Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanism of mammalian soluble epoxide hydrolase inhibition by chalcone oxide derivatives.

A series of substituted chalcone oxides (1,3-diphenyl-2-oxiranyl propanones) and structural analogs was synthesized to investigate the mechanism by which they inhibit soluble epoxide hydrolases (sEH). The inhibitor potency and inhibition kinetics were evaluated using both murine and human recombinant sEH. Inhibition kinetics were well described by the kinetic models of A. R. Main (1982, in Introduction to Biochemical Toxicology, pp. 193-223, Elsevier, New York) supporting the formation of a covalent enzyme-inhibitor intermediate with a half-life inversely proportional to inhibitor potency. Structure-activity relationships describe active-site steric constraints and support a mechanism of inhibition consistent with the electronic stabilization of the covalent enzyme-inhibitor intermediate. The electronic effects induced by altering the ketone functionality and the para-substitution of the phenyl attached to the epoxy C1 (i.e., the alpha-carbon) had the greatest influence on inhibitor potency. The direction of the observed influence was reversed for the inhibitory potency of glycidol (1-phenyl-2-oxiranylpropanol) derivatives. Recent insights into the mechanism of epoxide hydrolase activity are combined with these experimental results to support a proposed mechanism of sEH inhibition by chalcone oxides.
[Efficacy of Glidescope video laryngoscope in difficult airways: a meta-analysis of randomized controlled trials].

BACKGROUND Increased evidence indicates that the Glidescope video laryngoscope (GVL) is useful for difficult tracheal intubations. The aim of this meta-analysis was to assess the efficacy of the GVL in difficult tracheal intubations, comparing with that of Macintosh laryngoscopy. METHODS The systematic search, data extraction, critical appraisal, and pooled analysis were performed according to the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated by the Comprehensive Meta-analysis version 2.2. 040 software for dichotomous and continuous outcomes, respectively. RESULTS Fifteen randomized controlled trials including 860 tracheal intubations by GVL and 860 tracheal intubations by Macintosh laryngoscopy. GVL showed higher success rate (RR 1.065, 95% CI 1.017-1.117, P < 0.008) than does the Macintosh laryngoscope, whereas no difference was found in the duration for instrumentation. CONCLUSIONS Our meta-analysis showed that GVL has an advantage over Macintosh laryngoscope in respect to the success rate for difficult tracheal intubations.
The paradigm of personalized therapy in oncology

Introduction: Currently, anticancer therapy is mainly based on histology and on giving the same treatment to presumed homogeneous patients. The switch from histology-driven therapy to molecular clinical oncology is correlated with a better understanding of the ‘molecular taxonomy’ of each tumor that can provide us with targets for specific drugs. Cancer therapy is moving irreversibly towards personalized therapy that benefits selected patients. Once the potential therapeutic targets are identified, the availability of predictive biomarkers is the key element and their prospective evaluation should be a parallel component of the clinical evaluation of a new drug. Areas covered: The state of the art in clinical results of personalized therapy. The authors discuss the finding that, in patients with advanced disease, a limited number of targeted agents improve overall survival, whilst the majority only have an effect on response rate and/or time to tumor progression, with efficacy limited in time due to acquired resistance. Expert opinion: The mechanisms leading to resistance are related to tumor cell heterogeneity and in part explained by the cancer stem cell model and genetic instability. The steps toward the optimization of tailored therapy need validated predictive biomarkers, pharmacogenetics analysis and a close collaboration between bench and bedside.
A reappraisal of the role of abscisic acid and its interaction with auxin in apical dominance.

