cssi/SciSciGPT-SciSciNet huggingface dataset:
Histone methylase MLL1 coordinates with HIF and regulate lncRNA HOTAIR expression under hypoxia

Hypoxia signaling plays a critical role in tumor growth, angiogenesis, metastasis cancer, and aging. Under hypoxia, hypoxia-inducible factors (HIFs) are stabilized and they coordinate the process of hypoxia-induced gene expression and cell signaling leading to increased tumor growth. Recent studies indicate that non-coding RNAs which are closely associated with cancer are abnormally expressed under hypoxia. Here, we have investigated the transcriptional regulation of a cancer associated long non-coding RNA (lncRNA), HOTAIR, under hypoxic conditions. Our studies demonstrate that HOTAIR expression is upregulated under hypoxia in colon cancer and several other types of cancer cells. HOTAIR transcription is regulated by HIF1α which binds to the hypoxia response elements (HRE) present in the HOTAIR promoter under hypoxia. HIF1α knockdown results in decreased HOTAIR expression under hypoxia. Along with HIF1α, histone methylases MLL1 and histone acetylase p300 are enriched at the HOTAIR promoter under hypoxia. The levels of H3K4-trimethylation and histone acetylation are also enriched at the HOTAIR promoter. Furthermore, knockdown of MLL1 downregulated the hypoxia-induced HOTAIR expression, indicating key roles of MLL1 in hypoxia-induced HOTAIR expression. Overall, our studies demonstrate that histone methyl-transferase MLL1 coordinates with HIF1α and histone acetyltransferase p300 and regulate hypoxia-induced HOTAIR expression. The hypoxia-induced upregulation of HOTAIR expression may contribute to its roles in tumorigenesis.
A Framework for Modeling and Optimizing Dynamic Systems Under Uncertainty.

Abstract Algebraic modeling languages (AMLs) have drastically simplified the implementation of algebraic optimization problems. However, there are still many classes of optimization problems that are not easily represented in most AMLs. These classes of problems are typically reformulated before implementation, which requires significant effort and time from the modeler and obscures the original problem structure or context. In this work we demonstrate how the Pyomo AML can be used to represent complex optimization problems using high-level modeling constructs. We focus on the operation of dynamic systems under uncertainty and demonstrate the combination of Pyomo extensions for dynamic optimization and stochastic programming. We use a dynamic semibatch reactor model and a large-scale bubbling fluidized bed adsorber model as test cases.
A study of MRI gradient echo signals from discrete magnetic particles with considerations of several parameters in simulations.

Abstract Modeling MRI signal behaviors in the presence of discrete magnetic particles is important, as magnetic particles appear in nanoparticle labeled cells, contrast agents, and other biological forms of iron. Currently, many models that take into account the discrete particle nature in a system have been used to predict magnitude signal decays in the form of R2* or R2′ from one single voxel. Little work has been done for predicting phase signals. In addition, most calculations of phase signals rely on the assumption that a system containing discrete particles behaves as a continuous medium. In this work, numerical simulations are used to investigate MRI magnitude and phase signals from discrete particles, without diffusion effects. Factors such as particle size, number density, susceptibility, volume fraction, particle arrangements for their randomness, and field of view have been considered in simulations. The results are compared to either a ground truth model, theoretical work based on continuous mediums, or previous literature. Suitable parameters used to model particles in several voxels that lead to acceptable magnetic field distributions around particle surfaces and accurate MR signals are identified. The phase values as a function of echo time from a central voxel filled by particles can be significantly different from those of a continuous cubic medium. However, a completely random distribution of particles can lead to an R2′ value which agrees with the prediction from the static dephasing theory. A sphere with a radius of at least 4 grid points used in simulations is found to be acceptable to generate MR signals equivalent from a larger sphere. Increasing number of particles with a fixed volume fraction in simulations reduces the resulting variance in the phase behavior, and converges to almost the same phase value for different particle numbers at each echo time. The variance of phase values is also reduced when increasing the number of particles in a fixed voxel. These results indicate that MRI signals from voxels containing discrete particles, even with a sufficient number of particles per voxel, cannot be properly modeled by a continuous medium with an equivalent susceptibility value in the voxel.
Brief report: Circulating markers of fibrosis are associated with immune reconstitution status in HIV-infected men.

Introduction Lymphoid tissue fibrosis may contribute to incomplete immune reconstitution on antiretroviral therapy (ART) via local CD4+ T lymphocyte (CD4) depletion. Hyaluronic acid (HA) increases with fibrotic burden. CXCL4 concentrations increase in response to pro-fibrotic stimuli, but lower CXCL4 concentrations in HIV-infected individuals may reflect successful immune evasion by HIV. We investigated relationships between circulating HA and CXCL4 concentrations and immune reconstitution on ART in HIV-infected Multicenter AIDS Cohort Study participants. Methods HIV-infected men on ART for >1 year with cryopreserved plasma samples and suppressed post-ART HIV-1 RNA were included. Men with post-ART CD4 500 cells/mm3 served as controls (n = 49). HA and CXCL4 concentrations were measured via ELISA. Results Median pre-ART CD4 was 297 cells/mm3 for non-responders vs 386 cells/mm3 for controls. Median post-ART CD4 was 141 cells/mm3 for non-responders and 815 cells/mm3 for controls. HIV infection duration was 23 years, with median time on ART 13 years for non-responders vs 11 years for controls. Pre-ART HA and CXCL4 concentrations did not vary by eventual immune reconstitution status. Post-ART HA concentrations tended to be higher (85 vs 36 ng/mL, p = 0.07) and CXCL4 concentrations were lower (563 vs 1459 ng/mL, p = 0.01) among non-responders. Among men with paired pre-/post-ART samples, non-responders had greater HA increases and CXCL4 decreases than controls (HA: 50 vs 12 ng/mL, p = 0.04; CXCL4: -1258 vs -405 ng/mL, p = 0.01). Conclusions Higher circulating concentrations of HA and lower concentrations of CXCL4 are associated with failure of immune reconstitution on ART.
Application of phase-only filter on electronic nose data

