Miracle-dz/UniFAR-FTUs huggingface dataset:
Prospects for safety testing: A strategy for the application of transgenic rodent mutagenesis assays

The past several years have seen an enormous increase in the development and use of transgenic animal models to measure mutations in specific inserted reporter genes. These systems provide gene mutation data in vivo in a wide range of relevant tissues. Numerous laboratories are now using these systems with consistent results. This paper describes the unique niche that transgenic mutagenesis systems can fill in product development and registration strategies. In addition to tissue‐specific mechanistic studies, transgenic assays are available to follow up mutagenic effects demonstrated in Salmonella, Escherichia coli, mouse lymphoma (L5178Y) cells, or other in vitro systems. © 1996 Wiley‐Liss, Inc.
Application of models for multivariate mixed outcomes to medical device trials: coronary artery stenting

The approval process for some medical devices involves a single‐arm trial in which the outcomes associated with the new device are compared to the expected outcomes associated with approved devices, the latter denoted the objective performance criterion (OPC). In this paper, models for multivariate mixed outcomes are applied to derive the OPC for a medical device to be used in clinical evaluations of the same type of device. We illustrate the techniques by determining the OPC for coronary artery stents, metal cages used to widen blocked coronary arteries in patients with coronary artery disease, using data from seven randomized trials of stents approved for use in the U.S.A. involving 5806 patients. The OPC is based on two 9‐month endpoints: target lesion revascularization, a binary outcome, and proportion diameter stenosis, a continuous outcome. To account for the correlation between mixed outcomes we consider factorization of the likelihood into marginal and conditional components, or adoption of a latent variable model. Because the models have different structural forms, standard methods for model comparison (such as the AIC and BIC) cannot be used. We discuss how model identifiability and valid inference are achieved, and then adapt the deviance information criterion (DIC) and the pseudo‐Bayes factor (PSBF) to select the best model. Nine months post‐stenting, we find that the average posterior probability (standard deviation) of target lesion revascularization ranges from 0.086 (0.008) for non‐diabetics with one diseased vessel to 0.163 (0.022) for diabetics with three diseased vessels. When considering proportion diameter stenosis, the corresponding posterior means are 0.375 (0.020) and 0.427 (0.030). The correlation coefficient of the components of the OPC lies in the range 0.042 to 0.116. Copyright © 2003 John Wiley & Sons, Ltd.
Physical Factors Affecting Outflow Facility Measurements in Mice.

PURPOSE Mice are commonly used to study conventional outflow physiology. This study examined how physical factors (hydration, temperature, and anterior chamber [AC] deepening) influence ocular perfusion measurements in mice. METHODS Outflow facility (C) and pressure-independent outflow (Fu) were assessed by multilevel constant pressure perfusion of enucleated eyes from C57BL/6 mice. To examine the effect of hydration, seven eyes were perfused at room temperature, either immersed to the limbus in saline and covered with wet tissue paper or exposed to room air. Temperature effects were examined in 12 eyes immersed in saline at 20 °C or 35 °C. Anterior chamber deepening was examined in 10 eyes with the cannula tip placed in the anterior versus posterior chamber (PC). Posterior bowing of the iris (AC deepening) was visualized by three-dimensional histology in perfusion-fixed C57BL/6 eyes and by spectral-domain optical coherence tomography in living CD1 mice. RESULTS Exposure to room air did not significantly affect C, but led to a nonzero Fu that was significantly reduced upon immersion in saline. Increasing temperature from 20 °C to 35 °C increased C by 2.5-fold, more than could be explained by viscosity changes alone (1.4-fold). Perfusion via the AC, but not the PC, led to posterior iris bowing and increased outflow. CONCLUSIONS Insufficient hydration contributes to the appearance of pressure-independent outflow in enucleated mouse eyes. Despite the large lens, AC deepening may artifactually increase outflow in mice. Temperature-dependent metabolic processes appear to influence conventional outflow regulation. Physical factors should be carefully controlled in any outflow studies involving mice.
The Relative Functionality of Freshly Isolated and Cryopreserved Human Adipose-Derived Stromal/Stem Cells