BACKGROUND AND AIMS Evidence from pea rms1, Arabidopsis max4 and petunia dad1 mutant studies suggest an unidentified carotenoid-derived/plastid-produced branching inhibitor which moves acropetally from the roots to the shoots and interacts with auxin in the control of apical dominance. Since the plant hormone, abscisic acid (ABA), known to inhibit some growth processes, is also carotenoid derived/plastid produced, and because there has been indirect evidence for its involvement with branching, a re-examination of the role of ABA in apical dominance is timely. Even though it has been determined that ABA probably is not the second messenger for auxin in apical dominance and is not the above-mentioned unidentified branching inhibitor, the similarity of their derivation suggests possible relationships and/or interactions. METHODS The classic Thimann-Skoog auxin replacement test for apical dominance with auxin [0.5 % naphthalene acetic acid (NAA)] applied both apically and basally was combined in similar treatments with 1 % ABA in Ipomoea nil (Japanese Morning Glory), Solanum lycopersicum (Better Boy tomato) and Helianthus annuus (Mammoth Grey-striped Sunflower). KEY RESULTS Auxin, apically applied to the cut stem surface of decapitated shoots, strongly restored apical dominance in all three species, whereas the similar treatment with ABA did not. However, when ABA was applied basally, i.e. below the lateral bud of interest, there was a significant moderate repression of its outgrowth in Ipomoea and Solanum. There was also some additive repression when apical auxin and basal ABA treatments were combined in Ipomoea. CONCLUSION The finding that basally applied ABA is able partially to restore apical dominance via acropetal transport up the shoot suggests possible interactions between ABA, auxin and the unidentified carotenoid-derived branching inhibitor that justify further investigation.
Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation

Summary Activated platelets participate in arterial thrombosis by forming aggregates and potentiating the coagulation through exposure of procoagulant phosphatidylserine. The function of the two receptors for ADP, P2Y1 and P2Y12, is well-established in aggregation, but is incompletely understood in the platelet procoagulant response. We established that, in PRP from healthy subjects, ADP accelerated and potentiated tissue factor-induced throm-bin generation exclusively via stimulation of P2Y12 and not via P2Y1 receptors. The P2Y12 receptors also mediated the potentiating effect of PAR-1 stimulation on thrombin generation. Furthermore, ADP enhanced in a P2Y12-dependent manner the Ca2+ response induced by thrombin, which was either added externally or generated in-situ. This ADP effect was in part dependent of phosphoinositide 3-kinase and was paralleled by increased phosphatidylserine exposure. In PRP from (young) patients with either stroke or type-II diabetes, platelet-dependent thrombin generation was similarly enhanced by ADP or SFLLRN as in healthy subjects. In PRP from stroke patients of older age, the P2Y12-mediated contribution to thrombin generation was variably reduced by two weeks of clopidogrel medication. Remaining P2Y12 activity after medication correlated with remaining P2Y12-dependent P-selectin exposure, i.e. Ca2+-dependent secretion, likely due to incomplete antagonism of P2Y12 receptors. Together, these results indicate that physiological platelet agonists amplify phosphatidylserine exposure and subsequent thrombin generation by release of ADP and P2Y12-receptor stimulation. This P2Y12 response is accomplished by a novel Ca2+ signalling pathway. It is similarly active in platelets from control subjects and patients at thrombotic risk. Finally, the thrombo-gram method is useful for measuring incomplete P2Y12 inhibition with clopidogrel.
The Fontan procedure in adults

SETTING Tertiary adult congenital cardiac referral centre. DESIGN Retrospective cross sectional analysis. OBJECTIVES To report our 20 year experience with adult Fontan operations, and to compare late outcome in patients with single ventricle with definitive aortopulmonary or cavopulmonary shunt palliation. PATIENTS AND MAIN OUTCOME MEASURES Patients older than 18 years undergoing Fontan operation between 1 January 1982 and 31 December 1998 were identified. Mortality and late outcome were derived from hospital records. These patients were compared with a cohort of 50 adults with single ventricle who had not undergone a Fontan operation. RESULTS 61 adults, median age 36 years (range 18–47 years), with a median follow up of 10 years (range 0–21 years) were identified. Actuarial survival was 80% at one year, 76% at five years, 72% at 10 years, and 67% at 15 years. Compared with before the Fontan operation, more patients were in New York Heart Association (NYHA) functional class I or II at the latest follow up (80% v 58%, p < 0.001). Systolic ventricular function deteriorated during follow up such that 34% had moderate to severe ventricular dysfunction at the latest follow up compared with 5% before Fontan (p < 0.001). Arrhythmia increased with time (10% before Fontan v 57% after 10 years, p < 0.001). Fontan patients had improved NYHA functional class, ventricular function, atrioventricular regurgitation, and fewer arrhythmias than the non-Fontan group at the latest follow up. CONCLUSION The Fontan operation in adults has acceptable early and late mortality. Functional class, systolic ventricular function, atrioventricular regurgitation, and arrhythmia deteriorate late after surgery but to a lesser degree than in non-Fontan patients with a single ventricle.
Aerobic exercise in muscular dystrophy

