Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro metabolism of an estrogen‐related receptor γ modulator, GSK5182, by human liver microsomes and recombinant cytochrome P450s

GSK5182 (4‐[(Z)‐1‐[4‐(2‐dimethylaminoethyloxy)phenyl]‐hydroxy‐2‐phenylpent‐1‐enyl]phenol) is a specific inverse agonist for estrogen‐related receptor γ, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2 and M3. M1 and M3 were identified as N‐desmethyl‐GSK5182 and GSK5182 N‐oxide, respectively, on the basis of liquid chromatography‐tandem mass spectrometric (LC‐MS/MS) analysis. M2 was suggested to be hydroxy‐GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin‐containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N‐demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N‐oxide from GSK5182. The present data will be useful for understanding the pharmacokinetics and drug interactions of GSK5182 in vivo. Copyright © 2014 John Wiley & Sons, Ltd.
Association between perinatal hypoxic-ischemia and periventricular leukomalacia in preterm infants: A systematic review and meta-analysis

Background Although investigators have implicated hypoxic-ischemia (HI) as a potential cause of periventricular leukomalacia (PVL), the role of clinical risk factors or markers for HI in the development of PVL remains controversial. The aim of this study was to identify perinatal HI-related factors associated with PVL. Method The PubMed, EMBASE, and Cochrane Library databases were searched. The last search was performed on January 2017. Summary effect estimates (pooled odds ratios [ORs]) were calculated for each risk factor using fixed or random effects models with tests for heterogeneity and publication bias. Results Fifteen studies with a total of 12,851 participants were included in this meta-analysis, and 14 potential risk factors were analyzed. The pooled results showed that mothers with oligohydramnios (OR, 1.55; 95% confidence interval [CI], 1.05 to 2.30), preterm infants with acidemia (OR, 1.87; 95% CI, 1.18 to 2.97), 1-minute Apgar score <7 (OR 2.69; 95% CI, 1.13 to 6.41), 5-minute Apgar score <7 (OR, 1.89; 95% CI, 1.39 to 2.56), apnea (OR, 1.76; 95% CI, 1.07 to 2.90), respiratory distress syndrome (OR, 1.46; 95% CI, 1.04 to 2.03), and seizures (OR, 4.60; 95% CI, 2.84 to 7.46) were associated with increased risk of PVL. Conclusion This study identified perinatal HI-related risk factors for the development of PVL in preterm infants. Future large-scale prospective clinical studies are required to validate and extend these findings.
The Involvement of Two cdc2-related Kinases (CRKs) in Trypanosoma brucei Cell Cycle Regulation and the Distinctive Stage-specific Phenotypes Caused by CRK3 Depletion*

Cyclin-dependent protein kinases are among the key regulators of eukaryotic cell cycle progression. Potential functions of the five cdc2-related kinases (CRK) in Trypanosoma brucei were analyzed using the RNA interference (RNAi) technique. In both the procyclic and bloodstream forms of T. brucei, CRK1 is apparently involved in controlling the G1/S transition, whereas CRK3 plays an important role in catalyzing cells across the G2/M junction. A knockdown of CRK1 caused accumulation of cells in the G1 phase without apparent phenotypic change, whereas depletion of CRK3 enriched cells of both forms in the G2/M phase. However, two distinctive phenotypes were observed between the CRK3-deficient procyclic and bloodstream forms. The procyclic form has a majority of the cells containing a single enlarged nucleus plus one kinetoplast. There is also an enhanced population of anucleated cells, each containing a single kinetoplast known as the zoids (0N1K). The CRK3-depleted bloodstream form has an increased number of one nucleus-two kinetoplast cells (1N2K) and a small population containing aggregated multiple nuclei and multiple kinetoplasts. Apparently, these two forms have different mechanisms in cell cycle regulation. Although the procyclic form can be driven into cytokinesis and cell division by kinetoplast segregation without a completed mitosis, the bloodstream form cannot enter cytokinesis under the same condition. Instead, it keeps going through another G1 phase and enters a new S phase resulting in an aggregate of multiple nuclei and multiple kinetoplasts in an undivided cell. The different leakiness in cell cycle regulation between two stage-specific forms of an organism provides an interesting and useful model for further understanding the evolution of cell cycle control among the eukaryotes.
Myocyte Enhancer Factor-related B-MEF2 Is Developmentally Expressed in B Cells and Regulates the Immunoglobulin J Chain Promoter*

