Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8).

OBJECTIVE Hepatocellular uptake transporters are involved in the hepatobiliary elimination of endogenous and xenobiotic substances. Mutations in genes encoding these uptake transporters may be key determinants of interindividual variability in hepatobiliary elimination and drug disposition. Our aim was to investigate the functional consequences of mutations in the SLCO1B3 gene encoding the hepatic uptake transporter for organic anions OATP1B3, formerly termed OATP8. METHODS Mutations occurring in Caucasian Europeans and observed in databases were introduced into the SLCO1B3 cDNA and the consequences were analyzed in stably transfected canine MDCKII cells and human HEK293 cells. The functional consequences were examined for two frequent polymorphisms SLCO1B3-334T>G, encoding OATP1B3-S112A (allelic frequency of 74%) and SLCO1B3-699G>A, encoding OATP1B3-M233I (allelic frequency of 71%) and one rare polymorphism SLCO1B3-1564G>T, encoding OATP1B3-G522C (allelic frequency of 1.9%) and one artificial mutation SLCO1B3-1748G>A, encoding OATP1B3-G583E. RESULTS OATP1B3-S112A, OATP1B3-M233I, and the OATP1B3 protein corresponding to the reference sequence (accession NM_019844), showed a comparable lateral localization in stably transfected MDCKII cells, whereas OATP1B3-G522C and OATP1B3-G583E proteins were retained intracellularly. Both latter amino acid substitutions abolished the transport of bile acids mediated by OATP1B3, whereas other substrates, like bromosulfophthalein, were transported by all polymorphic variants of the protein. CONCLUSIONS The functional consequences of three polymorphisms and one artificial mutation include differences in the localization and in transport characteristics of several OATP1B3 proteins. This study demonstrates the importance of the analysis of genetic variations in genes encoding transport proteins for the understanding of individual variations in the hepatobiliary elimination of substances.
The Efficacy of Two Trabecular Bypass Stents Compared to One in the Management of Open-Angle Glaucoma.

OBJECTIVES To compare the outcomes of combined cataract surgery with two trabecular microbypass stents compared to one in patients with open-angle glaucoma. METHODS Patients with primary open-angle glaucoma were included. Primary outcome measures were intraocular pressure (IOP), postoperative medications, and postoperative adverse events. RESULTS The average patient age was 73.2 years. Thirty-nine eyes had phacoemulsification and one stent implanted (Group 1); 30 eyes had phacoemulsification and two stents implanted (Group 2). A significant reduction in mean IOP from baseline to 12 months was noted for both Group 1 (16.67 ± 4.1 mm Hg to 14.45 ± 3.8 mm Hg; p < 0.0251) and Group 2 (18.33 ± 3.99 mm Hg to 14.31 ± 1.8 mm Hg; p < 0.0014). Group 2 had a greater percent decrease in IOP at 12 months than Group 1, but this difference was not statistically significant. Only Group 2 demonstrated a statistically significant reduction in medication burden at 12 months. There were no serious complications in either group thought to be caused by the microbypass stents. CONCLUSIONS Both groups demonstrated a significant reduction in IOP at 12 months. Group 2 showed a greater percent decrease in IOP; however, it was not statistically significant. Only Group 2 demonstrated a statistically significant reduction in medication burden.
Imperfect rationality, macroeconomic equilibrium and price rigidities

We introduce some elements of Prospect Theory into a general equilibrium model with monopolistic competition in the good market and real wage rigidities due to (right to manage or efficient) wage bargaining, or to efficiency wages. We show that, under these types of labor market frictions, an increase in workers’ loss aversion: (i) reduces the equilibrium wage and in this way increases potential output; (ii) induces workers to work and consume less and in this way decreases potential output. If the former effect is greater (smaller) than the latter one, loss aversion increases(decreases) potential output. We also show that, under all the types of labor market frictions we consider, if loss aversion reduces equilibrium output, it also enhances the plausibility of nominal price rigidities.
Selection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpC.