One of the first questions patients and families ask when diagnosed with a neuromuscular disorder is “Will exercise help or hurt? ” This query is understandable given the multiple historical examples of exercise overcoming weakness and building strength, dating back to Milo of Croton in the 6th century, who practiced the progressive resistance of lifting his growing bull calf, up through more contemporary media proponents as Charles Atlas, Jane Fonda, and Tony Horton in the ubiquitous P90X infomercials. Until recently, however, definitive answers to this query have been elusive, with little hard data on which to base advice. Traditionally, patients with peripheral nerve and muscle disorders were often advised to reduce their physical activity in order to preserve their limited motor function for activities of daily living. Patients with acute radiculopathies, for example, were often admitted to inpatient services for extended bed rest as standard treatment.
Hydrothermal Synthesis of Nanooctahedra MnFe2O4 onto the Wood Surface with Soft Magnetism, Fire Resistance and Electromagnetic Wave Absorption

In this study, nanooctahedra MnFe2O4 were successfully deposited on a wood surface via a low hydrothermal treatment by hydrogen bonding interactions. As-prepared MnFe2O4/wood composite (MW) had superior performance of soft magnetism, fire resistance and electromagnetic wave absorption. Among them, small hysteresis loops and low coercivity (<±5 Oe) were observed in the magnetization-field curve of MW with saturation magnetization of 28.24 emu/g, indicating its excellent soft magnetism. The MW also exhibited a good fire-resistant property due to its initial burning time at 20 s; while only 6 s for the untreated wood (UW) in combustion experiments. Additionally, this composite revealed good electromagnetic wave absorption with a minimum reflection loss of −9.3 dB at 16.48 GHz. Therefore, the MW has great potential in the fields of special decoration and indoor electromagnetic wave absorbers.
Synchrotron radiation spectroscopy studies of ultrathin chromium films on titanium dioxide

We investigate the initial interaction of chromium in the sub-ML and ML regime with the surface of titanium dioxide. The reaction at the interface, in which TiO2 is reduced and forms TiO2-x, is monitored by electron spectroscopy. This reaction is reflected by appearance of Ti3+ state. Two chromium components are found already in the first step of growth. One component is assigned to Cr in the 3+ oxidation state, while the other one is assigned to metallic Cr. The reaction at the interface is also reflected by the appearance of two band gap states with a well defined character. With increasing overlayer thickness, the band gap emission develops to that of metallic Cr, but the properties are not bulk-like.
Intersectin 1 Enhances Cbl Ubiquitylation of Epidermal Growth Factor Receptor through Regulation of Sprouty2-Cbl Interaction

ABSTRACT Ubiquitylation of receptor tyrosine kinases plays a critical role in regulating the trafficking and lysosomal degradation of these important signaling molecules. We identified the multidomain scaffolding protein intersectin 1 (ITSN1) as an important regulator of this process (N. P. Martin et al., Mol. Pharmacol. 70:1463–1653, 2006) ITSN1 stimulates ubiquitylation of the epidermal growth factor receptor (EGFR) through enhancing the activity of the Cbl E3 ubiquitin ligase. However, the precise mechanism through which ITSN1 enhances Cbl activity was unclear. In this study, we found that ITSN1 enhances Cbl activity through disrupting the interaction of Cbl with the Sprouty2 (Spry2) inhibitory protein. We demonstrate that ITSN1 binds Pro-rich regions in both Cbl and Spry2 and that interaction of ITSN1 with Spry2 disrupts Spry2-Cbl interaction, resulting in enhanced ubiquitylation of the EGFR. Disruption of ITSN1 binding to Spry2 through point mutation of the Pro-rich ITSN1 binding site in Spry2 results in enhanced Cbl-Spry2 interaction and inhibition of receptor ubiquitylation. This study demonstrates that ITSN1 enhances Cbl activity by modulating the interaction of Cbl with Spry2. In addition, our results reveal a new level of complexity in the regulation of Cbl through the interaction with ITSN1 and Spry2.
Chemotherapy-Induced Nausea and Vomiting in Italian Cancer Centers: Results of CINVDAY, a Prospective, Multicenter Study