This article presents an application of Phase Only Filter (POF) to the classification of volatile compound samples with chemical sensor arrays. Sinusoidal temperature modulator excites the chemical sensor array. A system composed of multiple sensors for data acquisition requires the analysis of multiple data signals in order to classify the input data. One such system is the Electronic Nose system (eNose). The eNose data is in fact 1D data from multiple data sources. In this work five samples of three different kinds of coffee are used to build an odor database. An unknown test sample is then classified. In this research data, from such system will be analyzed and classified using the POF and compared to the more conventional K Nearest Neighbors (KNN) classifier. Both classifiers use only the mean and standard deviation as the classification feature space. The difference of the correlation between odor database and the auto correlation of the test sample is the measure of closeness for the POF. For the KNN, the measure of closeness is the difference between the odor database and the test sample.
JVM-Portable Sandboxing of Java’s Native Libraries

Although Java provides strong support for safety and security, native libraries used in a Java application can open security holes. Previous work, Robusta, puts native libraries in a sandbox to protect the integrity and security of Java. However, Robusta’s implementation modifies the internals of OpenJDK, a particular implementation of a Java Virtual Machine (JVM). As such, it is not portable to other JVM implementations. This paper shows how to make the idea of sandboxing native libraries JVM-portable. We present a two-layer approach for sandboxing without modifying the internals of a JVM. We also discuss our experience of sandboxing Java’s core native libraries. Experiments show that our approach of JVM-portable sandboxing incurs modest performance overhead on SPECjvm 2008 benchmark programs.
The Impact of a Flipped Classroom Model of Learning on a Large Undergraduate Statistics Class.

We examine the impact of a flipped classroom model of learning on student performance and satisfaction in a large undergraduate introductory statistics class. Two professors each taught a lecture-section and a flipped-class section. Using MANCOVA, a linear combination of final exam scores, average quiz scores, and course ratings was compared for the two groups after controlling for the effects of students’ previous achievement, gender, teacher, degree of learner autonomy, and attitudes about math and statistics. The results show significant improvement in the students’ performance and course satisfaction with the flipped classroom. Overall, the results showed that the flipped classroom model can be used in large lecture classes with the help of undergraduate teaching assistants and the use of additional labs. First published May 2018 at Statistics Education Research Journal Archives
Circulating BRAF V600E Cell-Free DNA as a Biomarker in the Management of Anaplastic Thyroid Carcinoma

PurposeAnaplastic thyroid cancer (ATC) is a deadly form of thyroid cancer. BRAF V600E is the only actionable mutation for which there is a Food and Drug Administration–approved drug combination. Rapid detection of BRAF V600E and initiation of therapy is critical. We explored the ability of droplet digital polymerase chain reaction (ddPCR) to identify this mutation in circulating cell-free DNA (cfDNA) in plasma.Materials and MethodsThe ddPCR assay was evaluated for its sensitivity, specificity for detection of BRAF V600E cfDNA, and concordance with tumor tissue. The assay also was used to evaluate its potential role as a biomarker of response.ResultsForty-four patients with ATC who were tested for the BRAF mutation by tumor tissue DNA sequencing or immunohistochemistry were included. Sixteen BRAF V600E–positive patients had treatment samples to evaluate cfDNA levels as a biomarker of response in correlation with restaging scans. Concordance of ddPCR with tumor tissue was 93%, with a sensitivity of 85% and ...
A Deep Neural Network Approach for Early Diagnosis of Mild Cognitive Impairment Using Multiple Features

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that is progressive and can be characterized mostly by neuronal atrophy, amyloid deposition, accompanied by cognition, behavioral and psychological deficits. In the recent decade, a variety of machine learning algorithms have been explored and used for AD diagnosis, focusing on its subtle prodromal stage of mild cognitive impairment (MCI) to assess essential features that characterize its early manifestation and to plan for early treatment. However, diagnosis of early MCI (EMCI) remains most challenging as it is extremely difficult to delineate from cognitively normal controls (CN), and as a consequence, most of the classification algorithms for these two groups are mixed with low classification accuracy results. In this study, a machine learning approach based on deep neural network (DNN) has been proposed in order to detect AD in its early stage using multimodal imaging, combining magnetic resonance imaging (MRI), positron emission tomography (PET) and standard neuropsychological test scores. The proposed approach makes use of the optimization method of Adam to update the learning weights in order to improve its accuracy. The algorithm is able to classify cognitively normal control group from EMCI with an unprecedented accuracy of 84.0%. Although the focus here is distinguishing the two groups of CN and EMCI for early diagnosis and treatment planning, this study also shows how the proposed deep learning algorithm can be extended for multiclass classification involving CN and all the stages of EMCI, late MCI (LMCI) and AD.
An Integrated Circuit Solution to Johnson Noise Thermometry Using Low-Cost and Fast CMOS Technology