OBJECTIVES Pseudomonas aeruginosa is an important nosocomial pathogen that can cause a wide range of infections resulting in significant morbidity and mortality. Avibactam, a novel non-β-lactam β-lactamase inhibitor, is being developed in combination with ceftazidime and has the potential to be a valuable addition to the treatment options for the infectious diseases practitioner. We compared the frequency of resistance development to ceftazidime/avibactam in three P. aeruginosa strains that carried derepressed ampC alleles. METHODS The strains were incubated in the presence of increasing concentrations of ceftazidime with a fixed concentration (4 mg/L) of avibactam to calculate the frequency of spontaneous resistance. The mutants were characterized by WGS to identify the underlying mechanism of resistance. A representative mutant protein was characterized biochemically. RESULTS The resistance frequency was very low in all strains. The resistant variants isolated exhibited ceftazidime/avibactam MIC values that ranged from 64 to 256 mg/L. All of the mutants exhibited changes in the chromosomal ampC gene, the majority of which were deletions of various sizes in the Ω-loop region of AmpC. The mutant enzyme that carried the smallest Ω-loop deletion, which formed a part of the avibactam-binding pocket, was characterized biochemically and found to be less effectively inhibited by avibactam as well as exhibiting increased hydrolysis of ceftazidime. CONCLUSIONS The development of high-level resistance to ceftazidime/avibactam appears to occur at low frequency, but structural modifications in AmpC can occur that impact the ability of avibactam to inhibit the enzyme and thereby protect ceftazidime from hydrolysis.
Evolution of Cytochrome c Oxidase in Hypoxia Tolerant Sculpins (Cottidae, Actinopterygii)

Vertebrate hypoxia tolerance can emerge from modifications to the oxygen (O2) transport cascade, but whether there is adaptive variation to O2 binding at the terminus of this cascade, mitochondrial cytochrome c oxidase (COX), is not known. In order to address the hypothesis that hypoxia tolerance is associated with enhanced O2 binding by mitochondria we undertook a comparative analysis of COX O2 kinetics across species of intertidal sculpins (Cottidae, Actinopterygii) that vary in hypoxia tolerance. Our analysis revealed a significant relationship between hypoxia tolerance (critical O2 tension of O2 consumption rate; Pcrit), mitochondrial O2 binding affinity (O2 tension at which mitochondrial respiration was half maximal; P50), and COX O2-binding affinity (apparent Michaelis-Menten constant for O2 binding to COX; Km,app O2). The more hypoxia tolerant species had both a lower mitochondrial P50 and lower COX Km,app O2, facilitating the maintenance of mitochondrial function to a lower O2 tension than in hypoxia intolerant species. Additionally, hypoxia tolerant species had a lower overall COX Vmax but higher mitochondrial COX respiration rate when expressed relative to maximal electron transport system respiration rate. In silico analyses of the COX3 subunit postulated as the entry point for O2 into the COX protein catalytic core, points to variation in COX3 protein stability (estimated as free energy of unfolding) contributing to the variation in COX Km,app O2. We propose that interactions between COX3 and cardiolipin at four amino acid positions along the same alpha-helix forming the COX3 v-cleft represent likely determinants of interspecific differences in COX Km,app O2.
Thermic effect of food after ingested versus tube-delivered meals.

We compared, in six subjects, the thermic effect of food (TEF) after the ingestion of a test meal with that observed after the delivery of an equivalent test meal directly into the stomach through a nasogastric tube. TEF was measured after each test meal (i.e., ingested or tube delivered) until postprandial metabolic rate was not different from fasting metabolic rate (as measured at approximately the same time of day on a previous day). TEF after the tube-delivered meal was not significantly different in magnitude or duration from TEF after the ingested meal. The two types of meals also resulted in similar changes in respiratory quotient. These results suggest that the majority of TEF arises after the food reaches the stomach and that very little of TEF is produced by sensory factors or by the mechanical aspects of eating.
Chinese entrepreneurs: The Chinese Diaspora in Australia

