Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand, in healthy volunteers

Abstract 1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of 14C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of tozadenant (240 mg containing 81.47 KBq of [14C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection. 3. At 4 h, the Cmax of tozadenant was 1.74 μg/mL and AUC(0–t) 35.0 h μg/mL, t1/2 15 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [14C] radioactivity, the Cmax was 2.29 μg eq/mL at 5 h post-dose and AUC(0–t) 43.9 h μg eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC(0–48h). At 312 h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites. 4. The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.
COCKLE SHELL ASH REPLACEMENT FOR CEMENT AND FILLER IN CONCRETE

The concepts of eco-friendly building are getting more attention today. The use of materials from natural sources is an alternative to the realization of the green building concept. Considering this approach, a study was conducted to investigate the potential of cockle shell ash as a material for partial cement replacement or a filler material. The study was to determine the chemical composition of cockle shell ash and were determined using Fluorescence X-ray analysis. The observation of on the morphology structure based on SEM analysis was also performed. The next phase involved in determining the concrete properties such as compressive strength, tensile, modulus of elasticity, water permeability and porosity made from mixture of cockle shell ash of 5%, 10%, 15%, 25%, 50% and compared to normal concrete cured in ordinary water at the 7, 28, 90 days and up to 120 days for water permeability test. As a result, with the inclusion of 5% and 10% of cockle shell ash, morphology structure seems compacted that effected the strength, modulus of elasticity, permeability and porosity of the concrete.
“I Can Only Work So Hard Before I Burn Out.” A Time Sensitive Conceptual Integration of Ideological Psychological Contract Breach, Work Effort, and Burnout

Employees often draw meaning from personal experiences and contributions in their work, particularly when engaging in organizational activities that align with their personal identity or values. However, recent empirical findings have demonstrated how meaningful work can also have a negative effect on employee’s well-being as employees feel so invested in their work, they push themselves beyond their limits resulting in strain and susceptibility to burnout. We develop a framework to understand this “double edged” role of meaningful work by drawing from ideological psychological contracts (iPCs), which are characterized by employees and their employer who are working to contribute to a shared ideology or set of values. Limited iPC research has demonstrated employees may actually work harder in response to an iPC breach. In light of these counterintuitive findings, we propose the following conceptual model to theoretically connect our understanding of iPCs, perceptions of breach, increases in work effort, and the potential “dark side” of repeated occurrences of iPC breach. We argue that time plays a central role in the unfolding process of employees’ reactions to iPC breach over time. Further, we propose how perceptions of iPC breach relate to strain and, eventually, burnout. This model contributes to our understanding of the role of time in iPC development and maintenance, expands our exploration of ideology in the PC literature, and provides a framework to understanding why certain occupations are more susceptible to instances of strain and burnout. This framework has the potential to guide future employment interventions in ideology-infused organizations to help mitigate negative employee outcomes.
Comparison of switching bipolar ablation with multiple cooled wet electrodes and switching monopolar ablation with separable clustered electrode in treatment of small hepatocellular carcinoma: A randomized controlled trial

Objective A randomized controlled trial was conducted to prospectively compare the therapeutic effectiveness of switching bipolar (SB) radiofrequency ablation (RFA) using cooled-wet electrodes and switching monopolar (SM) RFA using separable clustered (SC) electrodes in patients with hepatocellular carcinomas (HCCs). Materials and methods This prospective study was approved by our Institutional Review Board. Between April 2014 and January 2015, sixty-nine patients with 74 HCCs were randomly treated with RFA using either internally cooled-wet (ICW) electrodes in SB mode (SB-RFA, n = 36) or SC electrodes in SM mode (SM-RFA, n = 38). Technical parameters including the number of ablations, ablation time, volume, energy delivery, and complications were evaluated. Thereafter, 1-year and 2-year local tumor progression (LTP) free survival rates were compared between the two groups using the Kaplan-Meier method. Results In the SB-RFA group, less number of ablations were required (1.72±0.70 vs. 2.31±1.37, P = 0.039), the ablation time was shorter (10.9±3.9 vs.14.3±5.0 min, p = 0.004), and energy delivery was smaller (13.1±6.3 vs.23.4±12.8 kcal, p<0.001) compared to SM-RFA. Ablation volume was not significantly different between SB-RFA and SM-RFA groups (61.8±24.3 vs.54.9±23.7 cm3, p = 0.229). Technical failure occurred in one patient in the SM-RFA group, and major complications occurred in one patient in each group. The 1-year and 2-year LTP free survival rates were 93.9% and 84.3% in the SB-RFA group and 94.4% and 88.4% in the SM-RFA group (p = 0.687). Conclusion Both SB-RFA using ICW electrodes and SM-RFA using SC electrodes provided comparable LTP free survival rates although SB-RFA required less ablations and shorter ablation time.
Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses

ABSTRACT Interferon-induced transmembrane proteins (IFITMs) are restriction factors that inhibit the infectious entry of many enveloped RNA viruses. However, we demonstrated previously that human IFITM2 and IFITM3 are essential host factors facilitating the entry of human coronavirus (HCoV) OC43. In a continuing effort to decipher the molecular mechanism underlying IFITM differential modulation of HCoV entry, we investigated the roles of structural motifs important for IFITM protein posttranslational modifications, intracellular trafficking, and oligomerization in modulating the entry of five HCoVs. We found that three distinct mutations in IFITM1 or IFITM3 converted the host restriction factors to enhance entry driven by the spike proteins of severe acute respiratory syndrome coronavirus (SARS-CoV) and/or Middle East respiratory syndrome coronavirus (MERS-CoV). First, replacement of IFITM3 tyrosine 20 with either alanine or aspartic acid to mimic unphosphorylated or phosphorylated IFITM3 reduced its activity to inhibit the entry of HCoV-NL63 and -229E but enhanced the entry of SARS-CoV and MERS-CoV. Second, replacement of IFITM3 tyrosine 99 with either alanine or aspartic acid reduced its activity to inhibit the entry of HCoV-NL63 and SARS-CoV but promoted the entry of MERS-CoV. Third, deletion of the carboxyl-terminal 12 amino acid residues from IFITM1 enhanced the entry of MERS-CoV and HCoV-OC43. These findings suggest that these residues and structural motifs of IFITM proteins are key determinants for modulating the entry of HCoVs, most likely through interaction with viral and/or host cellular components at the site of viral entry to modulate the fusion of viral envelope and cellular membranes. IMPORTANCE The differential effects of IFITM proteins on the entry of HCoVs that utilize divergent entry pathways and membrane fusion mechanisms even when using the same receptor make the HCoVs a valuable system for comparative investigation of the molecular mechanisms underlying IFITM restriction or promotion of virus entry into host cells. Identification of three distinct mutations that converted IFITM1 or IFITM3 from inhibitors to enhancers of MERS-CoV or SARS-CoV spike protein-mediated entry revealed key structural motifs or residues determining the biological activities of IFITM proteins. These findings have thus paved the way for further identification of viral and host factors that interact with those structural motifs of IFITM proteins to differentially modulate the infectious entry of HCoVs.
Sex differences and serotonergic mechanisms in the behavioural effects of psilocin

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology – sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms – the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT1A receptor antagonist (WAY100635 1 mg/kg), 5-HT2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT2B receptor antagonist (SB215505 1 mg/kg) and 5-HT2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT1A and 5-HT2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT2A-mediated effects 5-HT1A and 5-HT2C/B receptors also play an important role. These findings have implications for recent clinical trials.
Kawasaki Disease at 50 Years.

Importance Kawasaki disease (KD) is the most recognized vasculitis of childhood. The condition's characteristic high fever, rash, mucositis, conjunctivitis, lymphadenopathy, and extremity changes are superficially unexceptional, and resolve spontaneously within a mean of 12 days. It is the acuity and the potential for life-changing damage to the coronary arteries that distinguish KD from conditions that mimic it and exemplify the unique aspects and challenges of vascular inflammation in children. Observations Although KD is an orphan disease, its role as a leading cause of acquired heart disease in children has led to significant efforts to determine its etiology, optimize diagnosis, and customize treatment according to individuals' needs. The result is that KD can now be controlled without sequelae in more than 95% of cases. Furthermore, advances in stratifying patients according to measurable risk factors allow therapy to be personalized in increasingly effective ways. High-risk patients, such as infants younger than 6 months, those with early evidence of coronary artery dilatation, and those with extreme abnormalities in laboratory test results, are often identified at presentation. This early identification allows them to be treated with corticosteroids in addition to intravenous immunoglobulin to improve their outcomes. Children with similar findings on laboratory tests and echocardiography may be treated based on algorithms for managing "incomplete KD" despite falling short of fulfilling classic diagnostic criteria. Children who do not respond to intravenous immunoglobulin are the focus of trials to minimize the duration of inflammation and thereby protect their coronary arteries in ways never before considered. Conclusions and Relevance Kawasaki disease is a hybrid condition at the junction of infectious diseases, immunology, rheumatology, and cardiology. Rather than being left an orphan disease, KD is bringing disciplines together to identify its genetic, pathophysiological, and hemodynamic features. In turn, this work promises to shed light on many other inflammatory conditions as well.
HIF-1α-induced upregulation of lncRNA UCA1 promotes cell growth in osteosarcoma by inactivating the PTEN/AKT signaling pathway