An integrated circuit solution to Johnson noise thermometry (ICJNT) using a low-cost and fast complementary metal–oxide–semiconductor (CMOS) technology is investigated in this paper. Benefits from both noise thermometry and integrated circuits (ICs) can be maintained in ICJNTs, which cost significantly less, work orders of magnitude faster than discrete-device JNTs, and can be applied to various applications. As a first attempt at an ICJNT, this paper presents the relevant analysis and design techniques, demonstrates the potential benefits of ICJNTs, and discusses the challenges unique to integrated circuit solutions. A prototype IC chip is fabricated using the 0.13- $\mu \text{m}$ CMOS technology with fully on-chip circuits, including sensing resistors, a pre-amplifier, and a flash analog-to-digital converter. To demonstrate the efficacy, a test PCB for the ICJNT was developed and measured in a standard industrial thermal chamber with a laboratory grade platinum resistance thermometer as a comparison reference. The test results show that this first ICJNT prototype is able to provide temperature measurement from 0 °C to 70 °C. The maximum deviation with two-point calibration is 1.2 °C at a measurement of 40 °C due to systematic error, and the standard deviation is approximately 2 °C. The measurement time is only 10 ms due to the fast IC technology. These results established the feasibility of the ICJNT concept. Since the ICJNT is a complete solution without discrete devices and the sensing resistors are not limited to specific IC materials, the ICJNT can be applied to various emerging applications, such as electric vehicles and microelectromechanical systems.
Conditional Coordination Games on Cyclic Social Influence Networks

Coordinated decision making is one of the fundamental attributes of intelligent behavior, and game theory has long served as a framework within which to model interactive decision making, especially for scenarios where decision makers are motivated to compete for the distribution of scarce resources. It is not obvious, however, that the standard game-theoretic framework is appropriate for complex social scenarios where agents are influenced by the attitudes and opinions of others and, consequently, the opportunity exists to make coordinated decisions in the pursuit of coherent group behavior. Noncooperative game theory is founded on the premise that choices ought to be strategically rational—agents make best-replies to the expected actions of others. However, when modeling groups whose members are responsive to social influence, a relevant notion of behavior is for them to coordinate rather than compete. The combination of conditional game theory and Bayesian network theory provides a framework within which to formalize a theory of coordinated decision making under social influence. As originally developed, however, conditional game theory applies only to acyclical networks involving unilateral influence propagation. This paper extends the theory to account for networks with cycles, where agents are able to exert multilateral influence on each other. The Markov convergence theorem establishes conditions for convergence to steady-state coordinated decisions, and demonstrates its use with a bilateral collaboration scenario. In addition, this paper provides a mathematical analysis of several canonical network topologies.
Physician payment in Canada, Germany, and the United States.

As the debate about reforming the U.S. health care system intensifies, interest has focused on three alternative delivery systems: the predominantly private-sector model in the United States, the provincial-government health insurance model of Canada, and the social insurance model of Germany. The organization of physician payment is an important part of all these health care systems. To maintain an affordable system that delivers high-quality care, payment to physicians must be sufficient to attract and maintain an able group of doctors, while not exceeding an amount that the country can afford. In this article, these three systems will be examined, and an attempt will be made to apply the lessons learned from Germany and Canada to the direction of physician payment reform in the United States.
Stress among Correctional Officers: an Organizational Justice Approach

Employees’ positive perceptions of organizational justice are crucial to the successful operation of correctional institutions. Employees who perceive their employer treats them justly and fairly report less job-related stress and happier home lives. Organizational justice has two primary components – procedural and distributive justice – that have been examined relative to job satisfaction and job performance. The current study builds on the existing literature and examines the effects that perceptions of procedural and distributive justice have on the strain-based form of work-family conflict. Specifically, the goal of this study is to determine whether these two forms of justice were related to the strain that correctional employees bring home with them. Data collected from a large Southern correctional institution indicate that perceptions of procedural justice related significantly to reported levels of the strain-based form of work-family conflict and that staff with the highest perceptions of procedural justice reported the lowest levels of strain-based work-family conflict. This did not hold true for distributive justice, however, which was found to be statistically unrelated to work-family strain.
Quantitative strain sensing in a multimode fiber using dual frequency speckle pattern tracking

We report an amplitude-measuring multimode fiber sensor capable of making quantitative strain measurements and extracting the algebraic sign of the strain. The Rayleigh-based sensor probes the fiber with pulses of alternating optical frequency and records the backscattered speckle patterns on a high-speed camera. We show that measuring the change in the speckle pattern induced by a change in optical frequency provides a form of in situ calibration, enabling the sensor to recover the magnitude and algebraic sign of the strain. The sensor, which can be positioned anywhere along 2 km of fiber, has a linear strain response, a 10 kHz bandwidth, and a strain noise of ${10.2}\;{\rm p}\unicode{x03B5} /\surd {{\rm Hz}} $10.2pe/√Hz.
Physical activity, sedentary time, and longitudinal bone strength in adolescent girls

