Miracle-dz/UniFAR-FTUs huggingface dataset:
The orphan nuclear receptor DAX1 is up‐regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors

The Ewing family of tumors harbors chromosomal translocations that join the N‐terminal region of the EWS gene with the C‐terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up‐regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up‐regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up‐regulation of DAX1 expression. © 2005 Wiley‐Liss, Inc.
Building Capability for Organizational Success: An Emerging Market Perspective

ABSTRACT In the world of business, developing the capability to succeed in the marketplace is a sine qua non for most organizations. An examination of studies on firm competitiveness indicates that market orientation, outsourcing, and technology transfer provide firms with the basis for building capability to succeed in the business environment. Nonetheless, in a developing nation context, the comparative influences of market orientation, outsourcing, and technology transfer on organizational success among foreign and local firms when considered together in a combined framework is yet to be investigated empirically. To gain clearer insights, three pathways through which market orientation, outsourcing, and technology transfer improve organizational success in Ghana are postulated. Findings of this study suggest that among foreign and Ghanaian businesses, there are variations in the contributions of market orientation, outsourcing, and technology transfer to developing capability and impacting on organizational success.
Mechanisms of resistance to fungicides in field strains of Botrytis cinerea.

Field strains of Botrytis cinerea Pers ex Fr, the causal agent of grey mould diseases, were collected from French vineyards between 1993 and 2000. Several phenotypes have been characterized according to the inhibitory effects of fungicides towards germ-tube elongation and mycelial growth. Two types of benzimidazole-resistant strains (Ben R1 and Ben R2) could be detected; negative cross-resistance to phenylcarbamates (e.g. diethofencarb) was only found in Ben R1. Benzimidazole resistance was related to point mutations at codon 198 (Ben R1) or 200 (Ben R2) of the beta-tubulin gene. Most dicarboximide-resistant strains were also weakly resistant to aromatic hydrocarbon fungicides (e.g. dicloran) but remained sensitive to phenylpyrroles (e.g. fludioxonil). These resistant field strains (Imi R1) contained a single base pair mutation at position 365 in a two-component histidine kinase gene, probably involved in the fungal osmoregulation. Three anilinopyrimidine-resistant phenotypes have been identified. In the most resistant one (Ani R1), resistance was restricted to anilinopyrimidines, but no differences were observed in the amino-acid sequences of cystathionine beta-lyase (the potential target site of these fungicides) from Ani R1 or wild-type strains. In the two other phenotypes (Ani R2 and Ani R3), resistance extended to various other groups of fungicide, including dicarboximides, phenylpyrroles and sterol biosynthesis inhibitors. This multi-drug resistance was probably determined by over-production of ATP-binding cassette transporters. The hydroxyanilide fenhexamid is a novel botryticide whose primary target site is the 3-keto reductase involved in sterol C-4 demethylations. Apart from the multi-drug-resistant strain Ani R3, three other fenhexamid-resistant phenotypes have been recognized. For two of them (Hyd R1 and Hyd R2) fenhexamid-resistance seemed to result from P450-mediated detoxification. Reduced sensitivity of the target site could be the putative resistance mechanism operating in the third resistant phenotype (Hyd R3). Increased sensitivity to inhibitors of sterol 14 alpha-demethylase recorded in Hyd R1 strains was related to two amino-acid changes at positions 15 and 105 of this enzyme.
Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?

Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the α (spasmodic, oscillator, cincinnati, Nmf11) or the β (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABAA receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.
Personalized Attraction Recommendation System for Tourists Through Check-In Data

Online social networks now play a prominent role in our daily lives and our decisions and behaviors in many areas. Of particular interest here is the application of social network data to give users access to tourist information. There is a growing need for information on tourism and tourist activities to satisfy user queries in this domain. Social networks, such as Facebook, Twitter, and Foursquare, among others, store substantial volumes of check-in data, which are a valuable resource for recommending tourism attractions. However, using Facebook check-in data has rarely been considered in conventional recommendation systems (RSs). This presents not only a new research challenge for the computer science and information technology fields but also an interesting opportunity for the tourism industry: knowing what kind of attractions tourists are interested in and how to acquire their user preferences without adding tasks to users of an RS. We propose a tourism RS that is based on its recommendations on data dynamically aggregated and extrapolated from the Facebook check-in data. In addition, the so-called “cold-start” problem has been resolved by using users’ Friends’ check-in data to analyze ongoing Facebook activity and update user profiles in the system. Most Facebook users have a well-extended list of Friends. Consequently, the proposed system can dynamically learn user behavior and appropriately adapt recommendations. This paper demonstrate the usefulness of the data available on Facebook through the example studies involving attraction recommendations, resolving the cold-start problem, and adapting the user model to improve recommendation quality in the tourism domain.
Carotid baroreflex responsiveness to head‐up tilt‐induced central hypovolaemia: effect of aerobic fitness