Immunoglobulin J chain gene expression is induced by the delivery of a lymphokine signal to antigen-activated B cells in a primary immune response. A major interleukin 2 (IL-2)-responsive region that contains two adjacent control elements (JA and JB) exists within the J chain promoter. Transcription factor PU.1 positively regulates J chain gene expression by binding to one of the control elements (JB) in the J chain promoter. In the present study we have determined that a myocyte enhancer factor 2 (MEF2)-related nuclear factor, named B-MEF2, positively regulates the J chain gene promoter activity via the second control element (JA). An in vitrotranslated MEF2 family member, MEF2C, was found to bind the JA site with identical properties as endogenously expressed B-MEF2 in B cell lines. Moreover, in vivo experiments showed that a dominant negative mutant of MEF2C blocked B-MEF2 regulation of the J chain promoter. Consistent with its role as positive regulator of J chain gene expression, B-MEF2 levels were enhanced in highly differentiated B cells. In addition, induction of an IL-2-responsive presecretor cell line BCL1 with IL-2 or IL-5 (which up-regulates J chain gene expression) resulted in an increased expression of B-MEF2. We conclude that a MEF2-related transcriptional factor, B-MEF2, acts as a stage-specific positive regulator of J chain gene expression in the B cell lineage.
Meaning and Centrality of Caring Activities Among Older Women

ABSTRACT This article explores the meaning and conditions of caring activities for older women. Taped, in-person interviews were conducted with 53 ethnically and economically diverse women, 55–84 years old. The interview guide contained open-ended questions regarding the process of taking on caring activities and the centrality of care to personal identity. Past activities were automatically assumed, in contrast to the present experience of choice. Caring activities provided meaning and continuity throughout the life course. Participants reported becoming more self-protective over the life course and offered seven explanations for their increased ability to be self-protective.
Increased fear‐ and stress‐related anxiety‐like behavior in mice lacking tuberoinfundibular peptide of 39 residues

Tuberoinfundibular peptide of 39 residues (TIP39) is synthesized by two groups of neurons, one in the subparafascicular area at the caudal end of the thalamus and the other in the medial paralemniscal nucleus within the lateral brainstem. The subparafascicular TIP39 neurons project to a number of brain regions involved in emotional responses, and these regions contain a matching distribution of a receptor for TIP39, the parathyroid hormone 2 receptor (PTH2‐R). We have now evaluated the involvement of TIP39 in anxiety‐related behaviors using mice with targeted null mutation of the TIP39 gene (Tifp39). Tifp39−/− mice (TIP39‐KO) did not significantly differ from wild‐type (WT) littermates in the open field, light/dark exploration and elevated plus‐maze assays under standard test conditions. However, the TIP39‐KO engaged in more active defensive burying in the shock‐probe test. In addition, when tested under high illumination or after restraint, TIP39‐KO displayed significantly greater anxiety‐like behavior in the elevated plus‐maze than WT. In a Pavlovian fear‐conditioning paradigm, TIP39‐KO froze more than WT during training and during tone and context recall but showed normal fear extinction. Disruption of TIP39 projections to the medial prefrontal cortex, lateral septum, bed nucleus of the stria terminalis, hypothalamus and amygdala likely account for the fear‐ and anxiety‐related phenotype of TIP39‐KO. Current data support the hypothesis that TIP39 modulates anxiety‐related behaviors following environmental provocation.
T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer.

PURPOSE An existing immunological paradigm is that high concentrations of soluble protein contribute to the maintenance of peripheral tolerance/ignorance to self protein. We tested this hypothesis in a clinical immunotherapy trial using class I-restricted peptide epitopes derived from alpha-fetoprotein (AFP). AFP is a self protein expressed by fetal liver at high levels, but transcriptionally repressed at birth. AFP is de-repressed in a majority of hepatocellular carcinomas (HCCs) and patients with active disease can have plasma levels in the mg/ml range. We previously identified four immunodominant HLA-A*0201-restricted peptides derived from human AFP that could stimulate specific T-cell responses in normal volunteer peripheral blood lymphocytes cultures. We wished to test the hypothesis that AFP peptide-reactive T cells could be expanded in vivo in HCC patients immunized with these four AFP peptides. EXPERIMENTAL DESIGN We undertook a pilot Phase I clinical trial in which HLA-A*0201 patients with AFP-positive HCC were immunized with three biweekly intradermal vaccinations of the four AFP peptides (100 microg or 500 microg each) emulsified in incomplete Freund's adjuvant. RESULTS All of the patients (n=6) generated T-cell responses to most or all of the peptides as measured by direct IFNgamma enzyme-linked immunospot (ELISPOT) and MHC class I tetramer assays. CONCLUSIONS We conclude that the human T-cell repertoire is capable of recognizing AFP in the context of MHC class I even in an environment of high circulating levels of this oncofetal protein.
Extremely low-birth-weight children and their peers. A comparison of school-age outcomes.

