly lower in the group on high antioxidant diet than those on low antioxidant diet, indicating suppression of 7-DHC peroxidation by antioxidants in vivo during embryonic stage. This study points to antioxidant supplementation as a potential therapy to SLOS.
Function of Membrane-Associated Proteoglycans in the Regulation of Satellite Cell Growth

Muscle growth can be divided into embryonic and postnatal periods. During the embryonic period, mesenchymal stem cells proliferate and differentiate to form muscle fibers. Postnatal muscle growth (hypertrophy) is characterized by the enlargement of existing muscle fiber size. Satellite cells (also known as adult myoblasts) are responsible for hypertrophy. The activity of satellite cells can be regulated by their extracellular matrix (ECM). The ECM is composed of collagens, proteoglycans, non-collagenous glycoproteins, cytokines and growth factors. Proteoglycans contain a central core protein with covalently attached glycosaminoglycans (GAGs: chondroitin sulfate, keratan sulfate, dermatan sulfate, and heparan sulfate) and N- or O-linked glycosylation chains. Membrane-associated proteoglycans attach to the cell membrane either through a glycosylphosphatidylinositol anchor or transmembrane domain. The GAGs can bind proteins including cytokines and growth factors. Both cytokines and growth factors play important roles in regulating satellite cell growth and development. Cytokines are generally associated with immune cells. However, cytokines can also affect muscle cell development. For instance, interleukin-6, tumor necrosis factor-α, and leukemia inhibitory factor have been reported to affect the proliferation and differentiation of satellite cells and myoblasts. Growth factors are potent stimulators or inhibitors of satellite cell proliferation and differentiation. The proper function of some cytokines and growth factors requires an interaction with the cell membrane-associated proteoglycans to enhance the affinity to bind to their primary receptors to initiate downstream signal transduction. This chapter is focused on the interaction of membrane-associated proteoglycans with cytokines and growth factors, and their role in satellite cell growth and development.
Surface Coating of Superfine Boron Particles With Lithium Fluoride

The surface of superfine boron powder was coated with lithium fluoride prepared by reacting LiOH with HF by the neutral precipitation method. The effect of the concentration of LiOH solution on the coating effectiveness of superfine boron particles was studied. Transmission Electron Microscope, rotary viscometer and X-ray photoelectron spectroscopy were used to analyze the coating effectiveness of boron particles coated with LiF. The results show that the film on the boron particles is well distributed and compact and the thickness of film is about 25 nm. The analysis results obtained by acidity-instrument and rotary viscometer show that coating of LiF can enhance the value of PH of the solution with boron and effectively reduce the viscosity of HTPB system. The analysis of ignition delay time and combustion residues shows the ignition delay time of B/MA/AP/HTPB propellant obviously reduced after coated by LiF from 70.475s to 23.585s. The burning efficiency of B in propellant was obviously improved after coated by LiF, and the amount of substance proportion between B and B_2O_3 decreases from 37.5∶1 to 3.1∶1.
Quantifying nonlocal informativeness in high-dimensional, loopy Gaussian graphical models

We consider the problem of selecting informative observations in Gaussian graphical models containing both cycles and nuisances. More specifically, we consider the subproblem of quantifying conditional mutual information measures that are nonlocal on such graphs. The ability to efficiently quantify the information content of observations is crucial for resource-constrained data acquisition (adaptive sampling) and data processing (active learning) systems. While closed-form expressions for Gaussian mutual information exist, standard linear algebraic techniques, with complexity cubic in the network size, are intractable for high-dimensional distributions. We investigate the use of embedded trees for computing nonlocal pairwise mutual information and demonstrate through numerical simulations that the presented approach achieves a significant reduction in computational cost over inversion-based methods.
Grain Boundaries in Sodium Chloride

Single crystals of optical-grade sodium chloride were joined to produce bicrystals and tricrystals of controlled orientation. The dislocation and small-angle grain boundary configurations of the melt zone were determined. The relative energy of different grain boundary orientations was estimated. The local strain was estimated by etch pit and optical birefringence techniques. Etch pit and electron microscopic determinations were used to study dislocation interaction with grain boundaries.
Extreme scale and bleeding edge technology lead to a need for resilient high performance computing systems