The association between baseline physical activity and sedentary time with 2-year longitudinal bone strength was evaluated. The effect of physical activity on bone depended on maturity status. Sedentary time did not negatively impact bone outcomes, regardless of maturity. Maturity should be considered when developing exercise interventions to improve bone outcomes. Physical activity during adolescence is important to obtain peak bone mass; however, adolescents are increasingly sedentary, potentially increasing risk for osteoporosis later in life. The aim of this study was to assess the association of physical activity and sedentary time with 2-year longitudinal bone outcomes in adolescent females (69% Hispanic/31% non-Hispanic). Bone strength was assessed at the 66% tibia, 20% femur, and 66% radius of 9- to 12-year-old girls (n = 131) using peripheral quantitative computed tomography at baseline and 2-year follow-up. Physical activity and sedentary time were assessed via accelerometry. Linear regression analyses were used to assess whether baseline vigorous physical activity (VPA), moderate physical activity (MPA), light physical activity (LPA), or sedentary time predict longitudinal bone outcomes, adjusting for relevant confounders. Significant interactions were found between maturity offset and physical activity. In weight-bearing bones, significant interactions were primarily identified between VPA and maturity offset. Interactions indicated that VPA was associated with favorable bone outcomes at the tibia and femur in girls further past the age of PHV. However, this favorable effect was not observed in girls closer to the age of PHV. At the radius, interactions were primarily observed between LPA and maturity offset. Again, LPA was more beneficial for girls further past the age of PHV. Sedentary time did not significantly influence bone outcomes. The effects of physical activity on bone may be dependent on maturity. Therefore, physical activity interventions, with attention to maturity status, may be required to optimize bone strength in girls.
Ryanodine Receptor Sensitivity Governs the Stability and Synchrony of Local Calcium Release during Cardiac Excitation-Contraction Coupling

Synchronous coordination of calcium-induced calcium release (CICR) across thousands of calcium release units (CRUs) within the cardiomyocyte is critical for normal excitation-contraction coupling (ECC). Here we utilize a novel “local control” mathematical model of ECC, designed to simulate a mouse cardiomyocyte, to investigate physiological and pathophysiological calcium (Ca2+) signaling. The model contains 20,000 independent CRUs each composed of 6 stochastically gated L-type Ca2+ channels (LCCs) in the transverse tubule membrane that are positioned across a local “dyadic subspace” from a junctional sarcoplasmic reticulum (JSR) compartment containing a cluster of 50 stochastically gated ryanodine receptors (RyR2s). Action potential depolarization of the sarcolemmal membrane activates LCC openings which elevate subspace [Ca2+] ([Ca2+]ds) across each of the cell's 20,000 CRUs. This rise in [Ca2+]ds promotes RyR2 opening to initiate the fundamental element of triggered Ca2+ release, the Ca2+ spark. The mechanistic design and true SR Ca2+ pump/leak balance displayed by our model allows us to quantify ECC fidelity and Ca2+ spark fidelity (the probability that a LCC opening or RyR2 opening induces a Ca2+ spark, respectively). We study the effect of excess SR Ca2+ leak in the context of “catecholaminergic polymorphic ventricular tachycardia (CPVT)” caused by the R33Q mutation in calsequestrin (CASQ2). CPVT is simulated by increasing RyR2 sensitivity to [Ca2+]i and reducing JSR Ca2+ buffering capacity to levels identified by prior studies of the CASQ2-R33Q “knock-in” mice. Our model effectively reproduces both normal and arrhythmogenic CPVT RyR2 [Ca2+]i sensitivity, local Ca2+ spark activity, and global Ca2+ signals. Under CPVT conditions enhanced RyR2 open probability is critical for the development of “unstable”, quiescent Ca2+ sparks that fail to terminate robustly as well as asynchronous systolic Ca2+ spark activity and increased diastolic SR Ca2+ leak.
Chapter 4 – Regular Expressions

Publisher Summary This chapter discusses the regular expressions. Every regular set can be represented by a regular expression and every regular expression represents a regular set. Algebraic manipulations with regular expressions, and transition graphs are discussed. Various theorems are proved in the chapter. The chapter reviews sets of words corresponding to transition graphs, and presents the proof of Kleene's theorem. A procedure for checking equality of regular expressions, and an axiomatic approach to regular expressions is reviewed. Applying the standard logical rules of inference, for example, substitutivity of equality, and sometimes also special additional rules, which become in some sense a part of the system of axioms, one derives theorems from the axioms. One also looks for a concrete model of a mathematical structure satisfying a given set of axioms. The non-sufficiency of a finite system of axioms is also discussed in the chapter.
Electrically Conductive 2D Metal-Organic Framework/Graphene Composite for the Electrochemical Reduction of Nitrogen to Ammonia Under Ambient Conditions

