cssi/SciSciGPT-SciSciNet huggingface dataset:
High-Fat Diet-Induced Dysregulation of Ovarian Gene Expression is Restored with Chronic Omega-3 Fatty Acid Supplementation

Abstract Chronic high-fat diet (HFD) consumption causes ovarian dysfunction in rodents. Acute dietary treatment with docosahexaenoic acid (DHA) increases oocyte quality and ovarian reserve at advanced reproductive age. We hypothesized that DHA supplementation after HFD exposure reverses HFD-induced ovarian defects. We conducted a dietary intervention with reversal to chow, DHA-supplemented chow, or DHA-supplemented HFD after HFD consumption. After 10 weeks, HFD-fed mice had impaired estrous cyclicity, decreased primordial follicles, and altered ovarian expression of 24 genes compared to chow controls. Diet reversal to either chow or chow + DHA restored estrous cyclicity, however only chow + DHA appeared to mitigated the impact of HFD on ovarian reserve. All dietary interventions restored HFD-dysregulated gene expression to chow levels. We found no association between follicular fluid DHA levels and ovarian reserve. In conclusion our data suggest some benefit of DHA supplementation after HFD, particularly in regards to ovarian gene expression, however complete restoration of ovarian function was not achieved.
Brown adipose tissue and cancer progression.

The purpose of our study was to determine the role of brown adipose tissue (BAT) in cancer progression. Our study was approved by our institutional review board and Health Insurance Portability and Accountability Act–compliant. Our study group comprised 132 cancer patients (116 f, 16 m; mean age 50 ± 16 years) who underwent F18-FDG PET/CT per standard clinical protocol, for staging or surveillance of cancer. We included patients who were BAT-positive on PET/CT and had clinical follow-up data available for at least 12 months or until tumor recurrence or tumor-related death, whichever occurred first. BAT volume by PET/CT was quantified by PET-CT Viewer shareware. Clinical information including tumor type, tumor recurrence, survival, and outside temperature at time of scan were recorded. Cox proportional hazard models were used to determine longitudinal associations between BAT volume and tumor recurrence/mortality. There were 55 tumor recurrences/tumor-related deaths over a median follow-up period of 71 (33; 110 interquartile range) months. Higher BAT volume was associated with an increased likelihood of tumor recurrence/tumor-associated mortality after adjustment for covariates (p = 0.03). BAT volume, assessed using routine PET/CT, is a predictor of tumor recurrence/mortality in patients with cancer, independent of other factors that can influence BAT activity, such as sex, age, BMI, or tumor type.
Study protocol to develop a patient-reported outcome measuring disability associated with unilateral vocal fold paralysis: a mixed-methods approach with the CoPE collaborative.

Introduction Patient-reported outcome (PRO) measures are increasingly developed with multisite, representative patient populations so that they can serve as a primary endpoint in clinical trials and longitudinal studies. Creating multisite infrastructure during PRO measure development can facilitate future comparative effectiveness trials. We describe our protocol to simultaneously develop a PRO measure and create a collaborative of tertiary care centres to address the needs of patients with unilateral vocal fold paralysis (UVFP). We describe the stakeholder engagement, information technology and regulatory foundations for PRO measure development and how the process enables plans for multisite trials comparing treatments for this largely iatrogenic condition. Methods and analysis The study has three phases: systematic review, measure development and measure validation. Systematic reviews and qualitative interviews (n=75) will inform the development of a conceptual framework. Qualitative interviews with patients with UVFP will characterise the lived experience of the condition. Candidate PRO measure items will be derived verbatim from patient interviews and refined using cognitive interviews and expert input. The PRO measure will be administered to a large, multisite cohort of adult patients with UVFP via the CoPE (vocal Cord Paralysis Experience) Collaborative. We will establish CoPE to facilitate measure development and to create preliminary infrastructure for future trials, including online data capture, stakeholder engagement, and the identification of barriers and facilitators to participation. Classical test theory psychometrics and grounded theory characterise our approach, and validation includes assessment of latent structure, reliability and validity. Ethics and dissemination Our study is approved by the University of Wisconsin Health Sciences Institutional Review Board. Findings from this project will be published in open-access journals and presented at international conferences. Subsequent use of the PRO measure will include comparative effectiveness trials of treatments for UVFP at CoPE Collaborative sites.
Who is the "Human" in Human-Centered Machine Learning: The Case of Predicting Mental Health from Social Media

"Human-centered machine learning" (HCML) combines human insights and domain expertise with data-driven predictions to answer societal questions. This area's inherent interdisciplinarity causes tensions in the obligations researchers have to the humans whose data they use. This paper studies how scientific papers represent human research subjects in HCML. Using mental health status prediction on social media as a case study, we conduct thematic discourse analysis on 55 papers to examine these representations. We identify five discourses that weave a complex narrative of who the human subject is in this research: Disorder/Patient, Social Media, Scientific, Data/Machine Learning, and Person. We show how these five discourses create paradoxical subject and object representations of the human, which may inadvertently risk dehumanization. We also discuss the tensions and impacts of interdisciplinary research; the risks of this work to scientific rigor, online communities, and mental health; and guidelines for stronger HCML research in this nascent area.
Strengthening the exclusion argument