Purpose Guideline consistency in the prevention of chemotherapy-induced nausea and vomiting (CINV) remains low (29% in the Pan European Emesis Registry study) and very low (11%) in regimens with a high emetogenic risk. The aim of this study was to evaluate the guideline consistency of CINV prophylaxis for acute emesis in daily clinical practice in Italy. Methods This was a prospective, observational, multicenter study. Patients scheduled to receive antitumor treatment on a single prespecified day were included. Data on patient characteristics (demographic and clinical), type of anticancer therapy, and type of antiemetic therapy prescribed for acute emesis were collected on electronic data capture forms. Chemotherapy regimens and antiemetic prophylaxis were categorized according to the MASCC 2011 guidelines. The study was approved by the local ethics committees. Results From July 2013 to February 2014, a total of 502 patients were enrolled at 26 study sites. Median age was 62 years (range 27–87 years). Colorectal cancer and breast cancer were the most common malignancies. The emetogenic potential of the chemotherapy regimens used was high (HEC) (23.7%), moderate (MEC) (40.6%), low (31.3%) or minimal (4.4%). Overall, guideline consistency was 19.3%. Consistency reached 45% when the various 5HT3 receptor antagonists were considered equivalent and interchangeable in MEC regimens. Adherence to guidelines was lowest for MEC and MINIMAL risk groups. Ten percent of patients in HEC and MEC regimens did not receive any 5HT3 receptor antagonists. NK1 receptor antagonists were used in 8% of all regimens. Conclusions Our study indicates that antiemetic guideline inconsistency remains an issue in daily clinical oncology practice in Italy.
Assessment of lead, cadmium and mercury in seafood marketed in Puglia and Basilicata (Italy) by inductively coupled plasma mass spectrometry

Lead, cadmium and mercury are non-essential heavy metals that may interfere with biological systems, exhibiting high toxicity to human and marine biota. Due to bioaccumulation of heavy metals in the food chain, seafood may concentrate high levels of these contaminants since they are often at the top of aquatic food chain. In this study, 342 seafood samples, subdivided into four categories (bivalve molluscs, cephalopod molluscs, blue-fish and other sea fish), were analysed by inductively coupled plasma mass spectrometry, in order to assess the levels of lead, cadmium and mercury. Contamination levels higher than allowable limits were verified. In particular, two bivalve mollusc samples were non-compliant for lead and cadmium, four cephalopod mollusc samples non-compliant for cadmium and 14 samples (4 blue-fish and 10 other sea fish) non-compliant for mercury. This survey confirmed the necessity to perform routinely controls related to this type of food inspection.
Intrahepatic cholestasis of pregnancy

Obstetric cholestasis is also known as intrahepatic cholestasis of pregnancy (ICP). ICP affects approximately 0.7% of pregnant women in the UK, equating to approximately 6000 women per year. Pruritus, elevated liver enzymes and raised serum bile acids are key to the diagnosis of ICP. There is an increased risk of adverse perinatal outcomes associated with severe ICP, including spontaneous preterm birth, meconium staining of the amniotic fluid and stillbirth. ICP may be treated with ursodeoxycholic acid (UDCA), with some improvement in serum biochemistry and pruritus; however, the impact on the fetus is uncertain.
Macugen (Pegaptanib Sodium), a Novel Ocular Therapeutic That Targets Vascular Endothelial Growth Factor (VEGF)