The conversion of N2 into ammonia is one of the most important processes in the chemical industry and the basis for the production of fertilizers necessary to maintain agricultural food production. The conventional Haber-Bosch process requires high energy input (1% of world energy supply) and suffers from harsh reaction conditions with an associated CO2 emission as a side product. More sustainable alternatives for ammonia synthesis are thus needed to sustain the growing demand. Electrochemical reduction of N2 (NRR) is an attractive approach that utilizes catalysts that can selectively favor one reduction product over the others at a lower reduction potentials. Despite the unprecedented efforts in utilizing metal-organic frameworks MOFs in the electrocatalytic N2 reduction, their powdery nature, high electrical resistance, poor product selectivity and low stability limits their use in catalytic applications. This presentation will describe a facile one-pot synthesis method that can modulate MOF's conductivity via growing 2D ultrathin copper/palladium-tetrakis (4-carboxyphenyl) porphyrin Cu(PdTCPP) layers interconnected with graphene sheets giving Cu(PdTCPP)@G. This technique favors the formation of free-standing large sheets of MOF/graphene. The strong interaction between the MOF and graphene sheets allows direct electron transfer through the MOF matrix enabling them to become electrically accessible. Palladium atoms act as the main catalytic sites for NRR in a system that offers high activity and selectivity giving NH3 yield rate of 5.45 µg h-1 mg-1 MOF (52 µg h-1 mg-1 Pd ) at -0.091 V vs RHE and a Faradaic efficiency of 8.45% in 0.1 M phosphate buffer. This material showed a very promising photocurrent generation making it attractive for further development of a photocatalytic NRR that can run under sunlight, with potential to become fully sustainable.
Actionable Risk Model for the Development of Surgical Site Infection after Emergency Surgery.

Background: Surgical site infections (SSIs) increase mortality and the economic burden associated with emergency surgery (ES). A reliable and sensitive scoring system to predict SSIs can help guide...
Deprotonation of Isoxazole: A Photoelectron Imaging Study

We report a photoelectron imaging study of gas-phase deprotonation of isoxazole in which spectroscopic data are compared to the results of electronic structure calculations for the anion products c...
Comparison of Aspirin Monotherapy versus Dual Antiplatelet Therapy Following Coronary Artery Bypass Grafting.

Aspirin remains the gold standard antiplatelet regimen following coronary artery bypass grafting (CABG), however, there is growing support for dual antiplatelet therapy (DAPT). This study compares outcomes of aspirin monotherapy versus DAPT following CABG. This was a propensity-matched retrospective study from a large, multi-hospital healthcare system. It included patients who received either aspirin monotherapy or DAPT following isolated CABG between 2011 and 2018. Patients prescribed aspirin monotherapy were started on 81 mg aspirin daily, and patients on DAPT were prescribed 81 mg aspirin daily and 75 mg clopidogrel daily. Patients received alternative drug dosing or antiplatelet agents other than clopidogrel only if this was prescribed for another diagnosis or they had a preexisting contraindication. Primary outcomes included overall survival and major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of death, myocardial infarction, stroke, or repeat revascularization. Kaplan-Meier analysis and the log-rank test were used to compare survival and cumulative incidence curves and Gray's test were used to compare MACCE. A total of 3,562 propensity-matched patients were included, 1,242 (34.9%) receiving aspirin monotherapy and 2,320 (65.1%) receiving DAPT. Groups were well-matched with respect to age, baseline comorbidity, indication for CABG, and completeness of revascularization. Median follow-up was 4.90 years (IQR 3.30 to 6.90 years). DAPT was associated with higher rate of postoperative transfusion (30.7% vs 25.4%, p = 0.001). Overall survival was comparable between groups (1-year aspirin 95.9% versus DAPT 97.2% and 5-years aspirin 86.3% versus DAPT 87.8%; log-rank p = 0.194). Rates of MACCE were also similar (1-year aspirin 9.4% versus DAPT 8.7% and 5-years aspirin 26.7% versus DAPT 24.7%; p = 0.798). In this propensity-matched analysis, DAPT did not confer any advantage in terms of improved survival or freedom from MACCE compared to aspirin monotherapy following isolated CABG, and was associated with a higher postoperative transfusion rate.
A Series of Reflections on 'Food Fight: An Examination of Recent Trends in Food Litigation and Where We Go From Here'

A series of reflections on "Food Fight: An Examination of Recent Trends in Food Litigation and Where We Go From Here."
Free Exercise and the Public Interest After Tandon v. Newsom

This very brief paper addresses the important Free Exercise case of Tandon v. Newsom, with an emphasis on the initial strict scrutiny determination, and then on applying the strict scrutiny test in appropriate cases.
Investigating Developmental Changes in Scalp-Cortex Correspondence Using Diffuse Optical Tomography Sensitivity in Infancy

