Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of Tumor-Free Distance and Depth of Myometrial Invasion as Prognostic Factors for Lymph Node Metastases in Endometrial Cancer

Introduction: Concurrent uterine lesions or an irregular endomyometrial junction can make accurate assessment of depth of myometrial invasion (DOI) and percentage of myometrial invasion (%MI) difficult, leading to patients being staged and or treated suboptimally. An alternative measurement, known as the tumor-free distance (TFD), which measures the distance between maximal myometrial invasion and the uterine serosa, has been proposed. Previous studies comparing the predictive abilities of DOI and TFD were underpowered and inconclusive. Our objective was to compare TFD, DOI, and %MI as predictors for lymph node involvement in surgically staged endometrial cancer patients. Methods: Patients with endometrioid adenocarcinoma of the endometrium treated between January 1997 and December 2007 were included. Tumor-free distance, DOI, and %MI were evaluated along with other pathological variables to determine their predictive ability for nodal involvement. Depth of myometrial invasion was measured between the endomyometrial junction and the maximal myometrial invasion. Tumor-free distance was calculated by subtracting the DOI from myometrial thickness (MT). Percentage MI was derived by dividing DOI by MT and expressed as a percentage of MT invaded. These 3 variables were transformed to z scores, and their ability to predict nodal involvement was compared. Results: A total of 338 patients were eligible for analysis. Mean (SD) MT was 18.7 (5.9) mm. Median DOI was 6 mm, and median TFD was 10.3 mm. On univariate analysis, all 3 variables showed significant associations with nodal involvement. On multivariate analysis, after adjusting for lymphovascular space invasion, cervical involvement, serosal/adnexal involvement, grade, %MI, and TFD, DOI retained its statistical significance along with lymphovascular space invasion and cervical involvement. Conclusions: Depth of myometrial invasion predicts nodal involvement independently when compared with TFD.
Plasma 24S‐hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer's disease

The conversion of brain cholesterol into 24S-hydroxycholesterol and its subsequent release into the periphery is probably an important step for the maintenance of brain cholesterol homeostasis. Recent findings suggest that plasma 24S-hydro-xycholesterol may be elevated in Alzheimer's disease (AD) and vascular dementia at least at some stage of the disease, suggesting increased brain cholesterol turnover during neuro-degeneration. We investigated whether plasma 24S-hydroxy-cholesterol concentrations depend on the severity of AD and on the apolipoprotein E (apoE) genotype. Severity of AD and inheritance of the apoE4 allele were independently associated with reduced plasma 24S-hydroxycholesterol/cholesterol ratios. The results suggest that the decrease of plasma 24S-hydroxycholesterol/cholesterol in severely affected AD patients is a peripheral marker for loss of cholesterol 24S-hydroxylase in the CNS. Inheritance of the apoE4 allele may be associated with increased apoE-mediated transport of brain cholesterol to the periphery or with decreased activity of the 24S-hydroxylase. Longitudinal studies will assess the validity of the ratio plasma 24S-hydroxycholesterol/cholesterol as a state marker for AD.
An investigation into the antioxidant activity of Allium nutans L.

Antioxidants are important species which possess the ability to protect the body from damage caused by free radical‐induced oxidative stress. There is currently much interest in the antioxidant role of fruit, vegetables, wines and teas. In this study the antioxidant activity of leaf, bulb and root of Allium nutants L. was investigated. Biochemical parameters were also determined: activities of antioxidant enzymes (superoxide dismutase, catalase, peroxidase, glutathione peroxidase), quantities of malonyldialdehyde, superoxide and hydroxyl radicals and reduced glutathione and contents of total flavonoids, chlorophylls a and b carotenoids, vitamin C and soluble proteins. Our results indicated that Allium nutants L. exhibits antioxidant ability in all investigated plant organs. The highest antioxidant ability was observed in the leaves where all investigated antioxidant enzymes were active and quantities of malonyldialdehyde and OH· low. Reduced glutathione, pigments and carotenoids present in the leaves contribute to the high antioxidant activity. ESR investigation conducted with Allium nutans L. phosphate buffer (pH 7) extract showed that the signal DMPO‐OH spin adducts in the presence of Allium nutans L. extract was reduced by 78.48%. Copyright © 1999 John Wiley & Sons, Ltd.
Licofelone abolishes survival of carcinogenic fibroblasts by inducing apoptosis