Recounts the history of the Chinese Diaspora in Australia, which dates back to the Gold Rush of the 1850s. In the past three decades, following the end of the white Australia policy, many ethnic Chinese immigrants have immigrated to Australia. Although there are only 300,000 people of Chinese ancestry living in Australia, Chinese immigration is a critical chapter of Australia’s immigration experience. Chinese entrepreneurs have played a major role in the history of the Chinese in Australia. Explores the experience of Chinese entrepreneurs in Australia from the earliest days till the present and reviews historical accounts of Chinese entrepreneurs in Australia, before presenting the results of recent research. Argues that it is necessary to investigate how ethnicity, gender and class have intersected to shape changing patterns of Chinese entrepreneurship in the Australian Chinese Diaspora. Suggests also that the dynamics of Chinese immigration and Chinese entrepreneurship in Australia have been shaped by the changing dynamics of globalisation, the state and the racialisation of Chinese immigrants in the Australian labour market and society as a whole.
Abscisic Acid Induces CBF Gene Transcription and Subsequent Induction of Cold-Regulated Genes via the CRT Promoter Element1

Many cold-regulated genes of Arabidopsis are inducible by abscisic acid (ABA) as well as by cold. This has been thought to occur via two separate signaling pathways, with ABA acting via ABA-responsive promoter elements and low temperature activating the C-repeat element (CRT; dehydration-responsive) promoter element via CBF (DREB1) transcription factors. We show here that ABA is also capable of activating the CRT promoter element. Although the more recently discovered ABA-inducible CBF4 transcription factor might have accounted for this, we show here that CBF1-3 transcript levels also increase in response to elevated ABA levels. This increase in CBF1-3 transcript levels appears to be at least in part due to increased activity of the CBF promoters in response to ABA. A total of 125 bp of the CBF2 promoter, which has previously been shown to be sufficient for cold-, mechanical-, and cycloheximide-induced expression, was also sufficient for ABA-induced expression. However, the ABA-responsive promoter element-like motif within this region is not needed for ABA-induced expression. An observed increase in CBF protein levels after ABA treatment, together with previous data showing that increased CBF levels are sufficient for cold-regulated gene induction, suggests that ABA-induced increases in CBF1-3 transcript levels do have the potential to activate the CRT. Our data indicate therefore that activation of the CRT may also occur via a novel ABA-inducible signaling pathway using the normally cold-inducible CBFs.
Transparency, Trust and Confidence in the Public Sector

This article forwarded findings from a research on public sector performance measurement regimes in a selected developed country. Amongst the issues explored in the research is on the public trusts and confidence in the government agencies and its influence on aspects of participation and voting decisions. Transparency is recognised for the means to improve trust. Therefore greater transparency in the public sector is also hope to enhance public confidence and trust in the government agencies. The research questions were answered using pragmatic paradigm which allows for mixed research methodologies. Utilising documents analysis, survey questionnaires and interviews, the study examine 22 cases. Findings on the aspects presented in this paper, suggest that enhanced transparency neither influence the voting decisions nor improved public participation in the local government activities. However, it does provide clearer views for the public service employees on the local government functions, and support them in delivering their work in more efficient manner.
Anti-angiogenic activity of melatonin in advanced cancer patients.

OBJECTIVES The anticancer activity of the indole melatonin has been explained to be due to its immunomodulatory, anti-prolferative and anti-oxidant effects, whereas at present no data are available about its possible influence on the angiogenesis, which has been shown to be one of the main biological mechanisms responsible for tumor dissemination. Vascular endothelial growth factor (VEGF) is the most active angiogenic factor, and the evidence of abnormally high blood levels or VEGF has been proven to be associated with poor prognosis in cancer patients. To investigate the influence of melatonin on angiogenesis, in this preliminary study we have evaluated the effects of melatonin therapy on VEGF blood levels in advanced cancer patients. MATERIAL & METHODS The study included 20 metastatic patients, who progressed on previous conventional antitumor therapies and for whom no other effective treatment was available. Melatonin was given orally at 20 mg/day in the evening for at least 2 months. Serum levels of VEGF were measured by an enzyme immunoassay on venous blood samples collected at 15-day intervals. RESULTS The clinical response consisted of minor response (MR) in 2, stable disease (SD) in 6 and progressive disease (PD) in the remaining 12 patients. VEGF mean levels decreased on therapy, without, however, statistical differences with respect to the pre-treatment values. In contrast, by evaluating changes in VEGF levels in relation to the clinical response, non-progressing patients (MR + SD) showed a significant decline in VEGF mean concentrations, whereas no effect was achieved in progressing patients. CONCLUSIONS This study, by showing that melatonin-induced control or the neoplastic growth is associated with a decline in VEGF secretion, would suggest that the pineal hormone may control tumor growth at least in part by acting as a natural anti-angiogenic molecule, with a following opposition or angiogenesis-dependent cancer proliferation.
Do Seller Disclosures Affect Property Values? Buyer Information and the Hedonic Model