The capability of multipotent mesenchymal stem cells to maintain cell viability, phenotype and differentiation ability upon thawing is critical if they are to be banked and used for future therapeutic purposes. In the present study, we examined the effect of 9-10 months of cryostorage on the morphology, immunophenotype, colony-forming unit (CFU) and differentiation capacity of fresh and cryopreserved human adipose-derived stromal/stem cells (ASCs) from the same donors. Cryopreservation did not reduce the CFU frequency and the expression levels of CD29, CD73, CD90 and CD105 remained unchanged with the exception of CD34 and CD45; however, the differentiation capacity of cryopreserved ASCs relative to fresh cells was significantly reduced. While our findings suggest that future studies are warranted to improve cryopreservation methods and agents, cryopreserved ASCs retain sufficient features to ensure their practical utility for both research and clinical applications.
Multiple enzymatic pathways involved in the metabolism of glyceryl trinitrate in Phanerochaete chrysosporium

A study of glyceryl trinitrate metabolism by a filamentous fungus, Phanerochaete chrysosporium, carried out with the 14C‐labeled substrate, provides evidence for a multienzymatic system leading to di‐ and mononitrate derivatives. At least two independent enzymatic activities were detected in the cytosolic fraction: an aerobic glutathione S‐transferase activity and an anaerobic NADPH‐dependent soluble cytochrome P450‐like activity. Other hemoproteins with enzymatic activities dependent upon the presence of NADPH or ferrous ions were also detected in the microsomal fraction. Electron paramagnetic resonance spectra characteristic of an interaction between a hemoprotein and nitric oxide appeared in these two subcellular fractions during the anaerobic metabolism of glyceryl trinitrate.
Lack of Evidence of Mitochondrial Dysfunction in the Offspring of HIV‐Infected Women: Retrospective Review of Perinatal Exposure to Antiretroviral Drugs in the Perinatal AIDS Collaborative Transmission Study

Abstract: A recent report suggesting mitochondrial dysfunction among eight HIV‐exposed but uninfected children exposed perinatally to nucleoside reverse transcriptase inhibitors (NRTIs) prompted a review within the Perinatal AIDS Collaborative Transmission Study (PACTS). A standardized retrospective review was conducted of 118 deaths at <5 years. Deaths were classified as unrelated to mitochondrial dysfunction (Class 1), unlikely related (Class 2), possibly related (Class 3), or likely related or proven (Class 4). Among 35 deaths recorded in HIV‐uninfected or indeterminate children, none were classified in either Class 2, 3, or 4. We also reviewed signs or symptoms consistent with possible mitochondrial dysfunction among 1,954 living uninfected children. Only one child was in Class 3 and two siblings were in Class 2; none had perinatal antiretroviral drug exposure. We found no evidence indicating that uninfected infants exposed to perinatal NRTIs died of mitochondrial disorders or that living exposed children had symptoms of mitochondrial dysfunction.
Rabbit Epididymal Secretory Proteins. III. Molecular Cloning and Characterization of the Complementary DNA for REP381

Abstract REP38 is a rabbit epididymal secretory protein of 38 kDa that has recently been shown to interact with spermatozoa. A rabbit epididymal cDNA expression library was screened with a polyclonal antibody raised against REP38. A single clone (REP38-c1) with an open reading frame encoding a polypeptide of 666 amino acids was obtained. Cleavage of a 22-amino acid N-terminal signal peptide revealed a mature protein with a theoretical molecular mass of 74.5 kDa. Northern blot analysis revealed the presence of two cross-hybridizing transcripts of approximately 1.3 and 2.5 kilobases that appear to result from alternative mRNA splicing. This finding may explain the discrepancies between the observed (38 kDa) and deduced molecular mass of REP38. Expression of both transcripts was epididymis specific and was detected only in regions 2–6. During development, the expression of REP38-c1 mRNA was initiated between 1 and 2 mo postnatum and therefore precedes the appearance of sperm within the lumen of the epididymis. These findings are in agreement with the immunohistochemical localization of the REP38 protein. Androgen deprivation induced by orchidectomy reduced REP38-c1 mRNA levels below the limit of detection, an effect that was reversed by administration of exogenous testosterone. Although REP38-c1 mRNA was detected only in the rabbit epididymis, database searches indicated homology with two rat testis specific cDNAs, KTT4 and odf2, which encode sperm outer dense fiber proteins.
Data-driven natural language generation using statistical machine translation and discriminative learning. (L'approche discriminante à la génération de la parole)