High Performance Computing (HPC) and supercomputing are an important sector of the computing field. Distinguishing itself from cloud computing, HPC systems are sized to run extremely large and important calculations such as tightly coupled numerical simulations. These often run for days to weeks on supercomputers and are used to inform scientific discovery and national security. It comes as no surprise then that reliable HPC systems are integral to producing believable scientific results. In this paper we build on years of experience studying supercomputers around the U.S. Department of Energy (DOE) and bring together insights about challenges and needs for HPC reliability. First, we discuss the state of the practice in HPC reliability. We look at a sampling of results from previous work and how reliability telemetry data is used by vendors, system architects, and end users. Finally, we discuss some changes coming in the next decade for HPC systems and how the technology we depend on will drive new reliability challenges that must be addressed and monitored.
Use of the reciprocal basis in neutral meson mixing

In the presence of $\mathrm{CP}$ violation, the effective Hamiltonian matrix describing a neutral meson-antimeson system does not commute with its Hermitian conjugate. As a result, this matrix cannot be diagonalized by a unitary transformation and one needs to introduce a reciprocal basis. Although known, this fact is seldom discussed and almost never used. Here, we use this concept to highlight a parametrization of the Hamiltonian matrix in terms of physical observables, and we show that using it reduces a number of long and tedious derivations into simple matrix multiplications. These results have a straightforward application for propagation in matter. We also comment on the (mathematical) relation with neutrino oscillations.
Outcomes After High-Concentration Peroxide Ingestions

Study objective In cases of high-concentration peroxide ingestion reported to US poison centers, we describe medical outcomes, examine the role of hyperbaric oxygen, and review the use of endoscopy. Methods The study was a retrospective analysis of a structured database, the National Poison Data System. The chart for each poison center case of a high-concentration (>10%) peroxide ingestion was obtained and abstracted in a standardized fashion; 1,054 cases were initially considered and 294 cases met inclusion criteria. The primary outcome of possible embolic event was defined as seizure, altered mental status, respiratory distress, hypoxia, hemodynamic instability, ECG changes, radiographic evidence of cerebrovascular accident, focal neurologic deficit on examination, pulmonary embolism, cardiac emboli, elevated troponin level, physician bedside diagnosis, or rapid improvement after hyperbaric oxygen therapy. Both descriptive statistics and logistic regression models were used to analyze the data. Results In the 10-year study period, 41 of 294 patients (13.9%; 95% confidence interval 10.2% to 18.4%) with symptoms after high-concentration peroxide ingestion demonstrated evidence of embolic events, and 20 of 294 (6.8%; 95% confidence interval 4.2% to 10.3%) either died or exhibited continued disability when the poison center chart was closed. Improved outcomes were demonstrated after early hyperbaric oxygen therapy. Endoscopy revealed grade 3 or 4 lesions in only 5 cases. Conclusion Symptomatic high-concentration peroxide exposures had a high incidence of associated embolic events in this cohort. Patients with evidence of embolic events had a high rate of death. Early hyperbaric oxygen therapy may be useful, but routine endoscopy is unlikely to be of benefit.
Alterations in corneal nerves following crack cocaine use mimic diabetes-induced nerve damage.

Summary The use of in vivo confocal microscopy (IVCM) is rapidly emerging as an important clinical tool to evaluate changes in corneal sensory nerves as a surrogate measure for diabetic peripheral neuropathy. Commonly used metrics to document and grade the severity of diabetes and risk for diabetic peripheral neuropathy include nerve fiber length, density, branching and tortuosity. In addition to corneal nerves, thinning of the retinal fiber layer has been shown to correlate with the severity of diabetic disease. Here, we present a case report on a pre-diabetic 60-year-old native American woman with abnormal corneal nerve morphology and retinal nerve fiber layer thinning. Her past medical history was positive for illicit substance abuse. IVCM showed a decrease in nerve fiber density and length, in addition to abnormally high levels of tortuosity. OCT revealed focal areas of reduced retinal nerve fiber layer thickness that were asymmetric between eyes. This is the first report of abnormally high levels of tortuosity in the corneal sub-basal nerve plexus in a patient with a past history of cocaine abuse. It also demonstrates, for the first time, that illicit substance abuse can have long-term adverse effects on ocular nerves for years following discontinued use of the drug. Studies using IVCM to evaluate changes in corneal nerve morphology in patients with diabetes need to consider a past history of illicit drug use as an exclusionary measure. Learning points Multiple ocular and systemic factors can impede accurate assessment of the corneal sub-basal nerve plexus by IVCM in diabetes.Although current history was negative for illicit substance abuse, past history can have longstanding effects on corneal nerves and the retinal nerve fiber layer.Illicit drug use must be considered an exclusionary measure when evaluating diabetes-induced changes in corneal nerve morphology and the retinal nerve fiber layer.
The Medical Transition from Pediatric to Adult-Oriented Care: Considerations for Child and Adolescent Psychiatrists

