Miracle-dz/UniFAR-FTUs huggingface dataset:
Rational design of YAP WW1 domain‐binding peptides to target TGFβ/BMP/Smad–YAP interaction in heterotopic ossification

The transforming growth factor‐β/bone morphogenic protein/Smad signaling pathway has been raised as a new and promising therapeutic target of heterotopic ossification, which is mediated by recruitment of transcription coactivator Yes‐associated protein (YAP) to Smad. Here, we described a successful integration of computational modeling and experimental assay to rationally design novel peptide aptamers to disrupt YAP–Smad interaction by targeting YAP WW1 domain. In the protocol, a computational genetic evolution strategy was used to improve a population of potential YAP WW1‐binding peptides generated from the YAP‐recognition site in Smad protein, from which several promising peptides were selected and their affinities toward YAP WW1 domain were determined using binding assay. In addition, a high‐activity peptide was further optimized based on its complex structure with YAP WW1 domain to derive a number of derivative peptides with higher binding potency to the domain. We also found that a strong YAP WW1 binder should have a negatively charged N‐terminus, a positively charged C‐terminus and a nonpolar core to match the electrostatic distribution pattern in peptide‐binding pocket of YAP WW1 domain, which may also form additional nonbonded interactions such as hydrogen bond, salt bridge and π–π stacking to confer stability and specificity for the domain–peptide recognition. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.
Considerations in Women with Hypertension

Abstract Cardiovascular disease is the most common cause of death in women in the United States, and hypertension is a major contributor to cardiovascular mortality. The incidence of hypertension in women is steadily increasing, paralleling the epidemics of obesity and diabetes. Blood pressure control rates among women are suboptimal, even when secondary causes are identified and treated. There are few high-quality data describing specific hypertension-related outcomes in women. Some data comparing hypertensive women to age-matched men suggest advantages to sex-specific strategies, but further study is needed to determine optimal regimens for women throughout their lives. Pregnancy and menopause present unique, complex challenges in hypertension management.
Effects of an environmentally relevant polychlorinated biphenyl (PCB) mixture on embryonic survival and cardiac development in the domestic chicken

A 58‐congener polychlorinated biphenyl (PCB) mixture based on contaminant analysis of spotted sandpiper eggs collected along the upper Hudson River, New York, USA, in 2004 was used to study in ovo PCB effects on cardiac development in the domestic chicken. Fertile eggs were injected prior to incubation with the following doses of the PCB mixture: untreated, sham, 0, 0.03, 0.08, 0.3, 0.5, 0.7, and 2.06 µg PCBs/g egg weight (toxic equivalent quotient [TEQ] range of 0.004–0.266 ng/g). In addition, there were untreated and sham‐control groups. Embryonic development was monitored throughout incubation and chicks were necropsied at hatch. Hatchability followed a dose‐dependent curve with significant (p < 0.05) mortality above the 0.5 µg PCBs/g egg weight treatment compared with controls. The median lethal dose (LD50) of this PCB mixture in hatchling chicks was estimated as 0.4 µg/g egg weight (0.052 ng TEQ/g egg wt) based on the lethality curve. Cardiac arrhythmia was observed at embryonic day 14 of development in embryos treated at concentrations of 0.5 µg/g egg weight and above. Histological analysis was utilized to characterize any cardiac abnormalities. Cardiomyopathies increased across treatments in a dose‐dependent manner compared with control groups. Identified abnormalities included the absence of the trabeculated layer of the ventricular wall, ventricular dilation, thinning of the ventricular walls, malformation of the septal wall, and most commonly, absence of the compact layer of the ventricular wall. Chick heart width, depth, total area, compact layer depth, septal width, chamber area, and ventricular wall dimensions did not differ across treatments. The present study supports prior reports of adverse developmental effects of PCBs on cardiovascular systems in birds. Although the eggs hatched, measured cardiomyopathies suggest potential deleterious long‐term impacts on individual health and fitness. Environ Toxicol Chem 2013;32:1325–1331. © 2013 SETAC
Prognostic value of retinal nerve fiber layer thickness for postoperative peripheral visual field recovery in optic chiasm compression.