The humanity has long been passionate about creating intellectual machines that can freely communicate with us in our language. Most modern systems communicating directly with the user share one common feature: they have a dialog system (DS) at their base. As of today almost all DS components embraced statistical methods and widely use them as their core models. Until recently Natural Language Generation (NLG) component of a dialog system used primarily hand-coded generation templates, which represented model phrases in a natural language mapped to a particular semantic content. Today data-driven models are making their way into the NLG domain. In this thesis, we follow along this new line of research and present several novel data-driven approaches to natural language generation. In our work we focus on two important aspects of NLG systems development: building an efficient generator and diversifying its output. Two key ideas that we defend here are the following: first, the task of NLG can be regarded as the translation between a natural language and a formal meaning representation, and therefore, can be performed using statistical machine translation techniques, and second, corpus extension and diversification which traditionally involved manual paraphrasing and rule crafting can be performed automatically using well-known and widely used synonym and paraphrase extraction methods. Concerning our first idea, we investigate the possibility of using NGRAM translation framework and explore the potential of discriminative learning, notably Conditional Random Fields (CRF) models, as applied to NLG; we build a generation pipeline which allows for inclusion and combination of different generation models (NGRAM and CRF) and which uses an efficient decoding framework (finite-state transducers' best path search). Regarding the second objective, namely corpus extension, we propose to enlarge the system's vocabulary and the set of available syntactic structures via integrating automatically obtained synonyms and paraphrases into the training corpus. To our knowledge, there have been no attempts to increase the size of the system vocabulary by incorporating synonyms. To date most studies on corpus extension focused on paraphrasing and resorted to crowd-sourcing in order to obtain paraphrases, which then required additional manual validation often performed by system developers. We prove that automatic corpus extension by means of paraphrase extraction and validation is just as effective as crowd-sourcing, being at the same time less costly in terms of development time and resources. During intermediate experiments our generation models showed a significantly better performance than the phrase-based baseline model and appeared to be more robust in handling unknown combinations of concepts than the current in-house rule-based generator. The final human evaluation confirmed that our data-driven NLG models is a viable alternative to rule-based generators.
TAKING SKEPTICISM SERIOUSLY : HOW THE ZHUANGZI CAN

This paper explores a few of the ways that the Zhuang-Zi can inform contemporary analytic epistemology. I begin, in section 1, by briefly outlining and summarizing the case for my fictionalist interpretation of the text. In section 2, I discuss how the Zhuang-Zi can be brought into productive dialogue with the question of how we should respond to skeptical arguments. Specifically, I argue that the Zhuang-Zi can be reasonably interpreted as exemplifying an approach that is different from dominant contemporary responses to skeptical arguments in three ways: (i) it is fictionalist; (ii) it motivates a skeptical perspective rather than a claim; and (iii) it accomplishes its aims in an atypical, but nonetheless contextually appropriate, way. However, the Zhuang-Zi is relevant to contemporary debates about skeptical arguments because it can be used: (i) to respond to the same sorts of skeptical arguments that occupy contemporary commentators; (ii) to address a number of questions that arise in connection with such arguments; and (iii) to suggest important new questions for epistemologists to pursue.
Processing content or location: Distinct brain activation in a memory task

Objects are defined by their content (“what”) and by their location (“where”). In the visual system, processing of these two types of information is segregated into distinct anatomical and functional pathways. Using H215O positron emission tomography to measure cerebral blood flow, we examined the differences in processing of “what” when compared with “where” information in human memory. We found that the detection of deviations from a previously learned image sequence activates distinct brain regions depending on whether the image's content or its location has changed. When deviations of an image's content had to be detected, the left medial temporal lobe (MTL) activation increased. In contrast, detection of deviations from the learned locations of the objects induced increased activation in the right MTL and in the right parietal cortex. These data demonstrate distinct contributions of the left and right MTL to the processing of “what” vs. “where” in memory. © 2005 Wiley‐Liss, Inc.
Learning Testing a Conception of How School Leadership Influences Student