More adolescents and young adults are surviving previously fatal childhood illness and need support to transition from pediatric care to adult-oriented care. There are many barriers, but guidelines and tools assist providers with emphasis on gradually addressing transition with patients and families. Child and adolescent psychiatrists should be particularly attuned to the needs of adolescents with previously identified mental illness who are at high risk of falling out of regular care during transition. Providers are also uniquely suited to address the needs of adolescents and young adults with intellectual and developmental disabilities.
Frequency Domain Reflectometry Modeling and Measurement for Nondestructive Evaluation of Nuclear Power Plant Cables

Cable insulation polymers are among the more susceptible materials to age-related degradation within a nuclear power plant. This is recognized by both regulators and utilities, so all plants have developed cable aging management programs to detect damage before critical component failure in compliance with regulatory guidelines. Although a wide range of tools is available to evaluate cables and cable systems, cable aging management programs vary in how condition monitoring and nondestructive examination is conducted as utilities search for the most reliable and cost-effective ways to assess cable system condition. Frequency domain reflectometry (FDR) is emerging as one valuable tool to locate and assess damaged portions of a cable system with minimal cost and only requires access in most cases to one of the cable terminal ends. This work examines a physics-based model of a cable system and relates it to FDR measurements for a better understanding of specific damage influences on defect detectability.
Study of PWM frequency and its impact to adjustable speed drive reliability

Pulse Width Modulation (PWM) control method has been widely studied and applied in the industrial area. For majority of the conditions, the PWM frequency is fixed to guarantee easier control implementation. However, the time constant of the IGBT thermal system is much lower than that of the inverter fundamental frequency at low speed. The lifetime of the inverter are severely reduced under low speed and high output conditions. To improve the lifetime of the inverter at lower speed without reduce the output current, a natural way is to reduce the PWM frequency under this condition. This paper evaluated the inverter performance under different PWM frequencies. After that, it studies the impact of PWM frequency to inverter losses, inverter reliability and system performance. It is concluded that operating the inverter at low switching frequencies may not sacrifice the output current waveform quality. Moreover, the inverter lifetime can be significantly increased. Analytical, simulation and experimental results will be presented to show its effectiveness.
A software-defined framework for the integrated management of smart manufacturing systems

Abstract This paper introduces software-defined control (SDC) as a framework that enables integrated and programmatic management of smart manufacturing systems. SDC consolidates information from the production and enterprise levels in a central controller that monitors performance and detects changing conditions. The integrated view of the system provided by the central controller supports the development of applications, which supply the central controller with new information and reconfiguration recommendations. SDC is designed to be scalable and compatible with current automation technologies. A simulation shows that the incorporation of plant-floor information in management decisions, as supported by SDC, has the potential to improve profitability.
A randomized controlled trial to prevent excessive gestational weight gain and promote postpartum weight loss in overweight and obese women: Health In Pregnancy and Postpartum (HIPP)

Abstract Background Interventions to prevent excessive gestational weight gain and promote postpartum weight loss have yielded modest results, particularly in overweight and obese women. Objectives To examine the impact of a theory-based lifestyle intervention on gestational weight gain, postpartum weight loss, and related maternal and child outcomes and to examine race differences in these outcomes. Design A randomized controlled trial (target N = 400; 200 intervention, 200 standard care; 200 African American, 200 white). Methods Overweight and obese African American and white women ≤ 16 weeks gestation are recruited from obstetrics and gynecology clinics in South Carolina. Intervention participants receive two in-depth counseling sessions (early pregnancy and postpartum), telephone counseling, behavioral podcasts, and social media support that target weight self-monitoring and increasing physical activity and healthy dietary behavior practices, guided by Social Cognitive Theory. Standard care participants receive monthly mailings and a matched number of podcasts on non-weight related topics. All intervention activities last from ≤ 18 weeks gestation to 6 months after delivery. Gestational weight gain is the primary outcome. Secondary outcomes are meeting gestational weight gain guidelines (inadequate, adequate, excessive), weekly rate of gestational weight gain, postpartum weight retention, physical activity and dietary behaviors, health-related quality of life, and offspring adiposity. Participants are assessed at baseline (≤ 16 weeks gestation), 32 weeks gestation, and 6 and 12 months postpartum, and offspring are assessed at 6 and 12 months. Summary HIPP is an innovative study that addresses significant gaps in the literature. Primary outcome results are expected in 2019.
Potential of Rice Bran Wax and Soybean Oil Oleogels as Pork Fat Replacements in Frankfurter-type Sausages