This investigation examined the interaction between carotid baroreflex (CBR) responsiveness during head‐up tilt (HUT)‐induced central hypovolaemia and aerobic fitness. Seven average fit (AF) individuals, with a mean maximal oxygen uptake (V̇O2max) of 49 ± 1 (ml O2) kg−1min−1, and seven high fit (HF) individuals, with a V̇O2max of 61 ± 1 (ml O2) kg−1 min−1, voluntarily participated in the investigation. After 10‐15 min supine, each subject was exposed to nine levels of progressively increasing HUT by 10 deg increments from −20 deg to +60 deg. During the final 3 min of each stage of HUT, the CBR responsiveness was measured using a rapid pulse (500 ms) train of neck pressure (NP) and neck suction (NS) ranging from +40 to −80 Torr. The maximal gain of the carotid‐HR (Gmax‐HR) and carotid‐MAP (Gmax‐MAP) baroreflex function curves was identified as measures of CBR responsiveness. During HUT‐induced decreases in thoracic admittance, an index of central blood volume (CBV), the Gmax‐HR and Gmax‐MAP of the AF subjects increased more than the Gmax‐HR and Gmax‐MAP of the HF subjects (P < 0.05). The data demonstrate that the increase in the CBR responsiveness during a tilt‐induced progressive unloading of the cardiopulmonary baroreceptors was attenuated in endurance‐trained subjects. These findings provide an explanation for the predisposition to orthostatic hypotension and intolerance in well‐trained athletes.
The Impact of Visual Aids and Enhanced Training on the Delivery of Positive Health, Dignity, and Prevention Messages to Adult Patients Living with HIV in Rural North Central Mozambique

Introduction Positive health, dignity, and prevention (PHDP) interventions target people living with HIV and AIDS (PLHIV) to promote well-being and prevent onward transmission. Concern that increased life expectancy and improved well-being would lead to increased risky sexual behaviour and subsequent HIV transmission motivated researchers to test novel strategies to support treatment adherence, encourage safer sex, STI treatment and partner testing, prevention of mother to child transmission, and support uptake of family planning. Methods We assessed the number and type of PHDP messages delivered to PLHIV before and after the implementation of an educational intervention for health providers combined with the distribution of visual job aids and monthly technical assistance. Results From April 21, 2013 to March 20, 2014, we documented 54,731 clinical encounters at three rural health centres in Zambézia province, Mozambique from 9,248 unique patients. The percentage of patients who received all seven PHDP messages during their last three visits was 1.9% pre-intervention vs. 13.6% post- intervention (p=<0.001). Younger patients (25 years vs. 35) and those with a recent HIV diagnosis (two weeks vs. two years) had higher odds of receiving any PHDP message (Odds Ratio [OR]: 1.22 and 2.79, respectively). Patients >59 days late collecting medications were not more likely to receive adherence messages than adherent patients (p=0.17). Discussion Targeting HIV prevention efforts to PLHIV is an effective HIV prevention approach to eliminate HIV transmission. Despite intensive training and support, PHDP message delivery remained unacceptably low in rural Mozambique. Patients at high risk for treatment abandonment were not more likely to be counselled about adherence and support measures, something that needs to be addressed. Conclusions We need to develop novel strategies to motivate health care providers to deliver these messages more consistently to all patients and develop a system that assists counsellors and clinicians to quickly and effectively determine which messages should be delivered.
The impact of ACE inhibition on all-cause and cardiovascular mortality in contemporary hypertension trials: a review

The renin–angiotensin–aldosterone system is a key therapeutic target in hypertension. The latest meta-analysis of mortality reduction with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in hypertension features 158,998 patients from 20 contemporary hypertension trials. ACE inhibitors and ARBs significantly reduced relative risk for all-cause mortality by 5% (p = 0.032) and cardiovascular mortality by 7% (p = 0.018) in populations with a high prevalence of hypertension (≥66%). ACE inhibitors produced a 10% reduction in relative risk for all-cause mortality (p = 0.004) and a trend toward a 12% reduction in cardiovascular mortality (p = 0.051), whereas ARBs had no effect. On balance, mortality evidence suggests that in hypertension, ACE inhibitors should be considered ahead of ARBs, and ARBs restricted to patients intolerant of ACE inhibitors.
Associations among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index