Purpose: This article describes and reports the results of testing a new conception of how leadership influences student learning (“The Four Paths”). Framework: Leadership influence is conceptualized as flowing along four paths (Rational, Emotions, Organizational, and Family) toward student learning. Each path is populated by multiple variables with more or less powerful effects on student learning. Leaders increase student learning by improving the condition or status of selected variables on the Paths. Research Methods: Evidence includes teacher responses to an online survey (1,445 responses) measuring distributed leadership practices in their schools (N = 199) and variables mediating leaders’ effects on students. Grade 3 and 6 math and literacy achievement data were provided by the province’s annual testing program. The 2006 Canadian Census data provided a composite measure of school socioeconomic status. Path modeling techniques were used to test six hypotheses. Results: The Four Paths model as a whole explains 43% of the variation in student achievement. Variables on the Rational, Emotions, and Family Paths explain similarly significant amounts of that variation. Variables on the Organizational Path were unrelated to student achievement. Leadership had its greatest influence on the Organizational Path and least influence Article at Ebsco Electronic Journals Service (EJS) on June 20, 2012 eaq.sagepub. com Downloaded from 672 Educational Administration Quarterly 46(5) on the Family Path. Implications: School leaders and leadership researchers should be guided much more directly by existing evidence about school, classroom, and family variables with powerful effects on student learning as they make their school improvement and research design decisions.
Obstetric Implications of Antiphospholipid Antibodies: Pregnancy Loss and Other Complications

A relation between antiphospholipid antibodies (aPL) and pregnancy loss has been formally recognized for nearly 20 years. It is now well accepted that aPL are a treatable “cause” of fetal loss and probably of recurrent preembryonic and embryonic loss. The growing interest in aPL and reproductive failure has encouraged investigation, prompted international symposia, and involved numerous medical specialists; however, this exciting field has also spawned plenty of controversy. This review describes the evolution of our understanding of aPL and pregnancy loss and critically examines the important questions in the field. A possible association between aPL and pregnancy loss was first suggested in case reports by Nilsson et al1 in 1975 and by Soulier and Boffa2 in 1980. Subsequent case series by Lubbe et al,3 Lockshin et al,4 and Branch et al5 confirmed this association. By the mid-1980s, the clinical criteria for the newly named antiphospholipid syndrome (APS) were established, and pregnancy loss was included as one of the clinical features of the disorder. In Harris’ 1987 proposal6 entitled The Syndrome of the Black Swan, Harris identified the APS pregnancy loss criterion as “fetal loss. ” Since that time, definitions and criteria have been expanded, with the 1999 clinical and laboratory criteria proposed at the International Antiphospholipid Symposium in Sapporo, Japan, identifying current consensus. The criteria include three types of pregnancy loss as clinical criteria for APS: 1) one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal morphology documented by ultrasound or direct examination of the fetus; 2) one or more premature births at or before the 34th gestational week as a consequence of severe preeclampsia or placental insufficiency; or 3) Correspondence: D. Ware Branch, MD, Room 2B200 Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132. CLINICAL OBSTETRICS AND GYNECOLOGY Volume 44, Number 1, pp 2–10 © 2001, Lippincott Williams & Wilkins, Inc.
Enhanced Uranium Immobilization and Reduction by Geobacter sulfurreducens Biofilms