This study demonstrated the technological potential of rice bran wax/soybean oil oleogels as animal fat replacers in frankfurter-type sausages while maintaining acceptable product sensory properties. These results complement those of recent studies that utilized ethylcellulose/canola oil oleogels as partial fat replacements in beef frankfurters and breakfast sausage. In addition, the evaluation of rice bran wax as a lower-cost and faster-melting gelator contributes useful practical knowledge to the application of this novel technology in processed meats.
Efficient Gene Silencing in Brain Tumors with Hydrophobically Modified siRNAs

Glioblastoma (GBM) is the most common and lethal form of primary brain tumor with dismal median and 2-year survivals of 14.5 months and 18%, respectively. The paucity of new therapeutic agents stems from the complex biology of a highly adaptable tumor that uses multiple survival and proliferation mechanisms to circumvent current treatment approaches. Here, we investigated the potency of a new generation of siRNAs to silence gene expression in orthotopic brain tumors generated by transplantation of human glioma stem-like cells in athymic nude mice. We demonstrate that cholesterol-conjugated, nuclease-resistant siRNAs (Chol-hsiRNAs) decrease mRNA and silence luciferase expression by 90% in vitro in GBM neurospheres. Furthermore, Chol-hsiRNAs distribute broadly in brain tumors after a single intratumoral injection, achieving sustained and potent (>45% mRNA and >90% protein) tumor-specific gene silencing. This readily available platform is sequence-independent and can be adapted to target one or more candidate GBM driver genes, providing a straightforward means of modulating GBM biology in vivoMol Cancer Ther; 17(6); 1251-8. ©2018 AACR.
Polar alignment of a protoplanetary disc around an eccentric binary – II. Effect of binary and disc parameters

In a recent paper Martin & Lubow showed that a circumbinary disc around an eccentric binary can undergo damped nodal oscillations that lead to the polar (perpendicular) alignment of the disc relative to the binary orbit. The disc angular momentum vector aligns to the eccentricity vector of the binary. We explore the robustness of this mechanism for a low mass disc (0.001 of the binary mass) and its dependence on system parameters by means of hydrodynamic disc simulations. We describe how the evolution depends upon the disc viscosity, temperature, size, binary mass ratio, orbital eccentricity and inclination. We compare results with predictions of linear theory. We show that polar alignment of a low mass disc may occur over a wide range of binary-disc parameters. We discuss the application of our results to the formation of planetary systems around eccentric binary stars.
The Detection of Non-Covalent Interactions in Nucleic Acids Using MALDI

The unfriendly conditions for the preparation of samples (an acidic matrix dissolved in organic solvents) has made MALDI (Matrix-Assisted Laser Desorption Ionization) inappropriate for the analysis of fragile complexes of macromolecules. Nevertheless, several authors have proved its feasibility in detecting non-covalent interactions between macromolecules, including: enzyme-substrate complexes (1), protein-polysaccharide interactions (2), peptide-DNA interactions (3), intact quaternary structures of proteins (4), and interactions between complementary oligodeoxynucleotides (5). These experimental results indicate that the ionization process itself might not be the denaturating step in the MALDI analysis. The preparation of the sample seems to play the key role in preserving the structure of the non-covalently bound biopolymers.
Benefits and Costs of Adopting Usage-Based Pricing in a Subnetwork

There has been a sustained argument in Internet community regarding the utility, feasibility, and sustainability of the usage-based Internet traffic pricing versus the attractiveness of non-usage-based pricing from consumer perspective. Using a simulated network of well defined services we investigate the benefits: (i) received by the system as a whole, and (ii) received by individuals and groups of customers, when part of the network has no-usage based pricing whereas the other part employs an economic usage based pricing. Our simulation results indicate that not only are the systemwide benefits enhanced by usage-based pricing, but also the users who lose out are precisely the people who should be denied access during the peak periods.
Some Ruminations on Women, Violence, and the Criminal Law