UNLABELLED OBJECT. : The authors' objective was to evaluate the predictive value of preoperative axonal loss for peripheral visual field recovery after surgery for optic chiasm compression. METHODS Consecutive patients with optic chiasm compression in the period from October 2010 through August 2012 were retrospectively studied. Time-domain optical coherence tomography (OCT) had been performed before surgery. Kinetic automated perimetry had been performed before and after surgical decompression. The area of the peripheral isopter (square degrees [deg(2)]) was assessed. Postoperative improvement was defined as an increase of 25 deg(2) or more. RESULTS Sixty-eight eyes in 34 patients were included in the analysis. In 44 eyes the visual field improved after surgery, and in 24 eyes it was unchanged or worse. Nasal retinal nerve fiber layer (RNFL) thickness was a good prognostic factor for peripheral visual field recovery (OR 1.56 per 15 μm, p = 0.041). CONCLUSIONS Peripheral visual field recovery after surgery for optic chiasm compression is predicted by nasal RNFL thickness, which is in accordance with the retinotopy of retinal ganglion cells, as nasal axons decussate at the optic chiasm.
Construction and psychometric evaluation of the Swedish language Person-centred Climate Questionnaire - staff version.

AIM The aim of the study was to construct and evaluate psychometric properties of the Swedish language Person-centred Climate Questionnaire - staff version. BACKGROUND Person-centred care is often quoted but ill defined, and the literature warrants the development of valid and reliable measurement tools. METHODS During 2006, a questionnaire was constructed and distributed to a sample of Swedish hospital staff (n = 600). Questionnaire data was subjected to item analysis and reduction. Psychometrical properties of the questionnaire were evaluated. RESULTS The 14-item Person-centred Climate Questionnaire showed satisfactory psychometric properties. Measures of validity were good, internal consistency was high, Cronbach's alpha was satisfactory for the total scale (0.88) and test-retest reliability was adequate. CONCLUSION The results indicate that the staff Person-centred Climate Questionnaire is a valid and reliable tool for assessing staff perceptions of the person centredness of hospital environments. IMPLICATIONS FOR NURSING MANAGEMENT This instrument makes it possible to study the degree of person-centredness in relation to different organizational systems, environments, staff groups and managerial styles. In addition, staff variables such as turnover rates, health outcomes and efficacy can be related to staff perceived person centredness of the organization.
Toll-Like Receptor 9 Can Be Expressed at the Cell Surface of Distinct Populations of Tonsils and Human Peripheral Blood Mononuclear Cells

ABSTRACT Unmethlylated CpG dinucleotides induce a strong T-helper-1-like inflammatory response, presumably mediated by Toll-like receptor 9 (TLR9). However, the nature and cellular localization of TLR9 in primary human cells remain controversial. Here we demonstrate, using flow cytometry and immunofluorescence microscopy techniques, that TLR9 can be expressed at the cell surface. The primary human cell subsets that were positive for TLR9 expression were distinct depending on the tissues analyzed. Specifically, in human peripheral blood mononuclear cells (PBMC) the majority of cell surface TLR9+ cells were confined to the major histocompatibility complex (MHC) class II+ CD19− populations that express CD11c and/or CD14, whereas in tonsils the same gated population contained primarily MHC class II+ CD19+ cells. Cells positive for surface expression represented a minor fraction of the total cell populations examined, varying between 2 and 10%. In addition, we found that TLR9 expression at the surface of PBMC was up-regulated approximately fourfold following stimulation with the gram-negative bacterial cell wall component lipopolysaccharide, suggesting a potential modulatory role of TLR4 agonists on TLR9 expression. Taken together, these data validate human TLR9 expression at the surface of primary cells, in addition to the previously described intracellular localization. Further, our results suggest that human antigen-presenting cells comprise the major cell populations expressing cell surface TLR9.
Degradation of basement membrane by prostate tumor heparanase.