ABSTRACT Biofilms formed by dissimilatory metal reducers are of interest to develop permeable biobarriers for the immobilization of soluble contaminants such as uranium. Here we show that biofilms of the model uranium-reducing bacterium Geobacter sulfurreducens immobilized substantially more U(VI) than planktonic cells and did so for longer periods of time, reductively precipitating it to a mononuclear U(IV) phase involving carbon ligands. The biofilms also tolerated high and otherwise toxic concentrations (up to 5 mM) of uranium, consistent with a respiratory strategy that also protected the cells from uranium toxicity. The enhanced ability of the biofilms to immobilize uranium correlated only partially with the biofilm biomass and thickness and depended greatly on the area of the biofilm exposed to the soluble contaminant. In contrast, uranium reduction depended on the expression of Geobacter conductive pili and, to a lesser extent, on the presence of the c cytochrome OmcZ in the biofilm matrix. The results support a model in which the electroactive biofilm matrix immobilizes and reduces the uranium in the top stratum. This mechanism prevents the permeation and mineralization of uranium in the cell envelope, thereby preserving essential cellular functions and enhancing the catalytic capacity of Geobacter cells to reduce uranium. Hence, the biofilms provide cells with a physically and chemically protected environment for the sustained immobilization and reduction of uranium that is of interest for the development of improved strategies for the in situ bioremediation of environments impacted by uranium contamination.
Milk fever in dairy cows. VII. Effect of continuous vitamin D feeding on incidence of milk fever.

Feeding of 20 to 30 million units of vitamin D for 3 to 8 days prepartum previously prevented about 80% of expected milk fever cases in mature Jersey cows with histories of milk fever. In this experiment vitamin D was fed continuously through the year via 32,000 units of vitamin D added to each . 455 kg of concentrate fed (approximately 100,000 to 580,000 units/day). Milk fever incidence was measured after 5 yr of age (third calf) at 43 parturitions in mature Jersey cows with histories of milk fever and at 139 parturitions in mature Jersey cows with no previous milk fever. Continuous feeding of vitamin D reduced incidence of milk fever in cows with previous milk fever from 60% in the controls to 26.1% in the group fed vitamin D. In the cows with no milk fever previously, feeding vitamin D did not reduce incidence of milk fever (controls 23.7%, vitamin-D-fed 28.3%).
Proteomic Analysis of in Vivo Phosphorylated Synaptic Proteins*

In the nervous system, protein phosphorylation is an essential feature of synaptic function. Although protein phosphorylation is known to be important for many synaptic processes and in disease, little is known about global phosphorylation of synaptic proteins. Heterogeneity and low abundance make protein phosphorylation analysis difficult, particularly for mammalian tissue samples. Using a new approach, combining both protein and peptide immobilized metal affinity chromatography and mass spectrometry data acquisition strategies, we have produced the first large scale map of the mouse synapse phosphoproteome. We report over 650 phosphorylation events corresponding to 331 sites (289 have been unambiguously assigned), 92% of which are novel. These represent 79 proteins, half of which are novel phosphoproteins, and include several highly phosphorylated proteins such as MAP1B (33 sites) and Bassoon (30 sites). An additional 149 candidate phosphoproteins were identified by profiling the composition of the protein immobilized metal affinity chromatography enrichment. All major synaptic protein classes were observed, including components of important pre- and postsynaptic complexes as well as low abundance signaling proteins. Bioinformatic and in vitro phosphorylation assays of peptide arrays suggest that a small number of kinases phosphorylate many proteins and that each substrate is phosphorylated by many kinases. These data substantially increase existing knowledge of synapse protein phosphorylation and support a model where the synapse phosphoproteome is functionally organized into a highly interconnected signaling network.
Next generation vaccines and vectors: Designing downstream processes for recombinant protein‐based virus‐like particles

In recent years, the development of novel recombinant virus‐like particles (VLPs) has been generating new perspectives for the prevention of untreated and arising infectious diseases. However, cost‐reduction and acceleration of manufacturing processes for VLP‐based vaccines or vectors are key challenges for the global health system. In particular, the design of rapid and cost‐efficient purification processes is a critical bottleneck. In this review, we describe and evaluate new concepts, development strategies and unit operations for the downstream processing of VLPs. A special focus is placed on purity requirements and current trends, as well as chances and limitations of novel technologies. The discussed methods and case studies demonstrate the advances and remaining challenges in both rational process development and purification tools for large biomolecules. The potential of a new era of VLP‐based products is highlighted by the progress of various VLPs in clinical phases.