Each one of us carries around his own personal demon, and mine has always been boredom and the fear of boredom. I resonate in sympathy with the John Berryman poem that begins “Life, friends, is boring” and have always understood—and see as more than mere wit—the suicide note of the actor George Sanders who claimed that he simply could not stand being bored any more.2
Poroelastic response of spherical indentation into a half space with a drained surface via step displacement

Abstract Indentation of a poroelastic solid by a spherical-tip tool is analyzed within the framework of Biot’ s theory. We seek the response of the indentation force and the field quantities as functions of time when a rigid pervious indenter is loaded instantaneously to a fixed depth. The particular case where the surface of the semi-infinite domain is permeable and under a drained condition is considered. Compressibility of both the fluid and solid phases is taken into account. The solution procedure based on the McNamee–Gibson displacement function method is adopted in this work. One of the difficulties in solving poroelastic contact problems theoretically is in evaluating integrals with kernels that oscillate rapidly. We show that such issues can be overcome by using alternative integral representations with exponentially decaying functions in the kernels. Special functions, such as the modified Struve functions and the modified Bessel functions, and the method of contour integration can be utilized to aid the removal of the oscillation. Problem formulation and the solution procedure are first introduced. Implications of the poroelastic solution for incipient failure in form of tensile crack initiation and onset of plastic deformation are then discussed. An interesting outcome from this analysis is that the transient response of the dimensionless indentation force shows only weak dependence on one derived material constant and can in fact be fitted by a simple elementary function, which can then be conveniently used for material characterization in the laboratory.
Device solutions for a challenging spine surgery: minimally invasive transforaminal lumbar interbody fusion (MIS TLIF)

Introduction: Lumbar interbody fusion remains a mainstay in the treatment of degenerative spinal pathology. Interbody devices are often used in an attempt to improve fusion rates and outcomes. Mini...
The Medication Level Variability Index (MLVI) as a potential predictive biomarker of graft-versus-host disease in pediatric hematopoietic stem cell transplant patients.

The purpose of this study was to examine the potential predictive value of the Medication Level Variability Index (MLVI) biomarker with graft-versus-host disease (GVHD) in the pediatric hematopoietic stem cell transplant (HSCT) patient during the acute phase post-transplant. This retrospective descriptive study evaluated a total of 406 tacrolimus levels in 64 patients over a varying number of weeks per participant (median = 8, min = 3, max = 11). Patients were followed until Day 100 post-transplant or tacrolimus taper began. A total of 72 episodes of non-therapeutic levels occurred during the acute phase. Of those, 40 (56%) were 15. Approximately 39% (n = 25 of 64) of the participants in the study developed GVHD post-discharge. Those with GVHD had a statistically significantly higher MLVI than those that did not (median = 3.1, IQR = 2.5-4.7 vs 2.3, IQR = 1.6-3.4, respectively, P = 0.024). Using a criterion of MLVI > 3, there was a statistically significant increased likelihood of GVHD (OR = 3.82, 95% CI=1.32 = 11.04, P = 0.013). Area under the curve (AUC) calculation for the sensitivity and specificity of using the MLVI for GVHD was also conducted. The AUC of 0.67 was statistically significant (95% CI 0.53-0.81, P = 0.024). This is the first-known study to report the use of the MLVI in HSCT patients. The MLVI is associated with a main adverse outcome related to HSCT, GVHD. These results are encouraging of a new potential biomarker to evaluate tacrolimus serum assay levels and identify patients at risk for developing GVHD.
When Participants Do Not Agree: Member Checking and Challenges to Epistemic Authority in Participatory Research:

Transactional validity, a common approach in participatory research, is attained when preliminary analyses of research results are discussed with research participants and their feedback is incorpo...
Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life.