As conceived by Kim, the causal exclusion argument targets all forms of nonreductive physicalism equally, but by restricting its focus to functionalist varieties of nonreductivism, I am able to develop a version of the argument that has a number of virtues lacking in the original. First, the revised argument has no need for Kim’s causal exclusion principle, which many find dubious if not simply false. Second, the revised argument can be adapted to either a production-based conception of causation, as Kim himself favors, or to any of a number of dependence-based conceptions, like the ones favored by many of Kim’s critics. And, finally, the revised argument does not have the objectionable consequence that all so-called higher-level properties are epiphenomenal, for it does not generalize in the way that Kim’s original version of the argument arguably does. Nor does it concede much to narrow the scope of the argument in the way proposed. Those who adopt nonreductive theories of mind do so, by and large, on the strength of functionalist arguments for the multiple realizability of mental states. If functionalism entails that mental properties are epiphenomenal, this thus deals a critical, if not quite fatal, blow to nonreductivism.
Self healing databases for predictive risk analytics in safety-critical systems

Abstract Assuring the quality, consistency and accuracy of safety data repositories is essential in safety-critical systems. In many systems, however, significant effort is required to identify, address, clean and repair data errors and inconsistencies, and to integrate safety data sets and repositories, particularly for risk analyses. Although some self healing and self repairing capabilities leveraging machine learning and predictive analyses have been employed to identify anomalies and monitor quality in structured safety-critical data sets, little attention has been focused on addressing shortcomings in heterogeneous—structured and unstructured—safety data sets, the focus of this work. The text mining and classification analysis employed in this research indicates that machine learning techniques can be employed to improve the accuracy and robustness of large-scale structured and unstructured database repositories, and to improve the effectiveness and efficiency of safety data repository maintenance. Hybrid machine learning approaches, leveraging machine learning, text mining and natural language processing, offer additional promise in future work.
Restoration of Regulatory T-Cell Function in Dry Eye Disease by Antagonizing Substance P/Neurokinin-1 Receptor.

Substance P (SP) is a tachykinin neuropeptide, implicated in the pathogenesis of various inflammatory conditions and a critical mediator in pain transmission. Recently, the role of SP was described in the pathogenesis of dry eye disease (DED) through its role in the maturation of antigen-presenting cells at the ocular surface after exposure to desiccating stress. However, the effect of SP on regulatory T cells (Tregs), which are functionally impaired in DED, remains unclear. This study examined the phenotypic and functional changes in Tregs in response to SP in DED. The in vitro cultures of normal Tregs in the presence of SP led to a significant reduction in both Treg frequencies and their suppressive function, which was prevented by the addition of an SP receptor (neurokinin-1 receptor) antagonist. Furthermore, in vivo treatment with the neurokinin-1 receptor antagonist in DED mice effectively restored Treg function, suppressed pathogenic T helper 17 response, and significantly ameliorated the disease. Our results show that a significant increase in SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and suppresses DED severity.
Prospective evaluation of the utility of magnetic resonance imaging in patients with non-MRI-conditional pacemakers and defibrillators.

Background Magnetic resonance imaging (MRI) in patients with legacy cardiovascular implantable electronic devices (CIEDs) in situ is likely underutilized. We hypothesized the clinical benefit of MRI would outweigh the risks in legacy CIED patients. Methods This is a single-center retrospective study that evaluated and classified the utility of MRI using a prospectively maintained database. The outcomes were classified as aiding in diagnosis, treatment, or both for the patients attributable to the MRI. We then assessed the incidence of adverse effects (AE) when the MRI was performed. Results In 668, MRIs performed on 479 patients, only 13 (1.9%) MRIs did not aid in the diagnosis or treatment of the patient. Power-on reset events without clinical sequelae in three scans (0.45%) were the only AE. The probability of an adverse event happening without any benefit from the MRI scan was 1.1 × 10-4 . A maximum benefit in diagnosis using MRI was obtained in ruling out space-occupying lesions (121/185 scans, 65.4%). Scans performed in patients for elucidating answers to queries in treatment were most frequently done for disease staging at long term follow-up (167/470 scans, 35.5%). Conservative treatment (184/470 scans, 39%) followed by medication changes (153/470 scans, 28.7%) were the most common treatment decisions made. Conclusions The utility of MRI in patients with non-MRI-conditional CIEDs far outweighs the risk of adverse events when imaging is done in the context of a multidisciplinary program that oversees patient safety.
Influence of Complications and Revision Surgery on Fulfillment of Expectations in Foot and Ankle Surgery.