Objective: The purpose of this study was to characterize the relationships among plasma adiponectin, essential hypertension, left ventricular diastolic function and left ventricular hypertrophy. Methods and Results: Plasma adiponectin concentration was assessed by radioimmunoassay, and body mass index (BMI) was measured in 275 patients (138 women and 137 men). Various echocardiographic parameters such as deceleration time (DT) and isovolumetric relaxation time (IVRT) were measured by using echocardiograms. The authors calculated left ventricular mass index (LVMI) and E/A ratio. Pulse wave velocity (PWV) was calculated by dividing the distance between the left subclavian artery ostium and the tip of the femoral sheath with the time interval between two pulse waves. The plasma adiponectin concentration of the hypertensive group was significantly lower than that of the non‐hypertensive group (9.9 ± 9.8 μg/ml vs. 12.9 ± 9.5 μg/ml, p = 0.019). PWV in the hypertensive group was 12.0 ± 3.9 m/s compared with 9.3 ± 2.8 m/s in the normotensive group (p < 0.001). LVMI in the hypertensive group was 135.1 ± 35.4 g/m 2 compared with 100.5 ± 18.7 g/m 2 in the normotensive group (p < 0.001). E/A ratio (0.8 ± 0.3 vs. 1.1 ± 0.4, p = 0.041) was lower in the hypertensive group. DT (200.0 ± 61.2 ms vs. 177.3 ± 40.8 ms, p = 0.048) and IVRT (106.9 ± 25.4 vs. 91.3 ± 27.6 ms, p = 0.243) were higher in the hypertensive group. Plasma adiponectin showed an inverse correlation with LVMI (r = −0.525; p < 0.001) and PWV (r = −0.557; p < 0.001), IVRT (r = −0.485; p = 0.008), and showed a positive correlation with E/A ratio (r = 0.359; p < 0.001). Multiple regression analyses showed that PWV and plasma adiponectin were able to explain the 73.3% of LVMI variability (r = 0.856; p < 0.001). Conclusion: The results suggest that a decrease in plasma adiponectin concentration is associated with the progression of left ventricular hypertrophy with diastolic dysfunction.
Increased Fat Mass and Cardiac Septal Hypertrophy in Newborn Infants of Mothers with Well-Controlled Diabetes during Pregnancy

Background: Improved glycaemic control during pregnancy in mothers with type 1 diabetes (T1DM) and gestational diabetes (GDM) has resulted in a marked reduction of perinatal mortality and morbidity, but the prevalence of macrosomia is usually high. Objective: We used non-invasive anthropometric methods to estimate the body composition and the thickness of the interventricular heart septum in 18 infants of mothers with well-controlled T1DM, 10 infants of mothers with GDM and 28 infants of healthy control mothers matched for gestational age and mode of delivery. Methods: Skinfold measurements were obtained with a Harpenden calliper within 48 h after delivery. Echocardiography was also performed to measure the thickness of the interventricular septum. Cord blood was sampled for assays of C-peptide, leptin and IGF-I. Results: The rates of macrosomia (gestational age-adjusted birth weight >2 standard deviation score, SDS) were 56 and 30% in infants of mothers with T1DM and GDM, respectively, compared to 10% in control infants. The body fat content was 40% (0.2 kg) higher and the interventricular heart septum thickness was increased by 20% in both groups of infants of diabetic mothers. We found no associations between maternal levels of HbA1c during pregnancy and body composition or interventricular heart septum thickness. Cord levels of C-peptide and leptin were significantly higher in infants of T1DM mothers than in control infants. Cord leptin level was associated with birth weight SDS and percent body fat in infants of T1DM mothers. IGF-I was associated with percent body fat in infants of GDM mothers and control mothers. A multiple-regression analysis showed that 50% of the variation in body weight SDS could be determined, with IGF-I, leptin and C-peptide as independent variables. Conclusion: Both fat mass and cardiac septal thickness are increased in newborn infants of women with T1DM and GDM in spite of efforts to achieve good glycaemic control during pregnancy.
A general approach to site-specific antibody drug conjugates