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play an important role in multiple biological processes including cell growth, differentiation, proliferation and invasion. Urothelial carcinoma associated 1 (UCA1) is a highly conserved nuclear ncRNA and a key regulator of cell proliferation and apoptosis in several types of cancers. However, its role in osteosarcoma progression is not well known. In the present study, we aimed to determine the biological role of UCA1 in osteosarcoma progression. RT-qPCR analysis showed that UCA1 expression was significantly increased in osteosarcoma cell lines and promoted cell growth in osteosarcoma. We then sought to determine the mechanism underlying the upregulation of UCA1 in osteosarcoma. Luciferase reporter assay and chromatin immunoprecipitation assay suggested that lncRNA UCA1 was induced by HIF-1α and HIF-1α interacts with the HIF-1α response element in the promoter region of UCA1. In addition, the gain- and loss-of-functional assay showed that HIF-1α promoted osteosarcoma cell growth through inducing the UCA1 expression level. More importantly, Cignal Signal Transduction Reporter Array and western blot assay showed that lncRNA UCA1 inactivated the PTEN/AKT signaling pathway. Finally, we observed that HIF-1α induced cell growth through the UCA1/PTEN/AKT signaling pathway. To conclude, our integrated approach demonstrates that UCA1 confers a tumor promoter function by promoting cell proliferation and silencing of the PTEN/AKT signaling pathway in osteosarcoma. Thus, UCA1 can serve as a promising therapeutic target for osteosarcoma patients.
Thermodynamic Analysis of Chemically Reacting Mixtures—Comparison of First and Second Order Models

Recently, a method based on non-equilibrium continuum thermodynamics which derives thermodynamically consistent reaction rate models together with thermodynamic constraints on their parameters was analyzed using a triangular reaction scheme. The scheme was kinetically of the first order. Here, the analysis is further developed for several first and second order schemes to gain a deeper insight into the thermodynamic consistency of rate equations and relationships between chemical thermodynamic and kinetics. It is shown that the thermodynamic constraints on the so-called proper rate coefficient are usually simple sign restrictions consistent with the supposed reaction directions. Constraints on the so-called coupling rate coefficients are more complex and weaker. This means more freedom in kinetic coupling between reaction steps in a scheme, i.e., in the kinetic effects of other reactions on the rate of some reaction in a reacting system. When compared with traditional mass-action rate equations, the method allows a reduction in the number of traditional rate constants to be evaluated from data, i.e., a reduction in the dimensionality of the parameter estimation problem. This is due to identifying relationships between mass-action rate constants (relationships which also include thermodynamic equilibrium constants) which have so far been unknown.
Stories of Non‐Becoming: Non‐Issues, Non‐Events and Non‐Identities in Asexual Lives

In contrast to conventional models of positively “becoming” an identity through social interaction, this article explores the inverse, negational process of “non-becoming,” whereby actors start but do not continue along an identity career trajectory. Through cumulative attrition, interactions and encounters at key moments create an overall pattern of non-progression. Using asexuality as an example, we identify three main trajectory stages of non-awareness, communicative negation and non-consolidation, each involving interactional contingencies. With a wider applicability to other repudiated identities, this model shows how even negational symbolic social objects (non-issues, non-events, and non-identities) are constituted through social interaction.
Sentinel: A Codesigned Platform for Semantic Enrichment of Social Media Streams

We introduce the Sentinel platform that supports semantic enrichment of streamed social media data for the purposes of situational understanding. The platform is the result of a codesign effort between computing and social scientists, iteratively developed through a series of pilot studies. The platform is founded upon a knowledge-based approach, in which input streams (channels) are characterized by spatial and terminological parameters, collected media is preprocessed to identify significant terms (signals), and data are tagged (framed) in relation to an ontology. Interpretation of processed media is framed in terms of the 5W framework (who, what, when, where, and why). The platform is designed to be open to the incorporation of new processing modules, building on the knowledge-based elements (channels, signals, and framing ontology) and accessible via a set of user-facing apps. We present the conceptual architecture for the platform, discuss the design and implementation challenges of the underlying stream-processing system, and present a number of apps developed in the context of the pilot studies, highlighting the strengths and importance of the codesign approach and indicating promising areas for future research.
Up-regulation of ribosome biogenesis by MIR196A2 genetic variation promotes endometriosis development and progression