Abstract Introduction There is keen interest in elucidating the biological mechanisms underlying recent failures of β-site amyloid precursor protein–cleaving enzyme-1 (BACE1) inhibitors in Alzheimer's disease trials. Methods We developed a highly sensitive and specific immunoassay for BACE1 in cell lines and iPSC-derived human neurons to systematically analyze the effects of eight clinically relevant BACE1 inhibitors. Results Seven of 8 inhibitors elevated BACE1 protein levels. Among protease inhibitors tested, the elevation was specific to BACE1 inhibitors. The inhibitors did not increase BACE1 transcription but extended the protein's half-life. BACE1 became elevated at concentrations below the IC50 for amyloid β (Aβ). Discussion Elevation of BACE1 by 7 of 8 BACE1 inhibitors raises new concerns about advancing such β-secretase inhibitors for AD. Chronic elevation could lead to intermittently uninhibited BACE1 when orally dosed inhibitors reach trough levels, abnormally increasing substrate processing. Compounds such as roburic acid that lower Aβ by dissociating β/γ secretase complexes are better candidates because they neither inhibit β- and γ-secretase nor increase BACE1 levels.
Infectious Triggers of Cytokine Storm Syndromes: Herpes Virus Family (Non-EBV)

The herpesviruses are the most common infectious agents associated with both primary and secondary cytokine storm syndromes (CSS). While Epstein–Barr Virus (EBV) is most frequently reported in association with CSS, cytomegalovirus (CMV) and many other herpesviruses (e.g., herpes simplex virus, varicella zoster virus, and human herpesviruses 6 and 8) are clearly associated with CSS in children and adults. Immunocompromised hosts, whether due to primary immunodeficiency or secondary immune compromise (e.g., solid organ or stem cell transplantation), appear to be at particularly increased risk of herpesvirus-associated CSS. In this chapter, the association of the non-EBV herpesviruses with CSS will be discussed, including predisposing factors and treatment considerations.
The compliance with a patient-safety bundle for management of placenta accreta spectrum†.

Objective: Our objective was to evaluate the compliance with a patient-safety bundle for placenta accreta spectrum (PAS) by comparing the implementation of the components of the patient-safety bund...
Aprendizaje y enseñanza de español como lengua de herencia mediante el aprendizaje-servicio comunitario en la ciudad de Nueva York

This study explores the effects of the implementation of a community service-learning component in a foreign language teaching methodology course. Participants ( N = 21), all heritage speakers of Spanish, were pre-service 7-12 Spanish teachers at two middle-sized, public postsecondary institutions in New York City. As part of their community engagement experience, participants selected a site from a list of middle and high schools where they would get the opportunity to work with heritage learners of Spanish. Throughout the semester, they had to identify classroom needs, select one of those needs, develop an action plan to address that specific need, and finally reflect on the impact of their intervention on student learning and on their own professional, academic, and linguistic growth. At the end of the semester they completed a post-community service-learning survey consisting of 27 statements and 5 open-ended questions. The results show that the experience helped participants gain a better understanding of the teaching profession and how to become more involved in education. Moreover, it allowed participants to see how course content could be applied to the teaching of Spanish. Conversely, results do not show a direct effect on how pre-service teachers view their identities as Hispanics/Latinos and as speakers of Spanish. The study concludes with pedagogical implications for heritage language instruction and the implementation of further community service-learning in languages for specific purposes and proposes directions for future research.
Making the Subjective Objective: Machine Learning and Rhinoplasty

BACKGROUND Machine learning represents a new frontier in surgical innovation. The ranking Convolutional Neural Network (CNN) is a novel machine learning algorithm that helps elucidate patterns and features of aging that are not always appreciable with the human eye. OBJECTIVES The authors sought to determine the impact of aesthetic rhinoplasty on facial aging employing a multidimensional facial recognition and comparison software. METHODS A retrospective chart review and subsequent analysis was carried out on all female patients who underwent open rhinoplasty with the senior author from 2014 through 2018 and had postoperative photos at 12 or more weeks follow-up. All photos were analyzed with Microsoft Azure Face API (Redmond, WA), which estimates patients' age by cropping the face from a photograph and then extracting a CNN-based prediction through multiple deep neural networks. RESULTS A total of 100 patients ultimately met full inclusion criteria. The average post-surgical follow up for this cohort was 29 weeks (median, 14 weeks; range, 12-64 weeks). Patients ranged from 16 to 72 years old (mean, 32.75 years; median, 28.00 years; standard deviation, 12.79 years). The ranking CNN algorithm on average estimated patients preoperatively to be 0.03 years older than their actual age. The correlation coefficient between actual age and predicted preoperative age was r = 0.91. On average, patients were found to look younger post-open rhinoplasty (-3.10 vs 0.03 years, P < 0.0001). CONCLUSIONS The ranking CNN algorithm is both accurate and precise in estimating human age before and after cosmetic rhinoplasty. Given the resulting data, the effects of open rhinoplasty on reversing signs of facial aging should be revisited. LEVEL OF EVIDENCE: 4
Structure of the Calcium-Rich Signature Domain of Human Thrombospondin-2.