Abstract Significance Diffuse optical tomography (DOT) uses near-infrared light spectroscopy (NIRS) to measure changes in cerebral hemoglobin concentration. Anatomical interpretations of NIRS data requires accurate descriptions of the cranio-cerebral relations and DOT sensitivity to the underlying cortical structures. Such information is limited for pediatric populations because they undergo rapid head and brain development. Aim The present study aimed to investigate age-related differences in scalp-to-cortex distance and mapping between scalp locations and cortical regions of interest (ROIs) among infants (2 weeks to 24 months with narrow age bins), children (4 and 12 years) and adults (20 to 24 years). Approach We used spatial scalp projection and photon propagation simulation methods with age-matched realistic head models based on MRIs. Results There were age-group differences in the scalp-to-cortex distances in infancy. The developmental increase was magnified in children and adults. There were systematic age-related differences in the probabilistic mappings between scalp locations and cortical ROIs. Conclusions Our findings have important implications in the design of sensor placement and making anatomical interpretations in NIRS and fNIRS research. Age-appropriate realistic head models should be used to provide anatomical guidance for standalone DOT data in infants.
Expedient Single Step Access to Strained Tricyclic Ketals

The synthesis of cyclopropyl methyl ketones and highly strained fused substituted dihydrobenzopyran cyclopropyl lactones derived from coumarin carboxylates and chloroacetone in the presence of potassium carbonate is reported. One step synthetic access to the previously unknown dihydrobenzopyran cyclopropyl tricyclic ketals is achieved with wide substrate scope. Substituted coumarin carboxylates, phenylamides or a quinolin-2(1H)-one possessing alkyl electron donating (methyl, t-butyl) and electron withdrawing groups (F, Cl, Br, NO2) in the 4 or 6 positions formed the highly strained dihydrobenzopyran cyclopropyl tricyclic ketals in moderate yield alongside the expected coumarin carboxylate. Saturation or substitution at the 5-position or 6-OMe afforded no tricyclic ketal compound but solely coumarin carboxylates. The formation of both structures in selected derivatives was confirmed by X-ray crystallography. A plausible mechanism is proposed for the formation of the fused lactone; via intramolecular rearrangement of cis cyclopropyl methyl ketones with phenolic acetate via the formation of a hemiacetal.
A practical approach for gmp-compliant validation of real-time PCR method for mycoplasma detection in human mesenchymal stromal cells as advanced therapy medicinal product.

Abstract Background Manufacturing of human Mesenchymal Stromal Cells as advanced therapy medicinal product (ATMP) for clinical use involves an ex vivo expansion, which leads to a risk of contamination by microbiological agents. Even if manufacturing under Good Manufacturing Practice (GMP) license minimizes this risk, contamination of cell cultures by mycoplasmas still represents a widespread problem. Furthermore, the absence of mycoplasma contamination represents one of ATMPs release criteria. Since July 2007, European Pharmacopoeia (EuPh) offers the possibility to replace official mycoplasma detection methods with Nucleic Acid Amplification techniques, after suitable validation. As an Italian authorized Cell Factory, we developed an in-house GMP-compliant validation of real-time PCR method for mycoplasma detection in human Mesenchymal Stromal Cells, according to EuPh sec. 2.6.7 and International Conference on Harmonization Q2. Materials and methods The study was performed in compliance with GMP international requirements with MycoSEQ™ Mycoplasma Detection Assay (Thermofisher) on QuantStudio5 real-Time PCR (Applied Biosystems). Assay validation was developed to evaluate sensitivity, interferences matrix-related, specificity and robustness. Results MycoSEQ™ Mycoplasma Detection Assay has been successfully validated on human Mesenchymal Stromal Cells as results comply with validation protocol acceptance criteria. Conclusions MycoSEQ™ Mycoplasma Detection Assay is a fast, sensitive and specific PCR-based Nucleic Acid Test assay that can be used as an alternative to official mycoplasma test methods for lot release of human Mesenchymal Stromal Cells as advanced therapy medicinal product (ATMP). Moreover, our study underlines the presence of interference on real-time PCR reaction due to matrix composition, pointing out a practical approach for method validation (i.e interference removal).
Evaluation of the Repeatability of the LacryDiag Ocular Surface Analyzer for Assessment of the Meibomian Glands and Tear Film.

Purpose This study aimed to determine the intra- and interobserver repeatability of the new LacryDiag Ocular Surface Analyzer and compare it to a similar all-in-one device, the OCULUS Keratograph 5M. Methods Thirty healthy subjects aged 18 years and above were recruited for this study. All patients were free of any existing ocular pathology. The LacryDiag Ocular Surface Analyzer was used to evaluate tear meniscus height, interferometry, noninvasive tear break-up time (NIBUT), and meibography. The same or analogous exams were performed using the OCULUS Keratograph 5M. Test equivalation was used to compare data from corresponding examinations. Paired t-tests and coefficient of variation were used to determine inter- and intraobserver repeatability. Bland-Altman analysis was used to determine level of agreement between devices. Results There were no differences in mean values for tear meniscus height, NIBUT, or tear film interferometry between observers for either device. Significant differences were found between observers for meibography when using the LacryDiag (P = 0.008 for percent loss calculation and P = 0.004 for grading scale). Intra-observer variability for NIBUT was significantly higher for the Keratograph (P = 0.0003 for observer A and P < 0.0001 for observer B). Conclusions There was a good correlation but poor agreement between devices for a given observer. This was likely influenced by the use of repeated testing and the non-dry eye cohort. Translational Relevance Both the repeatability of the testing device and the use of multiple outcome measures are essential for the diagnosis and monitoring of patients with dry eye disease (DED).
General Philosophical Background