Abstract Dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX) pathways of arachidonic acid metabolism prevent cancer development and induce apoptosis. One of the most promising compounds that blocks both of these pathways is licofelone. We questioned whether licofelone affects the survival and/or promotes apoptosis of H-ras transformed rat embryonic fibroblast (5RP7) cells in vitro. Using 5-fluorouracil (5-FU) and colchicine as positive controls, we determined cell viability with 3-3-(4,5-D-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, thyazolyl blue (MTT), apoptosis with flow cytometry and activity of caspase enzyme with real-time reverse transcription polymerase chain reaction (PCR). Compared to the control, all used six doses (10, 50, 100, 150, 250 and 250 µM) of 5-FU, colchicine and licofelone, which were cytotoxic and reduced the number of H-Ras transformed 5RP7 cells by as much as 78, 72 and 92%, respectively. In addition, we found that 150, 200 and 250 µM of licofelone induced apoptosis and necrosis of H-Ras transformed 5RP7 cells in a dose- and time-dependent manner. Each three tested drugs at 250 µM also increased the level of caspase-3 enzyme up to 5-fold. Although colchicine was effective in inducing early apoptosis, licofelone had much more capacity to induce the total of early plus late apoptosis by approximately 96% in cells after 48 hours. The present study reveals the possibility that licofelone posseses strong dose- and time-dependent anticancer and apoptotic properties on carcinogenic fibroblasts.
A Somatic Knockout of CBF1 in a Human B-Cell Line Reveals that Induction of CD21 and CCR7 by EBNA-2 Is Strictly CBF1 Dependent and that Downregulation of Immunoglobulin M Is Partially CBF1 Independent

ABSTRACT CBF1 is a cellular highly conserved DNA binding factor that is ubiquitously expressed in all tissues and acts as a repressor of cellular genes. In Epstein-Barr virus growth-transformed B-cell lines, CBF1 serves as a central DNA adaptor molecule for several viral proteins, including the viral transactivator Epstein-Barr virus nuclear antigen 2 (EBNA-2). EBNA-2 binds to CBF1 and thereby gains access to regulatory regions of target genes and activates transcription. We have inactivated the CBF1 gene by homologous recombination in the human B-cell line DG75 and characterized changes in cellular gene expression patterns upon loss of CBF1 and activation of EBNA-2. CBF1-negative DG75 cells were viable and proliferated at wild-type rates. Loss of CBF1 was not sufficient to release repression of the previously described EBNA-2 target genes CD21 or CCR7, whereas induction of both target genes by EBNA-2 required CBF1. In contrast, repression of immunoglobulin M by EBNA-2 was mainly CBF1 independent. CBF1-negative DG75 B cells thus provide an excellent tool to dissect CBF1-dependent and -independent functions exerted by the EBNA-2 protein in future studies.
Luteal Expression of Thyroid Hormone Receptors During Gestation and Postpartum in the Rat