Abstract There are five members of the thrombospondin (TSP) family in vertebrates. This family of proteins comprises two separate subsets, group A and group B. Group A includes TSP-1 and TSP-2. TSP-1 is a major platelet α-granule component and contains a polymorphism that has been linked to coronary artery disease (CAD). TSP-2, although not found in platelets, is important for megakaryopoiesis. TSPs contain a signature domain that is found with high fidelity throughout the TSP family and consists of tandem epidermal growth factor (EGF)-like modules, 13 aspartate-rich calcium-binding repeats and a C-terminal lectin-like module. The signature domains of TSP-1 and TSP-2, which have three EGF-like modules, share 77% identity, without any insertions or deletions. In this study, we describe the 2.6 angstrom resolution crystal structure of the glycosylated signature domain of human TSP-2. Components of the domain interact extensively to form three striking structural features: a stalk that consists of the two N-terminal EGF-like modules, a wire that consists of the asparate-rich repeats, and a globe that consists of the lectin-like module. The third EGF-like module serves as a clasp to tie together the globe and the ends of the wire. The TSP-2 signature domain is stabilized by 30 bound Ca2+ ions and 18 disulfide bonds. The structure reveals functions of the residues at the position of the CAD-linked polymorphism in TSP-1 and many of the positions of the over 100 skeletal dysplasia-linked mutations in TSP-5. Finally, the structure allows for a better understanding of interactions between TSPs and a number of binding partners, including integrins, CD47, vonWillebrand factor, type V collagen, fibroblast growth factor, cathepsin-G and neutrophil elastase.
Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale

Logistic regression is the primary analysis tool for binary traits in genome-wide association studies (GWAS). Multinomial regression extends logistic regression to multiple categories. However, many phenotypes more naturally take ordered, discrete values. Examples include (a) subtypes defined from multiple sources of clinical information and (b) derived phenotypes generated by specific phenotyping algorithms for electronic health records (EHR). GWAS of ordinal traits have been problematic. Dichotomizing can lead to a range of arbitrary cutoff values, generating inconsistent, hard to interpret results. Using multinomial regression ignores trait value hierarchy and potentially loses power. Treating ordinal data as quantitative can lead to misleading inference. To address these issues, we analyze ordinal traits with an ordered, multinomial model. This approach increases power and leads to more interpretable results. We derive efficient algorithms for computing test statistics, making ordinal trait GWAS computationally practical for Biobank scale data. Our method is available as a Julia package OrdinalGWAS.jl. Application to a COPDGene study confirms previously found signals based on binary case-control status, but with more significance. Additionally, we demonstrate the capability of our package to run on UK Biobank data by analyzing hypertension as an ordinal trait.
Extradyadic Sex and Psychological Distress among Married and Cohabiting Young Adults: An Examination of Internalized and Externalized Responses:

Extradyadic sex (EDS) is a major relationship violation, yet it occurs in nearly a quarter of U.S. cohabiting and marital unions. While many relationships dissolve in the wake of EDS, a majority remain intact. Theories of social stress suggest that substantial psychological distress should result unless EDS is a symptom of stress caused by involvement in a relationship marked by other negative characteristics. This study investigates how one's own EDS, a partner's EDS, and mutual EDS are related to internalizing and externalizing behaviors: depressive symptoms and heavy alcohol use, respectively. Analyses of data from the National Longitudinal Study of Adolescent to Adult Health suggest that one's own EDS is associated with heavy alcohol use among cohabiters and spouses and with depressive symptoms among spouses, while partner EDS has no association with either outcome net of confounders. We discuss the implications of these findings in the study's conclusions.
Hypothermic circulatory arrest through the left chest