Background:Fulfillment of patients’ expectations following foot and ankle surgery has been previously studied, and shown to be an effective modality in assessing patient-reported outcomes (PROs). A...
Key Technologies Research and Equipment Development of Smart Substation Automation System

Based on the requirements of smart substation proposed by State Grid Corporation, such as simple architecture, module integration, software visibility, human-computer friendliness, this paper designs smart substation automation system from systemic and global perspective. Initially, we study the development trend of the smart substation automation system. Then the essay proposes the system structure and soft-ware structure of the smart substation automation system. The following part introduces the key technologies of monitoring system, network information security system, error prevention system as well as the configuration technologies and the visual editing of software logic. After that we have verified the application prospect and economic benefits through engineering experiment. In the last, the paper has analyzed the next stage work plan.
Blood Glucose Level Prediction of Diabetic Type 1 Patients Using Nonlinear Autoregressive Neural Networks

Diabetes type 1 is a chronic disease which is increasing at an alarming rate throughout the world. Studies reveal that the complications associated with diabetes can be reduced by proper management of the disease by continuously monitoring and forecasting the blood glucose level of patients. Objective. The prior prediction of blood glucose level is necessary to overcome the lag time for insulin absorption in diabetic type 1 patients. Method. In this research, we use continuous glucose monitoring (CGM) data to predict future blood glucose level using the previous data points. We compare two neural network techniques. We apply the optimal feedforward neural network and then propose optimal nonlinear autoregressive neural networks for blood glucose prediction 15–30 minutes earlier for diabetic type 1 patients. We validate the proposed model with 2 virtual subjects using their 24-hour blood glucose level data. These two case studies have been compiled from AIDA, i.e., the freeware mathematical diabetes simulator. Results. In the prediction horizon (PH) of 15 and 30 minutes, improved results have been shown for minimal inputs for blood glucose level of a particular subject. Root mean square error (RMSE) is used for performance calculation. For the optimal feedforward neural network, the RMSE is 0.9984 and 3.78 ml/dl, and for the optimal nonlinear autoregressive neural network, it reduces the RMSE to 0.60 and 1.12 ml/dl for 15 min and 30 min prediction horizons, respectively, for subject 1. Similarly, for subject 2 for the optimal feedforward neural network, RMSE is 1.43 and 3.51 ml/dl which is improved using the optimal autoregressive neural network to 0.7911 and 1.6756 ml/dl for 15 min and 30 min prediction horizons, respectively. Validation. We further validate our proposed model using UCI machine learning datasets (Abalone and Servo), and it shows improved results on that as well. Conclusion and Future Work. The proposed optimal nonlinear autoregressive neural network model performs better than the feedforward neural network model for these time series data. In the future, we intend to investigate a greater collection of AIDA scenarios and data that are real and influence other factors of BGLs.
The impact of fertility preservation on the timing of breast cancer treatment, recurrence, and survival.

Background Many young women with breast cancer undergo fertility preservation (FP) before cancer treatment. This study examined the impact of FP on breast cancer outcomes. Methods The authors performed a retrospective cohort study of 272 women aged 20 to 45 years with newly diagnosed stage 0 to III breast cancer who underwent an FP consultation between 2005 and 2017. Among these women, 123 (45.2%) underwent FP (fertility preservation-positive [FP+]). The remaining 149 women did not undergo FP (fertility preservation-negative [FP-]). Results The characteristics at enrollment were similar with the exception of ethnicity (FP+, 87.8% White; FP-, 67.8% White; P = .002) and BRCA status (FP+, 27.7% BRCA+; FP-, 15.5% BRCA+; P = .021). The median follow-up was approximately 4 years. Women who underwent FP had longer times to first treatment (FP+, 37 days; FP-, 31 days; adjusted hazard ratio [aHR], 0.74; confidence interval [CI], 0.56-0.99) and neoadjuvant chemotherapy (FP+, 36 days; FP-, 26 days; aHR, 0.41; CI, 0.24-0.68) and from surgery to adjuvant chemotherapy (FP+, 41 days; FP-, 33 days; aHR, 0.58; CI, 0.38-0.90). Adjusted 3- and 5-year invasive disease-free survival (IDFS) rates were comparable between the 2 groups (3-year IDFS: FP+, 85.4%; FP-, 79.4%; P = .411; 5-year IDFS: FP+, 73.7%; FP-, 67.1%; P = .288). Similarly, no difference in overall survival (OS) was observed between the 2 groups (3-year OS: FP+, 95.5%; FP-, 93.5%; P = .854; 5-year OS: FP+, 84.2%; FP-, 81.4%; P = .700). Conclusions FP after a breast cancer diagnosis delays the time to treatment by a small amount, but this delay does not lead to inferior IDFS or OS.
Three-dimensional thermo-mechanical simulations of heterogeneous solid propellants

Abstract In this work, we present a numerical framework that describes thermo-mechanical deformations in a burning heterogeneous solid propellant. These deformations are quasi-static at time scales associated with combustion, and the resulting thermo-mechanical formulation is discretized on a Cartesian grid using a hypoelastic law. We use a weak form of Chorin-type projection method to deal with large difference in shear modulus of the constituent materials. Extending our previous two-dimensional work, grid convergence studies for a three-dimensional propellant configuration are presented for the stress, velocity, and reference map components. Finally, simulations are carried out for a random propellant pack that is coupled to a gas phase, and we present results for the pack undergoing combustion, with and without deformations.
Ceramide synthase 6 mediates sex-specific metabolic response to dietary folic acid in mice.