The development of Macugen (pegaptanib sodium), a pegylated antivascular endothelial growth factor (VEGF) RNA aptamer, represents an exciting new chapter in the management of ocular neovascular disease in that this novel therapeutic targets a key step in the pathogenesis of ocular neovascularization. Based on 2 prospective, multicenter, randomized, controlled, phase 3 trials collectively known as the VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N) trials, pegaptanib was the first ophthalmic antiangiogenic agent approved for the treatment of all angiographic subtypes of neovascular age-related macular degeneration (AMD). In addition, recent studies show promise for pegaptanib in the treatment of diabetic macular edema (DME) and macular edema secondary to central retinal vein occlusion (CRVO). Historically, therapies for ocular neovascular diseases have largely been ineffective, although the advent of photocoagulation and photodynamic therapy (PDT) with verteporfin provided limited options for some subsets of patients. Unlike pegaptanib, however, these destructive therapies do not address the underlying pathology of these diseases. This article will provide a brief overview of the pathogenesis of ocular neovascularization, with particular emphasis on the prominent contribution of VEGF165, and the rationale for targeting this presumed pathogenic isoform in contrast to approaches that provide nonselective isoform blockade and its possible additional safety concerns. The preclinical and clinical studies supporting the efficacy and safety of pegaptanib will then be discussed.
Perception of place of articulation in English fricatives by Spanish listeners

espanolEstablecer diferencias entre fonemas que no son funcionalmente distintivos en la lengua materna es una tarea ardua para oyentes no nativos. En el presente trabajo se exponen los resultados del experimento que se llevo a cabo con el fin de investigar la percepcion de contrastes no nativos por parte de 26 oyentes hispanohablantes, que se utilizaron como informantes. Un grupo de hablantes ingleses sirvio como el grupo de control. Los oyentes fueron expuestos al contraste ingles /s/ vs /∫/, que no es fonemico en espanol, en dos palabras sintentizadas, Sue y shoe. Los resultados mostraron que un gran numero de oyentes habian adquirido el contraste; ademas, se apreciaron diferencias en el uso de ciertos indices acusticos que senalaban el contraste, causadas por la influencia de la L1. Asimismo, los resultados no tuvieron correlacion ni con la edad ni el tiempo de aprendizaje de la L2, ni la edad del participante EnglishDifferentiating speech contrasts which are not functionally distinctive in the mother tongue is a difficult perceptual task for non-native listeners. A two-fold experiment was carried out in order to investigate the L2 perception by 26 Spanish listeners of English, with an English group used as a control. In the first part of the study, listeners were exposed to the English contrast /s/ vs. /∫/, which is not phonemic in Spanish, in two synthesized words, Sue and shoe. The results showed that a great number of listeners had already acquired the contrast and the existence of languagespecific differences in the use of some of the acoustic cues that signalled this contrast. Furthermore there was no correlation between the results obtained and the variables age of L2 learning, length of L2 learning, or listener’s age. The second part of the experiment, based on voicing differences, will be shown in a subsequent paper
Vascular Access Type and Changes in Infammatory Markers in Incident Dialysis Patients: A Pilot Study

Purpose To determine the association between the initial hemodialysis (HD) vascular access type and short-term changes in inflammation markers. Methods This is a prospective, observational study in incident chronic kidney disease (CKD) (stages 4 and 5) patients receiving their first HD vascular access. Serum samples were obtained pre-access placement, and 1 week, and 1 month post-access insertion. Samples were tested for high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) using ELISA. Patients with known inflammatory states (infection, malignancy, connective tissue disorders, organ transplantation and those on immune modulating agents) were excluded. The hsCRP and IL-6 values were transformed into logarithmic scale. Chi-square analysis, independent and paired t-tests were performed where appropriate, and a two-way ANOVA with time as a repeated measure was also performed. Significance was determined at p=0.05. Results One-month follow-up data was obtained in 48 patients (arteriovenous fistula (AVF), n=10; tunneled catheter (TC), n=28; arteriovenous graft (AVG), n=10). A significant increase in both hsCRP (p<0.05) and IL-6 (p=0.02) occurring 1 week after TC insertion was observed. Elevation of the IL-6 levels appeared to be sustained 1 month after TC insertion, although this finding was not statistically significant (p=0.68), whereas the hsCRP levels returned to baseline within 1 month. After AVG insertion only the hsCRP levels rose significantly (p=0.01) after 1 week and returned to baseline within 1 month. In the AVF group, inflammatory markers did not change for any time period. Conclusions In CKD patients, TC and AVG insertion result in a transient state of inflammation 1 week post-operatively, which is not observed after AVF surgery. Whether this is a persistent phenomenon after TC insertion requires a larger, longitudinal study.