Aberrant miRNA expression has been reported in endometriosis and miRNA gene polymorphisms have been linked to cancer. Because certain ovarian cancers arise from endometriosis, we genotyped seven cancer-related miRNA single nucleotide polymorphisms (MiRSNPs) to investigate their possible roles in endometriosis. Genetic variants in MIR196A2 (rs11614913) and MIR100 (rs1834306) were found to be associated with endometriosis development and related clinical phenotypes, such as infertility and pain. Downstream analysis of the MIR196A2 risk allele revealed upregulation of rRNA editing and protein synthesis genes, suggesting hyper-activation of ribosome biogenesis as a driving force for endometriosis progression. Clinical studies confirmed higher levels of small nucleolar RNAs and ribosomal proteins in atypical endometriosis lesions, and this was more pronounced in the associated ovarian clear cell carcinomas. Treating ovarian clear cells with CX5461, an RNA polymerase I inhibitor, suppressed cell growth and mobility followed by cell cycle arrest at G2/M stage and apoptosis. Our study thus uncovered a novel tumorigenesis pathway triggered by the cancer-related MIR196A2 risk allele during endometriosis development and progression. We suggest that anti-RNA polymerase I therapy may be efficacious for treating endometriosis and associated malignancies.
Treatment of Human Urinary Kallidinogenase Combined with Maixuekang Capsule Promotes Good Functional Outcome in Ischemic Stroke

Aims: To evaluate the clinical efficacy of Human Urinary Kallidinogenase (HUK) and Maixuekang capsule in the treatment of acute ischemic stroke (AIS) patients. Methods: In this study, from January 2016 to July 2016, 60 patients with acute ischemic stroke were enrolled and 56 patients with complete information of whom 21 patients received HUK+ basic treatment (HUK group), 16 patients received HUK+ Maixuekang capsule + basic treatment (HUK+ Maixuekang group), 19 patients received basic treatment (control group). 0.15 PNA unit of HUK injection plus 100 ml saline in intravenous infusion was performed in the HUK group and HUK+ Maixuekang group, with once a day for 14 consecutive days. 0.75 g Maixuekang capsules were taken in HUK+ Maixuekang group, with three times a day for 14 consecutive days. The National Institutes of Health Stroke Scale (NIHSS) scores in three groups were analyzed 7 days after treatment. The modified Rankin Scale (mRS) scores in three groups were analyzed 12 month after the treatment. Results: No difference was found in the NIHSS scores, age, gender, and comorbidities between three groups before treatment (p > 0.05). Seven days after treatment, the NIHSS scores in the HUK group and HUK+ Maixuekang group were significantly decreased than before (p HUK = 0.001, p HUK+Maixuekang < 0.001), and lower than that in the control group (p HUK = 0.032; p HUK+Maixuekang < 0.001). Twelve months after treatment, good functional outcome rate (12 month mRS score ≤ 2) in the HUK group and HUK+ Maixuekang group was significantly higher than that in the control group (p HUK = 0.049, p HUK+Maixuekang = 0.032). Conclusion: The treatment of HUK or HUK combined with Maixuekang capsule can effectively improve the neurological function and promote long-term recovery for AIS patients.
Prevalence of diagnosed temporomandibular disorders: A cross-sectional study in Brazilian adolescents

Background The prevalence of signs and symptoms of temporomandibular disorders (TMD) increases during adolescence and adulthood. Few studies have examined TMD prevalence in Brazilian adolescents. Aim To investigate the prevalence of TMD in Brazilian adolescents. Methods A representative population-based sample of 934 adolescents (10–14-years-old) was examined. TMD screening was performed using a questionnaire by the American Academy of Orofacial Pain. TMD diagnoses used research diagnostic criteria for temporomandibular disorders (RDC/TMD—Axis-I). Examinations were performed by a single calibrated examiner (kappa > 0.80). Results The prevalence of TMD symptoms was 34.9%; the most frequently reported symptoms were headache and neck ache (20.9%), followed by joint sounds (18.5%). Myofascial pain was the most prevalent type (10.3%), followed by disc displacement with reduction (8.0%) and arthralgia (3.5%). There was a significant association between sex and TMD symptoms; prevalence was significantly higher in girls (RP = 1.37; 95% CI = 1.14–1.65; p = 0.001). Myofascial pain of TMD and displacement with reduction were more prevalent in girls (RP = 1.76; p = 0.007 and RP = 2.06; p = 0.004, respectively). Conclusion TMD symptoms were present in 34.9% of adolescents, with myofascial pain being the most prevalent type (10.3%). TMD was significantly more common in girls. Routine pediatric dental care should include a TMD screening.
Deliberation Makes a Difference

Small and rural hospitals face special challenges to implement and sustain organization-wide quality improvement (QI) initiatives due to limited resources and infrastructures. We studied the implementation of TeamSTEPPS, a national QI initiative, in 14 critical access hospitals. Drawing on QI and organization development theories, we propose five strategic preparation steps for TeamSTEPPS: assess needs, reflect on the context, set goals, develop a shared understanding, and select change agents. We explore how hospitals’ practices correspond to suggested best practices by analyzing qualitative data collected through quarterly interviews with key informants. We find that the level of deliberation was a key factor that differentiated hospitals’ practices. Hospitals that were more deliberate in preparing for the five strategic steps were more likely to experience engagement, perceive efficacy, foresee and manage barriers, and achieve progress during implementation. We discuss potential steps that hospitals may take to better prepare for TeamSTEPPS implementation.