Abstract Objective Folic acid-fortified foods and multi-vitamin supplements containing folic acid (FA) are widely used around the world, but the exact mechanisms/metabolic effects of FA are not precisely identified. We have demonstrated that Ceramide Synthase 6 (CerS6) and C16:0-ceramide mediate response to folate stress in cultured cells. Here we investigated the dietary FA effects on mouse liver metabolome, with a specific focus on sphingolipids, CerS6 and C16:0-ceramide. Methods Wild-type and CerS6−/− mice were fed FA-deficient, control, or FA over-supplemented diets for 4 weeks. After dietary treatment, liver concentrations of ceramides, sphingomyelins and hexosylceramides were measured by LC-MS/MS and complemented by untargeted metabolomic characterization of mouse livers. Results Our study shows that alterations in dietary FA elicit multiple sphingolipid responses mediated by CerS6 in mouse livers. Folic acid-deficient diet elevated C14:0-, C18:0- and C20:0- but not C16:0-ceramide in WT male and female mice. Additionally, FA over-supplementation increased multiple sphingomyelin species, including total sphingomyelins, in both sexes. Of note, concentrations of C14:0- and C16:0-ceramides and hexosylceramides were significantly higher in female livers than in male. The latter were increased by FD diet, with no difference between sexes in total pools of these sphingolipid classes. Untargeted liver metabolomic analysis concurred with the targeted measurements and showed broad effects of dietary FA and CerS6 status on multiple lipid classes including sex-specific effects on phosphatidylethanolamines and diacylglycerols. Conclusions Our study demonstrates that both dietary FA and CerS6 status exhibit pleiotropic and sex-dependent effects on liver metabolism, including hepatic sphingolipids, diacylglycerols, long chain fatty acids, and phospholipids.
Venture Capital Time Bombs and New Ventures: Do Boards Limit the Damage?

Venture capital funds have a limited lifecycle, which requires venture capitalists (VCs) to liquidate investments and return capital by the end of the fund. VCs shift attention from growing to exit...
The Effects of a Self-Similar Avatar Voice in Educational Games

Avatar identification is one of the most promising research areas in games user research. Greater identification with one's avatar has been associated with improved outcomes in the domains of health, entertainment, and education. However, existing studies have focused almost exclusively on the visual appearance of avatars. Yet audio is known to influence immersion/presence, performance, and physiological responses. We perform one of the first studies to date on avatar self-similar audio. We conducted a 2 x 3 (similar/dissimilar x modulation upwards/downwards/none) study in a Java programming game. We find that voice similarity leads to a significant increase in performance, time spent, similarity identification, competence, relatedness, and immersion. Similarity identification acts as a significant mediator variable between voice similarity and all measured outcomes. Our study demonstrates the importance of avatar audio and has implications for avatar design more generally across digital applications.
Automated and Refined Application of Convolutional Neural Network Modeling to Metallic Powder Particle Satellite Detection

Research concerned with the identification as well as quantification of satellites found within metallic powders has recently demonstrated the promise of implementing Mask R-CNNs, instance segmentation, and transfer learning. Though the original research and development of such an approach demonstrated the functionality of the data-driven image analysis framework, questions remained in regards to the scale-ability of the Mask R-CNN-based model. Accordingly, the present work demonstrates the fact that the originally formulated model can be expanded to include scanning electron micrographs to various powder types at variate magnifications (rather than the original case of micrographs of a single powder type at a single magnification). Moreover, the present work establishes a process that enables users to specifically target which images will have most impact on increasing generalize-ability and performance in order to optimize maximum improvement of the model with the least amount of images annotated. Beyond this, we also outline a method of auto-labeling satellites in images by using a trained model to increase its own training set size.
Negotiation and the Global Information Economy

What role do diplomacy and negotiations play in economic globalization? Many argue that great powers shape diplomacy to their advantage, others that, in a 'flat world', diplomacy helps everyone. Going beyond these polarized views, this book explores the conditions under which negotiations matter and the ways in which diplomacy is evolving in the global commercial arena. J. P. Singh argues that where there is a diffusion or decentralization of power among global actors, diplomacy can be effective in allowing the adjustment of positions so that mutual gains will result. In contrast, when there is a concentration of power, outcomes tend to benefit the strong. There will be little alteration in perception of interest, and coercion by strong powers is common. Singh's book suggests that there are possibilities for transformational problem-solving through multilateral diplomacy. Empirically, the book examines the most important information-age trade issues.
Algal Flocculation with Synthetic Organic Polyelectrolytes