Background: Progesterone (P4) is the main steroid secreted by the corpora lutea (CL) and is required for successful implantation and maintenance of pregnancy. Although adequate circulating levels of thyroid hormone (TH) are needed to support formation and maintenance of CL during pregnancy, TH signaling had not been described in this gland. We determined luteal thyroid hormone receptor isoforms (TR) expression and regulation throughout pregnancy and under the influence of thyroid status, and in vitro effects of triiodothyronine (T3) exposure on luteal P4 synthesis. Methods: Euthyroid female Wistar rats were sacrificed by decapitation on gestational day (G) 5, G10, G15, G19, or G21 of pregnancy or on day 2 postpartum (L2). Hyperthyroidism and hypothyroidism were induced in female Wistar rats by daily administration of thyroxine (T4; 0.25 mg/kg subcutaneously) or 6-propyl-2-thiouracil (PTU; 0.1 g/L in drinking water), respectively. Luteal TR expression of mRNA was determined using real-time reverse-transcription quantitative polymerase chain reaction, and of protein using Western blot and immunohistochemistry. Primary cultures of luteal cells and of luteinized granulosa cells were used to study in vitro effects of T3 on P4 synthesis. In addition, the effect of T3 on P4 synthesis under basal conditions and under stimulation with luteinizing hormone (LH), prolactin (PRL), and prostaglandin E2 (PGE2) was evaluated. Results: TRa1, TRa2, and TRb1 mRNA were present in CL, increasing during the first half and decreasing during the second half of pregnancy. At the protein level, TRb1 was abundantly expressed during gestation reaching a peak at G19 and decreasing afterwards. TRa1 was barely expressed during early gestation, peaked at G19, and diminished thereafter. Expression of TRb1 and TRa1 at the protein and mRNA level were not influenced by thyroid status. T3 neither modified P4 secretion from CL of pregnancy nor its synthesis in luteinized granulosa cells in culture. Conclusions: This study confirms for the first time the presence of TR isoforms in the CL during pregnancy and postpartum, identifying this gland as a TH target during gestation. TR expression is modulated in this tissue in accordance with the regulation of P4 metabolism, and the abrupt peripartum changes suggest a role of TH during luteolysis. However, TH actions on the CL do not seem to be related to a direct regulation of P4 synthesis.
Day-by-day variation in affect, arousal and alcohol consumption in young adults.

INTRODUCTION AND AIMS Alcohol consumption has a well-established relationship with mood, with higher positive and negative affect predicting alcohol use. More recently, researchers have explored whether alcohol consumption occurs as a response to affect variability as an attempt to self-medicate and stabilise affect. Studies have revealed a positive association between alcohol use and intra- and inter-individual affect variability in clinical and university student samples; however not much is known of this relationship among the general community. DESIGN AND METHODS Ecological Momentary Assessment (EMA) methods were used to investigate the relationship between affect and arousal variability and alcohol use in 53 community volunteers. Participants self-reported affect and arousal at three to five randomly timed moments throughout the day, as well as every time they drank. RESULTS On a day-to-day basis, higher positive affect was associated with increased alcohol consumption. When analyses were restricted to self-reported affect prior to alcohol consumption, only increased arousal and decreased variability in arousal predicted the likelihood of alcohol consumption. Mean level of arousal was associated with the extent of alcohol consumed. DISCUSSION AND CONCLUSIONS In this moderate drinking sample day-to-day affect and arousal, and arousal variability, were associated with alcohol consumption. Analyses restricted to pre-drinking observations provide further evidence that self-medication accounts of alcohol consumption may explain drinking initiation but that the relationship between affect factors and drinking behaviour may change around the point of first drink.
The Differential Response of Protein Kinase A to Cyclic AMP in Discrete Brain Areas Correlates with the Abundance of Regulatory Subunit II

Abstract: We analyzed the expression and relative distribution of mRNA for the regulatory subunits (RIα, RIIα, and RIIβ) and of 150‐kDa RIIβ‐anchor proteins for cyclic AMP (cAMP)‐dependent protein kinase (PKA) into discrete brain regions. The subcellular distribution of both holoenzyme and free catalytic subunit was evaluated in the same CNS areas. In the neocortex and corpus striatum high levels of RIIβ paralleled the presence of specific RII‐anchoring proteins, high levels of membrane‐bound PKA holoenzyme, and low levels of cytosolic free catalytic activity (C‐PKA). Conversely, in brain areas showing low RIIβ levels (cerebellum, hypothalamus, and brainstem) we found an absence of RII‐anchoring proteins, low levels of membrane‐bound holoenzyme PKA, and high levels of cytosolic dissociated C‐PKA. Response to cAMP stimuli was specifically evaluated in the neocortex and cerebellum, prototypic areas of the two different patterns of PKA distribution. We found that cerebellar holoenzyme PKA was highly sensitive to cAMP‐induced dissociation, without, however, a consistent translocation of C‐PKA into the nucleus. In contrast, in the neocortex holoenzyme PKA was mainly in the undissociated state and poorly sensitive to cAMP. In nuclei of cortical cells cAMP stimulated the import of C‐PKA and phosphorylation of cAMP‐responsive element binding protein. Taken together, these data suggest that RIIβ (whose distribution is graded throughout the CNS, reaching maximal expression in the neocortex) may represent the molecular cue of the differential nuclear response to cAMP in different brain areas, by controlling cAMP‐induced holoenzyme PKA dissociation and nuclear accumulation of catalytic subunits.
Development of Snake‐Directed Antipredator Behavior by Wild White‐Faced Capuchin Monkeys: II. Influence of the Social Environment