The concept of profound hypothermic circulatory arrest (HCA) through an anterior mediastinal approach has been a widely employed technique for the protection of the central nervous and other organ systems in the treatment of complex congenital and cardiac lesions, as well as aneurysms of the aortic arch. The application of this technique in the treatment of aortic disease through a posterolateral approach has received far less attention. The rationale for the use of hypothermic circulatory arrest in the treatment of patients with aortic pathology beyond the left subclavian artery includes proximal extension of the aortic pathology into the transverse aortic arch, the inability to safely place proximal aortic cross clamp for anatomical reasons (size, rupture, friability, scar tissue from prior operation), or the use of hypothermia as a modality for organ protection (most importantly, the spinal cord). A number of clinical reports have demonstrated the effective use of cardiopulmonary bypass, hypothermic circulatory arrest, and posterolateral exposure for procedures on the thoracic aorta for diverse aortic pathology (1–8). This report is a retrospective review of the author’s experience using HCA for patients requiring replacement of the descending thoracic or thoracoabdominal aorta through the left chest where proximal cross clamping was not feasible or aneurysmal disease extended into the transverse aortic arch. The technique was not employed primarily for spinal cord or other organ protection in patients in whom proximal cross clamping was possible.
Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection

Cerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain's mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into the cisterna magna (CM) of mouse brains have shown evidence of pulsatile CSF flow in perivascular spaces surrounding pial arteries, with a bulk flow in the same direction as blood flow. However, the driving mechanism remains elusive. Several studies have suggested that the bulk flow might be an artifact, driven by the injection itself. Here, we address this hypothesis with new in vivo experiments where tracer particles are injected into the CM using a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure. Yet, particle-tracking reveals flows that are consistent in all respects with the flows observed in earlier experiments with single-syringe injection.
Modeling COTS System TID Response With Monte Carlo Sampling and Transistor Swapping Experiments

Modeling systems containing commercial-off-the-shelf (COTS) parts exposed to total ionizing dose (TID) are difficult due to large parameter variability in the parts as a function of dose. This article provides a rapid approach to predicting the system performance as a function of TID given these parameter variations. A radiation-aware model for an IRF510 power MOSFET is generated from a small population of irradiated parts, and this model is randomly sampled for each of the transistors in an example circuit, utilizing the degraded parameters. The simulations predict the circuit operating in one of three distinct modes, with circuits containing large variability in parts failing in some instances. The simulated data are compared to experimental data using a method that involves interchanging irradiated parts in a socketed printed circuit board (PCB) to produce a large number of different combinations of test circuits. The simulated data correctly predicted the circuit modes of operation, and the part-swapping technique eliminated the cost of building many test boards.
An Improved PWM Method for Minimum Common-Mode Circulating Current Operation of Six Phase Three Level Inverter

This paper presents a simple Pulse Width Modulation (PWM) technique to reduce the common-mode circulating current of a six-phase three-level inverter. Six-phase inverters generally suffer high common-mode circulating current when space vector PWM (SVPWM) or min-max method is used with a common neutral point. For common-mode circulating current reduction, Phase Disposition (PD) PWM with a compromised third harmonics injection method is proposed in this work. The selected third harmonics injection method removes the low-frequency common-mode circulating current. The absence of low frequency circulating current improves the THD of the load currents. Finally, the proposed method is tested in PLECS simulation with a 75KW system, and results are presented here.
A Blocked All-Pairs Shortest-Path Algorithm

We propose a blocked version of Floyd's all-pairs shortestpaths algorithm. The blocked algorithm makes better utilization of cache than does Floyd's original algorithm. Experiments indicate that the blocked algorithm delivers a speedup (relative to the unblocked Floyd's algorithm) between 1.6 and 1.9 on a Sun Ultra Enterprise 4000/5000 for graphs that have between 480 and 3200 vertices. The measured speedup on an SGI O2 for graphs with between 240 and 1200 vertices is between 1.6 and 2.
Practical Innovations: Technology-Assisted Referrals

Patients in the acute care setting often require referrals for post-hospital care. Before 2003, charts were copied manually and faxed to each nursing home separately, which was labor intensive, created delays, depended on legible notes, and did not ensure patient confidentiality. Social workers at our institution, in collaboration with 21 area nursing homes, successfully developed a program to streamline this process by using the electronic medical record and computer-assisted faxing. The patient's medical record (history/physical, nursing notes, pharmacy record, and therapy notes) was able to be transmitted quickly. This technology-assisted referral system had positive and successful outcomes, such as decreased length of stay, which resulted in an estimated cost savings of $2,008,512 per year.