OBJECTIVE To document 7-year developmental and educational outcomes in a cohort of predominantly white, middle-class, extremely low-birth-weight (ELBW, < 1000 g) children to address the incidence of increased developmental disability and the need for special educational services. DESIGN Observational study. PATIENTS Fifty-four ELBW children and 58 comparison children, who were matched for race, gender, and socio-economic status (30 with low birth weights [1500-2500 g] and 28 with birth weights > 2500 g). The ELBW cohort was drawn from 104 presurfactant survivors born between 1984 and 1986 and cared for in a single hospital. SETTING Suburban, university-based tertiary referral center. MAIN OUTCOME MEASURES Teachers' reports of classroom placement and special education services and tests of cognitive, motor, language, and visual-motor integration abilities were studied. RESULTS Twenty-seven (50%) of 54 ELBW children were in regular classrooms with no special services compared with 21 (70%) of 30 in the low-birth-weight group and 27 (93%) of 28 in the full-term group, indicating a significant trend toward increasing need for special services with decreasing birth weight across the 3 groups (P < .001). The ELBW group scored significantly lower than the comparison groups on all tests, although generally within the average range. Seventy-nine percent of ELBW children had average cognitive scores, but they averaged 14 to 17 points lower than the 2 comparison groups. Twenty percent of the ELBW children had significant disabilities including cerebral palsy, mental retardation, autism, and low intelligence with severe learning problems. CONCLUSIONS Even with optimal socioeconomic environments, 20% of ELBW children are significantly disabled, and 1 of every 2 ELBW children requires special educational services. Objective testing pinpointed weakness on all measures compared with matched peer groups.
Development and initial validation of an instrument to measure physicians' use of, knowledge about, and attitudes toward computers.

UNLABELLED This paper describes details of four scales of a questionnaire-- "Computers in Medical Care"--measuring attributes of computer use, self-reported computer knowledge, computer feature demand, and computer optimism of academic physicians. The reliability (i.e., precision, or degree to which the scale's result is reproducible) and validity (i.e., accuracy, or degree to which the scale actually measures what it is supposed to measure) of each scale were examined by analysis of the responses of 771 full-time academic physicians across four departments at five academic medical centers in the United States. The objectives of this paper were to define the psychometric properties of the scales as the basis for a future demonstration study and, pending the results of further validity studies, to provide the questionnaire and scales to the medical informatics community as a tool for measuring the attitudes of health care providers. METHODOLOGY The dimensionality of each scale and degree of association of each item with the attribute of interest were determined by principal components factor analysis with orthogonal varimax rotation. Weakly associated items (factor loading < .40) were deleted. The reliability of each resultant scale was computed using Cronbach's alpha coefficient. Content validity was addressed during scale construction; construct validity was examined through factor analysis and by correlational analyses. RESULTS Attributes of computer use, computer knowledge, and computer optimism were unidimensional, with the corresponding scales having reliabilities of . 79, . 91, and . 86, respectively. The computer-feature demand attribute differentiated into two dimensions: the first reflecting demand for high-level functionality with reliability of . 81 and the second demand for usability with reliability of . 69. There were significant positive correlations between computer use, computer knowledge, and computer optimism scale scores and respondents' hands-on computer use, computer training, and self-reported computer sophistication. In addition, items posited on the computer knowledge scale to be more difficult generated significantly lower scores. CONCLUSION The four scales of the questionnaire appear to measure with adequate reliability five attributes of academic physicians' attitudes toward computers in medical care: computer use, self-reported computer knowledge, demand for computer functionality, demand for computer usability, and computer optimism. Results of initial validity studies are positive, but further validation of the scales is needed. The URL of a downloadable HTML copy of the questionnaire is provided.
Association between serum adropin level and burden of coronary artery disease in patients with non-ST elevation myocardial infarction