BACKGROUND The degradation of basement membrane (BM) by cancer is an important event that characterizes invasive biological behavior. A component of BM is heparan sulfate proteoglycan (HSPG). The glycanase(s) that degrade HSPG in BM are not yet isolated. We recently identified HSPG-degrading activity (PC-3M heparanase) in the conditioned media (CM) of malignant prostate carcinoma cells (PC-3M and LNCaP C4-2). Antibodies (Abs) to a recently isolated heparanase from human platelets (CTAP-III), cross-react with PC-3M heparanase although they differ in size; under reduced conditions PC-3M heparanase is 60 kDa whereas CTAP-III is 10 kDa by polyacrylamide gel electrophoresis. PC-3M heparanase therefore shares homology with CTAP-III. The purpose of this study was to test the inhibition of PC-3M heparanase by Abs specific to the N- and C-terminals of CTAP-III. MATERIALS AND METHODS CM from PC-3M and LNCaP C4-2 cells were tested for heparanase activity. Each reaction contained substrate as [3H]glucosamine-labeled HSPG (>50 kDa) from the BM of the EHS tumor, CM from PC-3M or LNCaP C4-2 cells, and inhibitor or buffer (negative control). Protease inhibitors were present throughout. After incubation for 3-20 h at 37 degreesC and pH 5.8, the reaction was stopped with 0.2% SDS. Each reaction mixture was centrifuged in an Ultrafree-MC 30,000 NMWL filter unit (Millipore) and radioactivity in the filtrate counted by scintillation counting. Results. For both cell lines, there was a linear relationship between the amount (microgram) of CM and degradation of HSPG. Degradation was inhibited by 54.1% (mean) using carrageenan lambda (10 microgram/ml), a nonspecific glycanase inhibitor (P < 0.05 by ANOVA). Ab to the N-terminus of CTAP-III (anti-Hep A) reduced degradation by 10-50% (mean 31.1%) and to the C-terminus (anti-Hep C) by 38.8-64.3% (mean 51.1%) (P < 0.003 by ANOVA). CONCLUSIONS The degradation of HSPG by malignant prostate cancer cell lines is inhibited by both a nonspecific glycanase inhibitor, and specific Abs to a homologous platelet heparanase. Based upon molecular weight, PC-3M heparanase is different from platelet heparanase and degrades BM.
Revisiting the risk of celiac disease in children born small for gestational age: A sibling design perspective

Abstract Objective. An association between small for gestational age (SGA) and risk for celiac disease (CD) in childhood has previously been reported. However, this association may reflect residual confounding by genetic or environmental factors. For example, presence of subclinical CD in the mother might be a common cause of both SGA and CD in the offspring. We investigate whether SGA is causally associated with CD before age six years by applying both conventional population-based regression models and sibling analysis that investigates the association in siblings discordant for SGA. Material and methods. Using the Swedish Medical Birth Registry, we identified all singleton children born in Sweden during 1987–1993 (792,401). Of these we included 681,954 children in the study and identified 2641 cases of CD using the Swedish National In-Hospital Registry. We applied both conventional Cox regression analysis and a quasi-experimental sibling design that to some extent simulates a counterfactual situation of exposure, reducing possible confounding effects of genetic and shared environmental factors. Results. We identified an increased risk of CD in both boys (hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.25–2.32) and girls (HR 1.30, 95% CI 0.99–1.70) using conventional Cox regression models. Using sibling analysis, the association between SGA and CD was confirmed in boys (HR 4.23, 95% CI 1.19–15.04) but not in girls (HR 1.00, 95% CI 0.45–2.20). Conclusions. Our results support a causal association between SGA and CD risk in boys but not in girls, although the mechanisms underlying this difference are still unclear.
Identification of Differentially Expressed Genes Between Cloned and Zygote-Developing Zebrafish (Danio rerio) Embryos at the Dome Stage Using Suppression Subtractive Hybridization1