The feasibility of removing algae from water and wastewater by chemical flocculation techniques was investigated. Mixed cultures of algae were obtained from both continuous- and batch-fed laboratory reactors. Representative cationic, anionic, and nonionic synthetic organic polyelectrolytes were used as flocculants. Under the experimental conditions, chemically induced algal flocculation occurred with the addition of cationic polyelectrolyte, but not with anionic or nonionic polymers, although attachment of all polyelectrolyte species to the algal surface is shown. The mechanism of chemically induced algal flocculation is interpreted in terms of bridging phenomena between the discrete algal cells and the linearly extended polymer chains, forming a three-dimensional matrix that is capable of subsiding under quiescent conditions. The degree of flocculation is shown to be a direct function of the extent of polymer coverage of the active sites on the algal surface, although to induce flocculation by this method requires that the algal surface charge must concurrently be reduced to a level at which the extended polymers can bridge the minimal distance of separation imposed by electrostatic repulsion. The influence of pH, algal concentration, and algal growth phase on the requisite cationic flocculant dose is also reported.
Nemesis: preventing authentication & access control vulnerabilities in web applications

This paper presents Nemesis, a novel methodology for mitigating authentication bypass and access control vulnerabilities in existing web applications. Authentication attacks occur when a web application authenticates users unsafely, granting access to web clients that lack the appropriate credentials. Access control attacks occur when an access control check in the web application is incorrect or missing, allowing users unauthorized access to privileged resources such as databases and files. Such attacks are becoming increasingly common, and have occurred in many high-profile applications, such as IIS [10] and WordPress [31], as well as 14% of surveyed web sites [30]. Nevertheless, none of the currently available tools can fully mitigate these attacks. Nemesis automatically determines when an application safely and correctly authenticates users, by using Dynamic Information Flow Tracking (DIFT) techniques to track the flow of user credentials through the application's language runtime. Nemesis combines authentication information with programmer-supplied access control rules on files and database entries to automatically ensure that only properly authenticated users are granted access to any privileged resources or data. A study of seven popular web applications demonstrates that a prototype of Nemesis is effective at mitigating attacks, requires little programmer effort, and imposes minimal runtime overhead. Finally, we show that Nemesis can also improve the precision of existing security tools, such as DIFT analyses for SQL injection prevention, by providing runtime information about user authentication.
Applying the 3C Model to Groupware Development

This paper introduces an approach based on the 3C (communication, coordination and cooperation) collaboration model to the development of collaborative systems. The 3C model is studied by means of a detailed analysis of each of its three elements, followed by a case study of a learningware application and the methodology of a web-based course, both designed based on this model. Moreover, this paper describes a component-based system architecture following this 3C approach.
Synthesis of Iron(III)-Doped Titania Nanoparticles and its Application for Photodegradation of Sulforhodamine-B Pollutant

Iron(III)-doped titania nanoparticles were prepared by modified sol-gel method using titanium (IV) butoxide and inorganic precursor iron(III) nitrate nonahydrate. Spectroscopic measurements show the onset of the band-gap transition to be red-shifted (~λ = 475 nm) to the visible region with increasing iron(III) ion content. Characterizations were preformed by X-ray diffractometry, electron microscopy, energy dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy. Photocatalysis experiments were performed with dye pollutant sulforhodamine-B in aqueous environment. Direct photocatalytic effect was observed in the dye degradation experiments when irradiated with visible light into the band gap of the iron(III)-doped titania.
An electronmicroscopic study of the microgamete of Haemoproteus columbae Kruse.

SYNOPSIS. Microgametes of Haemoproteus columbae were studied by light microscopy and electron microscopy, using the single-stage replication technic. The filiform microgamete has a swelling or vesicle near the round end; the opposite end is asymmetrically tapered. The gamete is polarized, for it travels in sinuous movements with the round end (the putative anterior end) directed forward. There is no flagellum or undulating membrane and no mitochondrion. The vesicle may contain energy reserves for locomotion or lytic enzymes for penetration. Tubular material often is seen coming from the vesicle and anterior end and may be a kind of acrosomal filament.
Energy barriers for thermal reversal of interacting single domain particles

An analytic solution to the energy barriers of two interacting single domain particles is presented. Identical volumes and uniaxial anisotropies are assumed with easy axes parallel to an external magnetic field. The locations and heights of the system energy barriers are analytically determined when the line joining the two particles is either parallel or perpendicular to the easy axes and the external field. The lowest energy barriers are saddle points of the energy surface and correspond to reversal modes under thermal agitation. When dipole coupling is not strong, the mode of thermal switching is asymmetric fanning or asymmetric coherent rotation, depending upon the bond angle, rather than symmetric fanning or coherent rotation that occurs at the nucleation field. An effective volume that describes the cooperative effect is calculated and good agreement with the numerical results using the Fokker–Planck equation is obtained. The energy barriers can be used to calculate the superparamagnetic relaxation ...
Mathematical model of uptake and metabolism of arsenic(III) in human hepatocytes - Incorporation of cellular antioxidant response and threshold-dependent behavior.