When speaking of the schools of international law it is customary to referr to three 1: the positivist, the naturalist, and the eclectic or Grotian. These schools shade into one another, however, and each term is applied to several different conceptions of international law. Furthermore, the relationships among these various views of the law of nations, historically speaking, are often quite intricate.
An Agent Infrastructure to Build and Evaluate Multi-Agent Systems: The Java Agent Framework and Multi-Abent System Simulator

In this paper, we describe our agent framework and address the issues we have encountered designing a suitable environmental space for evaluating the coordination and adaptive qualities of multi-agent systems. Our research direction is to develop a framework allowing us to build different type of agents rapidly, and to facilitate the addition of new technology. The underlying technology of our Java Agent Framework (JAF) uses a component-based design. We will present in this paper, the reasons and the design choices we made to build a complete system to evaluate the coordination and adaptive qualities of multi-agent systems.
Abstract 16342: Rage Dependent Macropinocytosis Mediates Endocytosis of Enzyme Modified Non Oxidized LDL and Foam Cell Formation in Mouse Aortic Smooth Muscle Cells

Background: Vascular smooth muscle cell (SMC) derived foam cells contribute to human atherosclerosis. Enzymatically modified LDL (E LDL) induces SMC foam cells. Mechanism of E LDL uptake and the relative contribution of E LDL compared with other modified forms of LDL such as oxidized LDL in SMC foam cell formation are unknown. Methods and Results: Electrophoresis and FPLC analysis suggests E LDL (trypsin,cholesterol esterase modified) consists of fused LDL particles. Incubation of murine aortic SMCs with 10 μg/ml E LDL results in significant foam cell formation (analyzed by Oil Red O, lipid measurement) compared to SMCs incubated with acetylated LDL (500 μg/ml; -50%, p Conclusions: E LDL is highly potent in inducing foam cells in mouse aortic SMCs. This is mediated by Src, PI3K and RAGE regulated endocytosis of E LDL into SMCs. Inhibitors for macropinocytosis together with genetic ablation of RAGE completely prevents uptake of E LDL and foam cell formation in murine SMC.
Posttraumatic stress disorder and substance use disorder comorbidity among individuals with physical disabilities: findings from the National Comorbidity Survey Replication.

Co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD) affects multiple domains of functioning and presents complex challenges to recovery. Using data from the National Comorbidity Study Replication, a national epidemiological study of mental disorders (weighted N = 4,883), the current study sought to determine the prevalence of PTSD and SUD, the symptom presentation of these disorders, and help-seeking behaviors in relation to PTSD and SUD among individuals with physical disabilities (weighted n = 491; nondisabled weighted n = 4,392). Results indicated that individuals with physical disabilities exhibited higher rates of PTSD, SUD, and comorbid PTSD/SUD than nondisabled individuals. For example, they were 2.6 times more likely to meet criteria for lifetime PTSD, 1.5 times more likely for lifetime SUD, and 3.6 times more likely for lifetime PTSD/SUD compared to their nondisabled peers. Additionally, individuals with physical disabilities endorsed more recent/severe PTSD symptoms and more lifetime trauma events than nondisabled individuals with an average of 5 different trauma events compared to 3 in the nondisabled group. No significant pattern of differences was noted for SUD symptom presentation, or for receipt of lifetime or past-year PTSD or SUD treatment. Implications of these findings and recommendations for future research are discussed.
Antisense Promoter Mapping.

We have employed antisense methods to study the transcriptional functions of c-fos protein (Fos). Clones expressing inducible anti-fos RNA have been employed to inhibit c-fos expression, resulting in activation of c-fos transcription by inhibiting its normal repressor function. The sites of negative regulation by Fos have been mapped using this antisense mapping method which demonstrates that the serum response element represents the major site of repression by endogenous c-fos protein. A similar strategy (antisense cloning) has been employed to clone four target genes that are Fos dependent. These cDNAs encode mRNAs that are rapidly induced by serum (although this induction is blocked by cycloheximide) but are blocked by induction of anti-fos RNA. These inhibitory methods of studying transcription factor function are extremely useful for transcription factors (like Fos) that require cooperation with other factors to modulate gene transcription.
Celebrating the 100th anniversary of controlled, sustained, and powered air flight

This paper recognizes the 100th anniversary of the 17 December 1903 flight of the Wright brothers. This accomplishment demonstrated the first truly controlled, sustained, powered and heavier-than-air flight. This paper highlights the four special technical challenges the Wright brothers faced and how they were able to develop a flight system that could be safely utilized by humans. The paper also shows the three major contributions of the Wright brothers. Eventually, their work affected travel as well as shipping, farming, warfare, and many aspects of our daily lives.
The dissociation of Helix pomatia alpha-hemocyanin. Microheterogeneity at pH 5.7 in 0.4 m NaCl.