The hedonic method is widely used to infer the value of environmental amenities that are bundled with real property. The interpretation of hedonic prices as marginal values requires that households are “fully informed. ”Yet, there is evidence that buyers are often less informed than sellers. A graphical illustration in this study suggests that asymmetric information between buyers and sellers can affect hedonic prices. This intuition is confirmed by a quasi-random experiment that exploits spatial and information discontinuities stemming from a seller disclosure for flood zones. Results suggest a 4% decline in housing prices in flood zones after disclosures commenced. (JEL Q51, R52)
Comparing Shape-Changing and Vibro-Tactile Steering Wheels for Take-Over Requests in Highly Automated Driving

Automation shortcomings in highly automated driving (level 3) might require the driver to take over vehicle control. When the vehicle issues a take-over request (TOR), the driver has to immediately comprehend the situation, which highly demands visual attention. Therefore, haptic channel has the potential to be used for conveying information about driving context at take-over to assist decision making. In this work, we introduce the concept and prototype design of a shape-changing steering wheel which conveys contextual information at take-over. We evaluated this concept in comparison with an identical wheel with vibration cues. Results showed that haptic cues on steering wheel at TOR reassure drivers of their decisions rather than assisting them in decision making, and overall workload ratings are decreased using vibration cues. To assist decision making, contextual haptic cues in level 3 should be located on-body or on drivers' seat.
Abundant Tissue Butyrylcholinesterase and Its Possible Function in the Acetylcholinesterase Knockout Mouse

Abstract: We have described recently an acetylcholinesterase (AChE) knockout mouse. While comparing the tissue distribution of AChE and butyrylcholinesterase (BChE), we found that extraction buffers containing Triton X‐100 strongly inhibited mouse BChE activity. In contrast, buffers with Tween 20 caused no inhibition of BChE. Conventional techniques grossly underestimated BChE activity by up to 15‐fold. In Tween 20 buffer, the intestine, serum, lung, liver, and heart had higher BChE than AChE activity. Only brain had higher AChE than BChE activity in AChE +/+ mice. These findings contradict the dogma, based mainly on observations in Triton X‐100 extracts, that BChE is a minor cholinesterase in animal tissues. AChE +/‐ mice had 50% of normal AChE activity and AChE ‐/‐ mice had none, but all mice had similar levels of BChE activity. BChE was inhibited by Triton X‐100 in all species tested, except rat and chicken. Inhibition was reversible and competitive with substrate binding. The active site of rat BChE was unique, having an arginine in place of leucine at position 286 (human BChE numbering) in the acyl‐binding pocket of the active site, thus explaining the lack of inhibition of rat BChE by Triton X‐100. The generally high levels of BChE activity in tissues, including the motor endplate, and the observation that mice live without AChE, suggest that BChE has an essential function in nullizygous mice and probably in wild‐type mice as well.
Effects of food limitation on 9 metal concentrations in liver and polycyclic aromatic hydrocarbon metabolites in bile of juvenile turbot (Scophthalmus maximus) previously exposed to contaminated sediments