Abstract Comparative analyses of differentially expressed genes between somatic cell nuclear transfer (SCNT) embryos and zygote-developing (ZD) embryos are important for understanding the molecular mechanism underlying the reprogramming processes. Herein, we used the suppression subtractive hybridization approach and from more than 2900 clones identified 96 differentially expressed genes between the SCNT and ZD embryos at the dome stage in zebrafish. We report the first database of differentially expressed genes in zebrafish SCNT embryos. Collectively, our findings demonstrate that zebrafish SCNT embryos undergo significant reprogramming processes during the dome stage. However, most differentially expressed genes are down-regulated in SCNT embryos, indicating failure of reprogramming. Based on Ensembl description and Gene Ontology Consortium annotation, the problems of reprogramming at the dome stage may occur during nuclear remodeling, translation initiation, and regulation of the cell cycle. The importance of regulation from recipient oocytes in cloning should not be underestimated in zebrafish.
Transporter‐Mediated Hepatic Uptake Plays an Important Role in the Pharmacokinetics and Drug–Drug Interactions of Montelukast

Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug–drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems. Single‐dose rifampicin, an OATP inhibitor, decreased montelukast clearance in rats and monkeys. Clinical DDIs of montelukast were evaluated using physiologically based pharmacokinetic modeling; and simulation of the interactions with gemfibrozil–CYP2C8 and OATP1B1/1B3 inhibitor, clarithromycin–CYP3A and OATP1B1/1B3 inhibitor, and itraconazole–CYP3A inhibitor, implicated OATPs‐CYP2C8‐CYP2C8 interplay as the primary determinant of montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions.
The White Clover enod40 Gene Family. Expression Patterns of Two Types of Genes Indicate a Role in Vascular Function1

Enod40 is one of the genes associated with legume nodule development and has a putative role in general plant organogenesis. We have isolated a small enod40 gene family from white clover (Trifolium repens), with three genes designated Trenod40-1, Trenod40-2, and Trenod40-3, all containing the conservedenod40 regions I and II. Trenod40-1 andTrenod40-2 share over 90% homology in the transcribed regions and high levels of similarity in their upstream regulatory sequences. Trenod40-1 and Trenod40-2 are similar to the enod40 genes of legumes forming indeterminate nodules (group II) and are predominantly expressed in nodules. Trenod40-3 shares only 32.8% identity withTrenod40-1 and Trenod40-2 within the transcribed region. Trenod40-3 is similar to theenod40 genes of legumes with determinate nodules (group I) and is not predominantly expressed in nodules. To our knowledge, this is the first report of both group I- and group II-typeenod40 genes being expressed in a single legume species. In situ hybridization studies revealed that Trenod40genes were highly expressed in non-symbiotic tissues, particularly in stolon nodes during nodal root and lateral shoot development. High levels of Trenod40 transcripts were also present in the vascular bundles of mature plant organs, mainly at sites of intensive lateral transport, suggesting a role in vascular tissue function. The expression pattern of Trenod40 genes was analyzed further using Trenod40 promoter-gusfusions in transgenic white clover and tobacco (Nicotiana tabacum), indicating that white clover and tobacco share the regulatory mechanisms for Trenod40-1/2 promoters and some aspects of Trenod40-3 regulation.
Health disparities and health equity: concepts and measurement.

There is little consensus about the meaning of the terms "health disparities," "health inequalities," or "health equity. " The definitions can have important practical consequences, determining the measurements that are monitored by governments and international agencies and the activities that will be supported by resources earmarked to address health disparities/inequalities or health equity. This paper aims to clarify the concepts of health disparities/inequalities (used interchangeably here) and health equity, focusing on the implications of different definitions for measurement and hence for accountability. Health disparities/inequalities do not refer to all differences in health. A health disparity/inequality is a particular type of difference in health (or in the most important influences on health that could potentially be shaped by policies); it is a difference in which disadvantaged social groups-such as the poor, racial/ethnic minorities, women, or other groups who have persistently experienced social disadvantage or discrimination-systematically experience worse health or greater health risks than more advantaged social groups. ("Social advantage" refers to one's relative position in a social hierarchy determined by wealth, power, and/or prestige.) Health disparities/inequalities include differences between the most advantaged group in a given category-e.g., the wealthiest, the most powerful racial/ethnic group-and all others, not only between the best- and worst-off groups. Pursuing health equity means pursuing the elimination of such health disparities/inequalities.
Molecular Footprints of Neurotoxic Amphetamine Action