Arsenic is an environmental pollutant, potent human toxicant, and oxidative stress agent with a multiplicity of health effects associated with both acute and chronic exposures. A semi-mechanistic cellular-level toxicokinetic (TK) model was developed in order to describe the uptake, biotransformation and clearance of arsenical species in human hepatocytes. Notable features of this model are the incorporation of arsenic-glutathione complex formation and a "switch-like" formulation to describe the antioxidant response of hepatocytes to arsenic exposure. The cellular-level TK model applies mass action kinetics in order to predict the concentrations of trivalent and pentavalent arsenicals in hepatocytes. The model simulates uptake of arsenite (iAsIII) via aquaporin isozymes 9 (AQP9s), glutathione (GSH) conjugation, methylation by arsenic methyltransferase (AS3MT), efflux through multidrug resistant proteins (MRPs) and the induced antioxidant response via thioredoxin reductase (TR) activity. The model was parameterized by optimization of model estimates for arsenite (iAsIII), monomethylated (MMA) and dimethylated (DMA) arsenicals concentrations with time-course experimental data in human hepatocytes for a time span of 48 hours, and dose-response data at 24 hours for a range of arsenite concentrations from 0.1 to 10 μM. Global sensitivity analysis of the model showed that at low doses the transport parameters had a dominant role, whereas at higher doses the biotransformation parameters were the most significant. A parametric comparison of the TK model with an analogous model developed for rat hepatocytes from the literature demonstrated that the biotransformation of arsenite (e.g. GSH conjugation) has a large role in explaining the variation in methylation between rats and humans. The cellular-level TK model captures the temporal modes of arsenical accumulation in human hepatocytes. It highlighted the key biological processes that influence arsenic metabolism by explicitly modelling the metabolic network of GSH-adducts formation. The parametric comparison with the TK model developed for rats suggests that the variability in GSH conjugation could have an important role in inter-species variability of arsenical methylation. The TK model can be incorporated into larger-scale physiologically based toxicokinetic (PBTK) models of arsenic for improving the estimates of PBTK model parameters.
Modified silica-containing matrices towards the MALDI-TOF-MS detection of small molecules

Abstract The new silica-based matrices were designed to demonstrate the concept of using silica to immobilize classic MALDI matrix materials for the analysis of small molecules (
A modified least squares algorithm for solving sparse n × n sets of nonlinear equations

Abstract In this paper we describe an algorithm for solving sparse n × n sets of nonlinear algebraic equations. This algorithm is like the Levenberg-Marquardt algorithm in that at each iteration the step size taken affects the direction selected to search; this direction lies between the Newton and gradient directions. Unlike the Levenberg-Marquardt schemes the sparsity of the original equations is preserved and thus spare matrix methods can be employed for solving the linearized system of equations.
Rare B Decays at Cdf

The confidence level limits of the CDF search for the B{sub s}{sup 0} and B{sub d}{sup 0} {yields} {mu}{sup +}{mu}{sup -} rare decays and the branching ratio measurement of B{sub s}{sup 0} {yields} D{sub s}{sup +} D{sub s}{sup -} are presented.
Type definitions with parameters

It has long been known that recursively defined types in a highly typed language such as Algol 68 or Pascal may be tested for structural equivalence by the same algorithm that compares finite automata [5,11]. Several authors (for example, [3,8,9,16]) have proposed that classes of types be simultaneously defined by the use of parameterized type definitions, such asType list(x) = record val:x; next:↑list(x) end .This paper shows that unless the use of such parameterized definitions is restricted, new (unparameterized) types may be defined which more closely resemble deterministic context-free languages. In fact, the equivalence problem for such types becomes as hard as the (currently unsolved) deterministic pushdown automaton equivalence problem. Several restrictions on type definitions are considered which allow known equivalence algorithms to be applied.
Matrix-assisted laser-desorption/ionization mass spectrometric approaches for the identification of gel-separated proteins in the 5-50 pmol range.