The careful equilibrium light-scattering study by Engelborghs and Lontie (1973, J. Mol. Biol., 77, 577–587) of the dissociation into half molecules of the α-component of Helix pomatia hemocyanin demonstrated that, although complete dissociation was achieved in the presence of 1 m NaCl in 0. 1 m sodium acetate buffer at pH 5.7, incomplete dissociation occurred in 0.4 m NaCl in the same buffer in such a way that it could not be explained by simple application of the law of mass action. On the basis of their light-scattering data in acetate buffer containing 0.4 m NaCl, these authors indicated that the protein sample behaved like a mixture of thermodynamic species characterized by a multiplicity of dissociation constants. In this respect their conclusions were similar to those of Siezen and van Driel (1973, Biochim. Biophys. Acta, 295, 131–139) from their study of the influence of pH on association-dissociation processes at alkaline pH values. One simple model which actually fits the data of Engelborghs and Lontie reasonably well assumes the presence of some incompetent whole molecules, unable to dissociate into halves in 0.4 m NaCl: With a formation constant of 0.18 – 0.23 liters/g for whole molecules from half molecules, 30–35% of the material would be in the form of incompetent whole molecules. On the basis of this model, the major point of reinterpretation is that the sedimentation velocity diagram contains a fast Schlieren peak representing incompetent whole molecules and a slow peak representing a reaction mixture, rather than half molecules. This picture explains why the ratio of peak areas is independent of concentration, why material separated by ultracentrifugation appears not to reequilibrate when resubjected to ultracentrifugation, and why, on the other hand, mixing experiments have indicated rapid reequilibration of species.
Assessment of pulmonary/systemic blood flow ratio after first-stage palliation for hypoplastic left heart syndrome: Development of a new index with the use of Doppler echocardiography☆

Abstract Objective: Circulatory maldistribution is believed to be a major cause of early death after first-stage palliation for hypoplastic left heart syndrome. Flow reversal in the reconstructed aorta may reflect the pulmonary/systemic blood flow ratio. The purpose of our study was to investigate the utility of arterial PO 2 , arterial oxygen saturation, and a newly developed Doppler-derived flow index in predicting the pulmonary/systemic flow ratio after first-stage palliation for hypoplastic left heart syndrome. Methods: Twenty-four infants who underwent first-stage palliation for hypoplastic left heart syndrome or a variant were studied. Superior vena cava blood samples were drawn to estimate the mixed venous saturation and permit calculation of the pulmonary/systemic blood flow ratio. Fifty-four samples were evaluated within the first 24 hours after surgery. Simultaneous blood draw and Doppler echocardiography were performed with interrogation in the distal aspect of the arch reconstruction. The ratio of the Doppler velocity-time integral of retrograde flow to the velocity-time integral of forward flow was calculated and compared with the pulmonary/systemic blood flow ratio Results: The median mixed venous saturation for the 54 samples was low (38.5%; range, 18%-64%). The median calculated pulmonary/systemic blood flow ratio was 1.4:1 (range, 0.3:1 to 4.2:1). Pulse pressure, mixed venous saturation, and arterial PO 2 were not statistically significant predictors of the measured pulmonary/systemic blood flow ratio. Although both aortic oxygen saturation ( R 2 = 0.84, P R 2 = 0.94, P Conclusion: Measures of arterial oxygen saturation and arterial PO 2 may be misleading in assessing the circulatory status of infants after first-stage palliation for hypoplastic left heart syndrome. Doppler echocardiography, through use of the Doppler flow reversal ratio, provides a more useful measure of pulmonary/systemic blood flow ratio. Low mixed venous saturation after surgery may be due to factors other than pulmonary overcirculation, such as ventricular dysfunction and low cardiac output. (J Thorac Cardiovasc Surg 2000;120:81-7)
The effects of clomiphene citrate in patients with pituitary-gonadal disorders.

Abstract The following observations in 41 women and 15 men receiving clomiphene citrate illustrate its effects and imply a primary mechanism of action. Antiestrogenic effects. Vaginal cornification, cervical mucus arborization, and endometrial growth were inhibited. These effects were related to the dose and duration of therapy. Hot flushes occurred in 13 of 33 women with functioning ovaries. Amelioration of fibrocystic mastitis resulted in each of 5 patients treated. Estrogenic effects. In estrogen-deficient women, hot flushes and gonadotropin titers were decreased. Gonadotropin stimulating effects. In an estrogen-treated patient with Turner's syndrome, the suppressed gonadotropin secretion was increased.In all male patients with normal urinary gonadotropins,FSH andLH increased proportionately, in females, total gonadotropin excretion increased in 4 and decreased in 1 patient.The titer was increased in 1 of 2 patients with reduced excretion of gonadotropins, and decreased in the other. In 3 patients without urinary gonadotropins, no change was observed. Gonadal stimulating effects. A moderate to marked increase in sperm counts was observed in 10 out of 11 oligospermic males.In 25 anovulatory women, ovulation was induced in 35 of 77 cycles. Regular ovulation was induced in 7 patients in whom it was previously irregular.Urinary neutral 17-ketosteroids increased in 5 males with normal titers of gonadotropins. No definite increase was found in 3 gonadotropin-deficient males or in any of the female patients.These data are interpreted to indicate that clomiphene citrate, a weak estrogen, inhibits the effects of endogenous estrogen at the cellular level, which produces a reflex hypersecretion of gonadotropin and consequent gonadal stimulation.