Young animals are known to direct alarm calls at a wider range of animals than adults. If social cues are safer and/or more reliable to use than asocial cues for learning about predators, then it is expected that the development of this behavior will be affected by the social environment. Our study examined the influence of the social environment on antipredator behavior in infant, juvenile, and adult wild white‐faced capuchin monkeys (Cebus capucinus) at Lomas Barbudal Biological Reserve in Costa Rica during presentations of different species of model snakes and novel models. We examined (a) the alarm calling behavior of the focal animal when alone versus in the vicinity of conspecific alarm callers and (b) the latency of conspecifics to alarm call once the focal animal alarm called. Focal animals alarm called more when alone than after hearing a conspecific alarm call. No reliable differences were found in the latencies of conspecifics to alarm call based on age or model type. Conspecifics were more likely to alarm call when focal individuals alarm called at snake models than when they alarm called at novel models. Results indicate (a) that alarm calling may serve to attract others to the predator's location and (b) that learning about specific predators may begin with a generalized response to a wide variety of species, including some nonthreatening ones, that is winnowed down via Pavlovian conditioned inhibition into a response directed toward specific dangerous species. This study reveals that conspecifics play a role in the development of antipredator behavior in white‐faced capuchins. Am. J. Primatol. 75:292‐300, 2013. © 2012 Wiley Periodicals, Inc.
Seasonal and annual genotypic variation and the effect of climate on population genetic structure of the cereal aphid Sitobion avenae in northern France

Abstract Changes in the genetic structure and genotypic variation of the aphid Sitobion avenae collected from cereal crops in northern France were examined by analysing variation at five microsatellite loci across several years and seasons. Little regional and temporal differentiation was detected, as shown by very low FST among populations. Repeated genotypes, significant heterozygote deficits, positive FIS values and frequent linkage disequilibria were found in nearly all samples, suggesting an overall pattern of reproductive mode variation in S. avenae populations. In addition, samples from Brittany (Bretagne) showed greater signs of asexual reproduction than those from the north of France, indicating a trend toward increasing sexuality northward. These patterns of reproductive variation in S. avenae are consistent with theoretical models of selection of aphid reproductive modes by climate. Contrasting with little changes in allelic frequencies, genotypic composition varied substantially in time and, to a lesser extent, in space. An important part of changes in genotypic arrays was due to the variation in frequency distribution of common genotypes, i.e. those that were found at several instances in the samples. Genotypic composition was also shown to vary according to climate, as genotypic diversity in spring was significantly correlated with the severity of the previous winter and autumn. We propose that the genetic homogeneity among S. avenae populations shown here across large temporal and spatial scales is the result of two forces: (i) migration conferred by high dispersal capabilities, and (ii) selection over millions of hectares of cereals (mostly wheat) bred from a narrow genetic base.
β-Arrestin Scaffolding of the ERK Cascade Enhances Cytosolic ERK Activity but Inhibits ERK-mediated Transcription following Angiotensin AT1a Receptor Stimulation*