A 2‐step experimental design was employed in the present study on juvenile turbot (Scophthalmus maximus): 1) juveniles were exposed for 26 d to 2 contaminated sediments and a reference one, and 2) they were transferred in clean seawater with clean sediment for 35 d, feeding fish once a day, twice a week, or once a week. Fish exposed to contaminated sediments presented a significant increase of hepatic Cd, Cu, and Pb concentrations compared with the reference condition after the 26‐d exposure. Higher fluorescence signals of polycyclic aromatic hydrocarbon (PAH) metabolites were found in bile from turbot exposed to contaminated sediments for 26 d compared with reference. These signals returned to values similar to reference fish after depuration whatever the food quantity. The metal bioaccumulation of Cd, Cu, and Pb was no longer observed after 35‐d depuration with once‐a‐day feeding but was still found with restricted feeding conditions. Results on reference fish also showed significantly higher concentrations of most metals analyzed in fish fed twice a week and once a week compared with fish fed once a day. These results could be related to a decrease of fish hepatosomatic index with food limitation and, thus, a dilution effect on metal concentrations. The present study clearly demonstrates that changes in feeding status have significant effects on metal concentrations in fish and no observed effect on PAH metabolites. Environ Toxicol Chem 2013;32:2552–2557. © 2013 SETAC
What is the value of eGovernment – and how can we actually realize it?

Purpose – The purpose of this paper is to promote academic discourse around the understanding of the concept of value of eGovernment and how a diverse set of benefits or values can be realized from eGovernment efforts.Design/methodology/approach – The paper is designed as a viewpoint paper with emphasis on grounding a set of arguments on current practice and relevant scholarly papers.Findings – Although not based on a formal, structured review, the paper proposes that the concept of value in relation to eGovernment is insufficiently discussed and defined in the eGovernment literature. Based on the high failure rates of eGovernment efforts, it further proposes that structured approaches to benefits realization, in combination with increased focus on (public) value, can be fruitful avenues for future research. The complexity of the context and the research challenges makes interdisciplinary research teams a necessity.Originality/value – If addressed, the research propositions can lead to an increased unders.
Approximate mean value analysis of client-server systems with multi-class requests

Stochastic Rendezvous Networks (SRVNs) are performance models for multitasking parallel software with intertask communication via rendezvous introduced in [1], which are very appropriate to model client-server systems. SRVNs differ from Queueing Networks (QNs) in two ways: nodes act as both clients and servers (allowing for nested service), and servers have two distinct phases of service—the first one “in RV” with the client, and the second “after RV”, executed in parallel with the client. Early work on solving SRVN models has used a kind of approximate Mean Value Analysis based on heuristic ad hoc assumptions to determine the task queue properties at the instant of RV request arrivals. Approximation are necessary since SRVN violates product form. Recently, a more rigorous approach was proposed in [2] for the solution of SRVN models, based on a special aggregation (named “Task-Directed Aggregation” TDA) of the Markov chain model describing the interference of different clients that contend for a single server with FIFO queueing discipline and different service times. The algorithm derived in [2] has the limitation that each client may require only a single class of service. In general, a software server offers a range of services with different workloads and functionalities, and a client may need more than one service. The present paper uses the TDA approach to derive an extended algorithm which allows a client to require any number of services from a server by changing randomly the request class. The new algorithm is incorporated into a decomposition method for models with any number of servers. The SRVN modelling technique is applied to a large case study of a distributed database system, giving insight into the behaviour of the system and helping to identify performance problems such as software bottle-neck.
Angel Investors’ and Entrepreneurs’ Intentions to Exit Their Ventures: A Conflict Perspective

This study examines the relationships among angel investor–entrepreneur relationship conflicts, task conflicts, and goal conflicts on the one hand and their intentions to exit on the other. I evaluate the hypotheses with survey data from 65 angel investors and 72 entrepreneurs belonging to 54 ventures located in either California or Belgium. Regression analyses indicate that entrepreneurial intentions to exit are higher for entrepreneurs who face more task and goal conflicts. Angel investors’ intentions to exit are only increased when faced with more goal conflicts. Together, these results indicate the importance of taking into account investor–entrepreneur relations when studying their respective exit processes.