Objective: Previous studies revealed the relationship between stable coronary artery disease (CAD) and serum adropin level, but this relationship has not been investigated in patients with non-ST segment elevation myocardial infarction (NSTEMI). The present study is an analysis of the relationship between adropin and severity of CAD assessed based on SYNTAX score in patients with NSTEMI. Methods: A total of 109 participants, 80 patients with NSTEMI and 29 healthy individuals, were prospectively enrolled in the study. Patients with NSTEMI were divided to 2 groups: high SYNTAX score (≥32) (35 patients) and low SYNTAX score (<32) (45 patients). Adropin level was measured from blood serum samples using enzyme-linked immunosorbent assay test. Results: Patients with NSTEMI and high SYNTAX score had significantly lower serum adropin level (2357.30 pg/mL±821.58) compared to NSTEMI patients with low SYNTAX score (3077.00 pg/mL±912.86) and control group (3688.00±956.65). Adropin cut-off value for predicting high SYNTAX score on receiver-operating characteristic curve analysis was determined to be 2759 pg/mL, with a sensitivity of 63% and a specificity of 57%. Adropin was an independent predictor for high SYNTAX score (odds ratio=0.999; 95% confidence interval: 0.998–1.000; p=0.007). Conclusion: Adropin could be an alternative blood sample value for predicting severity of CAD.
Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

Background: Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes. Methods: We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA. Results: In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy. Conclusions: Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.
A Novel Glutathione Peroxidase in Bovine Eye

Bovine ciliary body contains a selenium-independent glutathione peroxidase (GPX) with a molecular mass of about 100 kDa that is composed of four identical subunits and exhibits no glutathione S-transferase activity. In this study, we isolated cDNA clones and determined the nucleotide sequence to deduce the primary structure of the enzyme. The cDNA contained 672 base pairs encoding a polypeptide with an estimated molecular mass of 25,064 Da. Translation of bovine ciliary mRNA produced a protein which was immunologically indistinguishable from GPX and showed high enzyme activity. The encoded amino acid sequence of the protein was 95% identical with that of a human keratinocyte gene product expressed in response to keratinocyte growth factor. It also showed sequence identity to bacterial alkyl hydroperoxide reductases and thiol specific antioxidant enzymes. GPX mRNA level was highest in the ciliary body, followed by the retina and iris. In various rat organs, the level of GPX mRNA was highest in the lung, followed by the muscle, liver, eye, heart, testis, thymus, kidney, and spleen. A very low level of mRNA was detected in the brain. Enzyme-linked immunosorbent assay with an antibody raised against the NH2-terminal sequence of GPX detected GPX protein in all rat tissues examined.
Source Consistency, Distinctiveness, and Consensus: The Three Dimensions of the Kelley ANOVA Model in Persuasion

Based on a conceptual analysis and existing research, the authors propose that the three source dimensions specified in the ANOVA model play similar roles in persuasion as other source characteristics (e.g., expertise). Two studies test assumptions derived from this approach regarding the effects of different combinations of consistency and consensus (Study 1) and distinctiveness and consensus (Study 2). Combinations resulting in contradictory (vs. similar) inferences regarding message validity should affect judgmental confidence and, consequently, affect message scrutiny. Study 1 shows that, as predicted, high consistency/low consensus and low consistency/high consensus (incongruent combinations) lead to higher desired confidence and more extensive message elaboration than high consistency/high consensus and low consistency/low consensus (congruent combinations). Similarly, Study 2 reveals heightened message scrutiny given incongruent (vs. congruent) combinations of distinctiveness and consensus. Results are discussed with respect to majority/minority influence processes and multiple source characteristics.
Gait Characteristics When Walking on Different Slippery Walkways

Objective: This study sought to determine the changes in muscle activity about the ankle, knee, and hip in able-bodied people walking at steady state on surfaces with different degrees of slipperiness. Methods : Muscle activity was measured through electromyographic signals from selected lower limb muscles and quantified to directly compare changes across surface conditions. Results: Our results showed distinct changes in the patterns of muscle activity controlling each joint. Muscles controlling the ankle showed a significant reduction in activity as the surface became more slippery, presumably resulting in a compliant distal joint to facilitate full contact with the surface. Select muscles about the knee and hip showed a significant increase in activity as the surface became more slippery. This resulted in increased knee and hip flexion likely contributing to a lowering of the body's center of mass and stabilization of the proximal leg and trunk. Conclusion : These findings suggest a proximal-distal gradient in the control of muscle activity that could inform the future design of adaptable prosthetic controllers. Significance: Walking on a slippery surface is extremely difficult, especially for individuals with lower limb amputations because current prostheses do not allow the compensatory changes in lower limb dynamics that occur involuntarily in unimpaired subjects. With recent advances in prosthetic control, there is the potential to provide some of these compensatory changes; however, we first need to understand how able-bodied individuals modulate their gait under these challenging conditions.