Significance Here we demonstrate the ability to genetically incorporate nonnative amino acids into proteins in mammalian cells using both transient and stable platform expression systems that provide yields and fidelities compatible with commercial applications. To illustrate the utility of this methodology we have generated chemically homogeneous antibody drug conjugates (NDCs) with precise control over the site and stoichiometry of drug conjugation. In rodent xenograft models these NDCs display improved properties, including half-life, efficacy and safety, relative to conventional heterogeneous ADCs. These advances allow the generation of therapeutic antibody drug conjugates with medicinal chemistry like control over structure, which should greatly facilitate the optimization of their pharmacological activities. Using an expanded genetic code, antibodies with site-specifically incorporated nonnative amino acids were produced in stable cell lines derived from a CHO cell line with titers over 1 g/L. Using anti-5T4 and anti-Her2 antibodies as model systems, site-specific antibody drug conjugates (NDCs) were produced, via oxime bond formation between ketones on the side chain of the incorporated nonnative amino acid and hydroxylamine functionalized monomethyl auristatin D with either protease-cleavable or noncleavable linkers. When noncleavable linkers were used, these conjugates were highly stable and displayed improved in vitro efficacy as well as in vivo efficacy and pharmacokinetic stability in rodent models relative to conventional antibody drug conjugates conjugated through either engineered surface-exposed or reduced interchain disulfide bond cysteine residues. The advantages of the oxime-bonded, site-specific NDCs were even more apparent when low–antigen-expressing (2+) target cell lines were used in the comparative studies. NDCs generated with protease-cleavable linkers demonstrated that the site of conjugation had a significant impact on the stability of these rationally designed prodrug linkers. In a single-dose rat toxicology study, a site-specific anti-Her2 NDC was well tolerated at dose levels up to 90 mg/kg. These experiments support the notion that chemically defined antibody conjugates can be synthesized in commercially relevant yields and can lead to antibody drug conjugates with improved properties relative to the heterogeneous conjugates formed by nonspecific chemical modification.
Stressors and stress symptoms of mothers with children in the PICU.

The purpose of this study was a description of sources of stress and stress symptoms over time for mothers with a child in the pediatric intensive care unit (PICU) and a comparison with mothers with a child in a general care unit (GCU). The sample contained 31 PICU mothers and 32 GCU mothers who were studied during four time periods over 6 months using the Parental Stressor Scale: PICU and the Symptom Checklist-90-Revised. Findings showed all the PICU mothers were stressed from the total intensive care experience and the use of monitors. PICU mothers experienced more stress symptoms than the GCU mothers did during all four time periods. This is valuable information because nurses should know how mothers of critically ill children feel and what stresses them in order to help the mothers and teach them about what changes to expect in themselves. Nursing practice must enable parents to continue in their family roles to be effective and therapeutic to their children.
On Time for the Future: Student Perspectives of a High School-Community College Dual-Enrollment Program

approved: __________________________________________________________________ Richard A. Settersten Kelly D. Chandler In the current global economy, higher education is critical for gaining and keeping living-wage jobs. The need for a college-educated labor force has increased interest among youth in pursuing higher education (National Center for Education Statistics, 2013). Despite these demands, the United States has struggled to effectively increase college completion rates, particularly among low-income and first-generation college students. Dual-enrollment programs, in which students are concurrently enrolled in high school and college, are one example of education interventions designed to increase college enrollment and completion. Applying life course (Elder, 1998; Settersten, 2007) and possible selves theory (Markus & Nurius, 1986) frameworks, the present study explores how an education intervention program influences rural youth identity development. Specifically, the research questions were: (a) What benefits do students perceive themselves to gain as they participate in dual-enrollment programs? (b) How does the perceived significance of these benefits vary based on socioeconomic status, geography, and gender? Participants in this study (N = 17) were students in a dual-enrollment partnership between a local community college and three area high schools. Via focus groups, students from these high schools were invited to share their experiences as high school students taking classes at their local community college. Particular attention was paid to how youth incorporate the college experience into a vision of a possible self. Students reflected on their motivation for participating in the program, whether and how they perceived it to be a turning point in their lives, and the importance of this opportunity at this particular juncture in life. All students reported that a benefit of the dual-enrollment program was free college tuition, which enabled them to gain knowledge about the expectations and skills associated with being a college student and expand their sense of possible selves for the future. However, the significance of the free college tuition was interpreted differently based on household SES, geography, and gender. Students from low SES households, students from more rural communities, and female students perceived a higher degree of personal gain and increased opportunities for the future based on their participation in the program. The findings from this study may be helpful in informing education interventions to increase college enrollment for underrepresented student groups and in guiding policies to increase the affordability of college for economically vulnerable students. ©Copyright by Terese Jones January 8, 2018 All Rights Reserved On Time for The Future: Student Perspectives of a High School-Community College DualEnrollment Program