The ability to identify and characterize low picomole quantities of gel-separated proteins has greatly benefited from recent advancements in mass spectrometric analysis methods, particularly peptide-mass search routines. We are investigating the use of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)) to gain as much mass information as possible from a single gel-separated protein species. This report details results obtained from one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separations, under nonreducing conditions, of known quantities of three proteins, followed by blotting to Immobilon-CD. Three methods were used to obtain MALDI-MS data from a single blotted protein band: (i) direct MALDI-MS of ∼10% of the band, (ii) cyanogen bromide (CNBr) cleavage of another ∼10% of the band, and (iii) enzymatic (endoproteinase Lys-C) digestion of the remaining ∼70–80% of the band followed by MALDI-MS. At the level of 50 pmol of protein loaded onto the gel, data was obtained from all three approaches. At levels down to 5 pmol of protein loaded onto the gel, MALDI-MS data was obtained from the latter two methods, CNBr and Lys-C digestions, but not direct MALDI-MS. Sufficient peptide masses were obtained from the 5 pmol loads to identify two of the three test proteins using four mass search programs. Only limited peptide mass data was obtained from fetuin, a sialylated glycoprotein with six disulfides and no methionines, but it was identified.
Plant maturity and kenaf yield components

Abstract Kenaf (Hibiscus cannabinus L.), an alternative fiber crop for paper pulp production, is normally grown during the entire summer growing season (150 days and longer) to maximize fiber production. However, it may be advantageous to harvest the kenaf crop earlier than 150 days after planting (DAP) depending on the harvesting conditions (e.g. soil moisture or equipment availability) or marketing opportunities (price fluctuations or alternative uses). In addition to affecting the final stalk yield, harvesting kenaf at an earlier maturity may significantly alter the composition of the kenaf plant. The objective of this field study was to determine the effect of kenaf plant maturity on kenaf yield components. Kenaf cultivar ‘Everglades 41’ was planted at Lane, Oklahoma, USA, in the spring of 1996, 1997, and 1998 on 76 cm row spacing at 250 000 plants per hecatre. Kenaf plots were harvested at four harvest dates, 60, 90, 120, and 150 DAP. At each harvest date, plants from a 3 m length of row were cut at ground level and used to determine plant population, plant height, stalk, leaf and whole plant yields, stalk and leaf percentage by weight, and the rate of plant growth during the selected growing season. The experiment was a randomized complete block design with five replications. Harvest age (60, 90, 120, and 150 DAP) did not significantly affect plant populations, but significantly affected all other yield parameters. Kenaf plant height, stalk yield, stalk percentage, and total plant biomass yields were consistently significantly greater at 150 DAP than at 60, 90, and 120 DAP for the 3 year study. Although the growth rates per day did level off or even decreased after 120 DAP, the significant increases in stalk yields after 120 DAP justify the additional 30 day growth. This research provides information that can be applied to both kenaf fiber and forage production, especially in gaining a greater understanding of the relative response of the kenaf yield components and partitioning of dry matter during the growing season. The research procedures can also be used for evaluating kenaf cultivars that may be more suitable for forage production, by identifying cultivars that have greater leaf biomass yields and leaf percentages earlier in the season and increasing values throughout the growing season.
the usefulness of whole-exome sequencing in routine clinical practice

Reports of the use of whole-exome sequencing in clinical practice are limited. We report our experience with whole-exome sequencing in 115 patients in a single center and evaluate its feasibility and clinical usefulness in clinical care. Whole-exome sequencing was utilized based on the judgment of three clinical geneticists. We describe age, gender, ethnicity, consanguinity, indication for testing, family history, insurance, laboratory results, clinician interpretation of results, and impact on patient care. Most patients were children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in eight, altered management in fourteen, novel therapy in two, identification of other familial mutation carriers in five, and reproductive planning in six. Our results show that whole-exome sequencing is feasible, has clinical usefulness, and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing. Our results also suggest phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods. Genet Med 16 12, 922–931.
Times of Metamorphism in the Franciscan Terrain of the Northern Coast Ranges, California

Field relationships, K/Ar dates, and metamorphosed fossils define two periods of high-pressure, low-temperature metamorphism in the Leech Lake Mountain-Black Butte region of the northern California Coast Ranges. For the older metamorphism, coarse white mica from glaucophane-lawsonite metabasalts, interbedded with jadeite+quartz metagraywacke, yields K/Ar dates of 150 m.y. These dates are older than the time of deposition of Tithonian through Valanginian (approximately 145 to 130 m.y.) Buchia fossils found at a number of localities in this region. These fossiliferous rocks have been metamorphosed to the lawsonite-albite-chlorite-aragonite metagraywacke facies and yield K/Ar whole-rock dates that spread from 127 to 104 m.y. The age of the younger metamorphism is thus fixed by the fossils and K/Ar dates to within a short period of time in the Lower Cretaceous. In addition, there are still-younger periods of sedimentation, metamorphism, and deformation in the Franciscan terrain.
Human progesterone receptor complexed with the antagonist RU 486 binds to hormone response elements in a structurally altered form.