β-Arrestins are cytosolic proteins that mediate homologous desensitization of G protein-coupled receptors (GPCRs) by binding to agonist-occupied receptors and by uncoupling them from heterotrimeric G proteins. The recent finding that β-arrestins bind to some mitogen-activated protein (MAP) kinases has suggested that they might also function as scaffolds for GPCR-stimulated MAP kinase activation. To define the role of β-arrestins in the regulation of ERK MAP kinases, we examined the effect of β-arrestin overexpression on ERK1/2 activation and nuclear signaling in COS-7 cells expressing angiotensin II type 1a receptors (AT1aRs). Expression of either β-arrestin1 or β-arrestin2 reduced angiotensin-stimulated phosphatidylinositol hydrolysis but paradoxically increased angiotensin-stimulated ERK1/2 phosphorylation. The increase in ERK1/2 phosphorylation in β-arrestin-expressing cells correlated with activation of a β-arrestin-bound pool of ERK2. The β-arrestin-dependent increase in ERK1/2 phosphorylation was accompanied by a significant reduction in ERK1/2-mediated, Elk1-driven transcription of a luciferase reporter. Analysis of the cellular distribution of phospho-ERK1/2 by confocal immunofluorescence microscopy and cellular fractionation revealed that overexpression of β-arrestin resulted in a significant increase in the cytosolic pool of phospho-ERK1/2 and a corresponding decrease in the nuclear pool of phospho-ERK1/2 following angiotensin stimulation. β-Arrestin overexpression resulted in formation of a cytoplasmic pool of β-arrestin-bound phospho-ERK, decreased nuclear translocation of phospho-ERK1/2, and inhibition of Elk1-driven luciferase transcription even when ERK1/2 was activated by overexpression of cRaf-1 in the absence of AT1aR stimulation. These data demonstrate that β-arrestins facilitate GPCR-mediated ERK activation but inhibit ERK-dependent transcription by binding to phospho-ERK1/2, leading to its retention in the cytosol.
Use of viscogens, dNTPalphaS, and rhodium(III) as probes in stopped-flow experiments to obtain new evidence for the mechanism of catalysis by DNA polymerase beta.

The kinetic mechanism and the structural bases of the fidelity of DNA polymerases are still highly controversial. Here we report the use of three probes in the stopped-flow studies of Pol beta to obtain new, direct evidence for our previous interpretations: (a) Increasing the viscosity of the reaction buffer by sucrose or glycerol is expected to slow down the conformational change differentially, and it was shown to slow down the first (fast) fluorescence transition selectively. (b) Use of dNTPalphaS in place of dNTP is expected to slow down the chemical step preferentially, and it was shown to slow down the second (slow) fluorescence transition selectively. (c) The substitution-inert Rh(III)dNTP was used to show for the first time that the slow fluorescence change occurs after mixing of Pol beta.DNA. Rh(III)dNTP with Mg(II). These results, along with crystal structures, suggest that the subdomain-closing conformational change occurs before binding of the catalytic Mg(II) while the rate-limiting step occurs after binding of the catalytic Mg(II). These results provide new evidence to the mechanism we suggested previously, but do not support the results of three recent papers of computational studies. The results were further supported by a "sequential mixing" stopped-flow experiment that used no analogues, and thus ruled out the possibility that the discrepancy between experimental and computational results is due to the use of analogues. The methodologies can be used to examine other DNA polymerases to answer whether the properties of Pol beta are exceptional or general.
Robust position and velocity estimation methods in integrated navigation systems for inland water applications

As the Global Navigation Satellite Systems (GNSS) are intensively used as main source of Position, Navigation and Timing (PNT) information for maritime and inland water navigation, it becomes increasingly important to ensure the reliability of GNSS-based navigation solutions for challenging environments. Although an intensive work has been done in developing GNSS Receiver Autonomous Integrity Monitoring (RAIM) algorithms, a reliable procedure to mitigate multiple simultaneous outliers is still lacking. The presented work evaluates the performance of several methods for multiple outlier mitigation based on robust estimation framework and compares them to the performance of state-of-the-art RAIM methods. The relevant methods include M-estimation, S-estimation, LMS and RANSAC-based approaches as well as corresponding modifications for C/N0-based weighting schemes. The snapshot positioning methods are also tested within the quaternion-based Cubature Quadrature Kalman filter for integrated inertial/GNSS solution. The presented schemes are evaluated using real measurement data from challenging inland water scenarios with multiple bridges and a waterway lock. The initial results are encouraging and clearly indicate the potential of the discussed methods both for classical snapshot solutions as well for the methods with complementary sensors.