Methamphetamine (METH) and 3,4‐methylenedioxymethamphetamine (MDMA or Ecstasy) are amphetamine analogs with high abuse potential. These drugs also cause damage to dopamine and serotonin nerve terminals in vivo. The mechanisms by which these drugs cause neurotoxicity are not known, but a great deal of attention has been focused on reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of this toxicity. ROS and RNS have very short biological half‐lives in vivo, and it is virtually impossible to measure them in brain directly. However, ROS and RNS are also characterized by their extreme reactivity with proteins and nucleotides. Tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH), the initial and rate limiting enzymes in the synthesis of serotonin and dopamine, respectively, are identified targets for the actions of METH and MDMA. Using recombinant forms of these proteins, we have found that nitric oxide, catechol‐quinones, and peroxynitrite, all of which are potentially produced by the neurotoxic amphetamines, covalently modify both TPH and TH. The ROS and RNS cause reductions in catalytic function of these enzymes in a manner that is consistent with the effects of METH and MDMA in vivo. Protein‐bound ROS or RNS may serve as molecular footprints of neurotoxic amphetamine action.
Intracerebral transplantation of mesenchymal stem cells derived from human umbilical cord blood alleviates hypoxic ischemic brain injury in rat neonates

Abstract Aims: Fetal hypoxic-ischemic brain injury (HIBI) is a severe condition for which no effective therapy exists. In this study mesenchymal stem cells (MSCs) from human umbilical cord blood (UCB) of full-term newborns were isolated and intracerebrally transplanted into rat neonates after HIBI induction. Nerve function was assessed by the modified neurological severity scores (mNSS) to establish if MSCs could alleviate nerve injury. Results: Immunostaining showed the transplanted MSCs migrated to the hippocampus. Rats receiving MSCs treatment showed significant improvement in the mNSS when compared with controls. Also, histochemical study showed alleviation of brain tissue injury after MSCs treatment. Differentiation of MSCs to astrocytes, but not neurons, was observed. Conclusions: The results indicate a beneficial effect of intracerebral transplantation of MSCs on the functional recovery of rat neonates with HIBI.
Phosphorylation of Human Retinoid X Receptor α at Serine 260 Impairs Its Subcellular Localization, Receptor Interaction, Nuclear Mobility, and 1α,25-Dihydroxyvitamin D3-dependent DNA Binding in Ras-transformed Keratinocytes*

Human retinoid X receptor α (hRXRα) plays a critical role in DNA binding and transcriptional activity through heterodimeric association with several members of the nuclear receptor superfamily, including the human vitamin D receptor (hVDR). We previously showed that hRXRα phosphorylation at serine 260 through the Ras-Raf-MAPK ERK1/2 activation is responsible for resistance to the growth inhibitory effects of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), the biologically active metabolite of vitamin D3. To further investigate the mechanism of this resistance, we studied intranuclear dynamics of hVDR and hRXRα-tagged constructs in living cells together with endogenous and tagged protein in fixed cells. We find that hVDR-, hRXRα-, and hVDR-hRXRα complex accumulate in the nucleus in 1α,25(OH)2D3-treated HPK1A cells but to a lesser extent in HPK1ARas-treated cells. Also, by using fluorescence resonance energy transfer (FRET), we demonstrate increased interaction of the hVDR-hRXRα complex in 1α,25(OH)2D3-treated HPK1A but not HPK1ARas cells. In HPK1ARas cells, 1α,25(OH)2D3-induced nuclear localization and interaction of hRXRα are restored when cells are treated with the MEK1/2 inhibitor UO126 or following transfection of the non-phosphorylatable hRXRα Ala-260 mutant. Finally, we demonstrate using fluorescence loss in photobleaching and quantitative co-localization with chromatin that RXR immobilization and co-localization with chromatin are significantly increased in 1α,25(OH)2D3-treated HPK1ARas cells transfected with the non-phosphorylatable hRXRα Ala-260 mutant. This suggests that hRXRα phosphorylation significantly disrupts its nuclear localization, interaction with VDR, intra-nuclear trafficking, and binding to chromatin of the hVDR-hRXR complex.