Structural and functional properties of human progesterone receptors (PR) bound with the antiprogestin, RU 486, and the progestin agonist, R5020, were compared in order to identify receptor mechanisms responsible for the inability of RU 486 to activate the transcriptional capacity of receptors. RU 486 interaction with human PR did not inhibit receptor transformation as assessed by dissociation of nontransformed 8-10S oligomeric receptors (in vitro and in vivo) and by tight binding of PR to nuclei]/chromatin in whole cells. Assays based on immunoprecipitation of PR-DNA complexes with an antibody to human PR and gel retardation were used to analyze the effect of RU 486 on receptor binding to the hormone response element (HRE) of the mouse mammary tumor virus (MMTV). RU 486 did not impair PR recognition of the MMTV HRE. Quantitative affinity constants and kinetic parameters of PR binding to these specific DNA sites were similar for receptors complexed with either agonist or antagonist. However, PR-RU 486 com...
A stepwise approach to transanal endoscopic microsurgery for rectal cancer using a single-incision laparoscopic port.

Background Radical rectal resection with total mesorectal excision is the current standard of care for the operative treatment of rectal cancer. Local excision is an acceptable alternative in selected patients with early disease (Tis0−T1) and low-risk features, in whom radical resection may be associated with unacceptably high morbidity. With recent data demonstrating favorable results in well-selected patients, the role of local excision for rectal cancer is expanding.1,2 Transanal endoscopic microsurgery (TEM), which requires the use of an operating anoscope, has been used for the local excision of mid-upper rectal tumors. We describe an alternative approach to TEM for rectal cancer.
Proteasome inhibition for antibody-mediated allograft rejection.

Antibody-mediated rejection (AMR) is a major risk factor for graft loss following kidney transplantation. Traditional anti-humoral therapies provide suboptimal therapy and they do not deplete plasma cells, which are the source of antibody production. Proteasome inhibitors (PI) have been shown to deplete both transformed and nontransformed plasma cells in human transplant recipients and animal models; and therefore, offer a new paradigm for AMR, ie, plasma cell–targeted therapy. Bortezomib, a first in class proteasome inhibitor approved by the US Food and Drug Administration for treatment of multiple myeloma, has been used to treat AMR in several solid organ transplant recipients. The greatest experience with PI therapy for treating AMR is in kidney transplant recipients. Experiences to date with PI therapy have demonstrated that: (1) early AMR (within the first 6 months post-transplant) responds better than late AMR, and (2) the nature of the plasma cell clonal population influences sensitivity to PI therapy with plasma subsets greater than long-lived bone marrow niche-resident plasma cells. In conclusion, plasma cell–targeted therapy with PIs is a method for targeting plasma cells (the source of antibody production) with a well-elucidated mechanism of action and subsequent points of synergy, thereby providing an exciting new potential means for enhancing anti-humoral therapies.
FDA's perspectives on cardiovascular devices.

The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, §903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA’s review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.
The modulating influence of cyclic nucleotides upon lymphocyte-mediated cytotoxicity.

The capacity of allosensitized thymus-derived lymphocytes to destroy target cells bearing donor alloantigens is modulated by the cellular levels of cyclic AMP and cyclic GMP. Increases in the cyclic AMP levels of attacking lymphocytes by stimulation with prostaglandin E1, isoproterenol, and cholera toxin inhibit lymphocyte-mediated cytotoxicity; whereas, depletion of cyclic AMP with imidazole enhances cytotoxicity. The augmentation of cytotoxicity produced by cholinergic stimulation with carbamylcholine is not associated with alterations in cyclic AMP levels and is duplicated by 8-bromo-cyclic GMP. The effects of activators of adenylate cyclase, cholinomimetic agents, and 8-bromocyclic GMP are upon the attacking and not the target cells and occur at the time of initial interaction of attacking and target cells. Indeed, the level of cyclic nucleotide (cyclic AMP and cyclic GMP) at the time of initial cell-to-cell interaction determines the extent of cytotoxicity.
Remote sensing of tropospheric chemistry using lidars from geostationary orbit

Tropospheric chemistry is considered to be the next frontier of atmospheric chemistry, and understanding and predicting the global influence of natural and human-induced effects on tropospheric chemistry will be the next challenge for atmospheric research over the foreseeable future. A geostationary Earth orbit (GEO) vantage point provides an ideal location for measuring spatially and temporally resolved distributions of trace gas species. One powerful technique for making this measurement is LIght Detection And Ranging (lidar) using solid-state lasers. Presently, NASA has a notional plan for using lidars for tropospheric chemistry measurements, but from low Earth orbit (LEO). While permitting high spatially resolved measurements, LEO measurements, however, lack the temporal resolution required to monitor important atmospheric processes and transport. A GEO instrument will require a more energetic and efficient lidar system in order to permit accurate measurements. In this study, we investigated the capability of a lidar for tropospheric profiling of chemical species and we develop a roadmap for the requisite technologies.
Optical characterization of silica aerogel

Two optical methods are described for mapping the local variations of refractive index within monoliths of porous silica aerogel. One is an interferometrie measurement that produces “iso-index” fringes in a two dimensional image; an orthogonal view gives the third dimension information. The other method uses the deflection of a He-Ne laser beam to map the gradient index within a sample. The quantification of the measurements is described and the accuracy of the results is discussed.