Miracle-dz/UniFAR-FTUs huggingface dataset:
Drugs as CYP3A Probes, Inducers, and Inhibitors

Human cytochrome P450 (CYP) 3A subfamily members (mainly CYP3A4 and CYP3A5) mediate the metabolism of approximately half all marketed drugs and thus play a critical role in the drug metabolism. A huge number of studies on CYP3A-mediated drug metabolism in humans have demonstrated that CYP3A activity exhibits marked ethnic and individual variability, in part because of altered levels of CYP3A4 expression by various environmental factors and functionally important polymorphisms present in CYP3A5 gene. Accumulating evidence has revealed that CYP3A4 and CYP3A5 have a significant overlapping in their substrate specificity, inducers and inhibitors. Therefore, it is difficult to define their respective contribution to drug metabolism and drug-drug interactions. Furthermore, P-glycoprotein and CYP3A are frequently co-expressed in the same cells and share a large number of substrates and modulators. The disposition of such drugs is thus affected by both metabolism and transport. In this review, we systematically summarized the frequently used CYP3A probe drugs, inducers and inhibitors, and evaluated their current status in drug development and research.
Hypertensive target organ damage and the risk for vascular events and all-cause mortality in patients with vascular disease

Objective: Presence of hypertensive target organ damage is related to increased vascular risk and mortality. Whether combined presence of hypertensive target organ damage confers higher vascular risk compared to single presence is unknown. This study evaluates the separate and combined effects of impaired renal function [estimated glomerular filtration rate (eGFR) ⩽60 ml/min per 1.73 m2], albuminuria (albumin/creatinine-ratio men ≥2.5 mg/mmol, women ≥3.5 mg/mmol) and left-ventricular hypertrophy (LVH) (Sokolow–Lyon and/or Cornell-voltage criterion) on the occurrence of vascular events and mortality in patients with vascular disease (coronary artery disease, cerebrovascular disease, and peripheral arterial disease). Methods and results: A cohort of patients with vascular diseases (n = 4319) was followed (median 4.4 years) for the occurrence of vascular events (stroke, myocardial infarction, vascular death) and mortality. LVH was present in 11%, impaired renal function in 15%, and albuminuria in 18%. Presence of at least two hypertensive target organ damage was prevalent in 8%. The risk for vascular events was hazard ratio 1.5 [95% confidence interval (CI) 1.2–1.9] for presence of one hypertensive target organ damage and hazard ratio 3.8 (95% CI 2.3–6.3) for three manifestations of hypertensive target organ damage (adjusted for age, sex). For mortality this was hazard ratio 1.4 (95% CI 1.1–1.7) and hazard ratio 3.2 (95% CI 1.9–5.2). Hazard ratios for single presence of different types of organ damage were comparable and independent of the presence of hypertension. Conclusions: Impaired renal function, albuminuria, and LVH are prevalent in patients with vascular disease and confer independent and additive risk for vascular events and mortality. Measurement of hypertensive target organ damage in patients with vascular disease identifies patients at very high risk and may have treatment implications.
Attitude transfer and brand extension evaluation: Exploring the influence of self-construal and parent brand's culture specificity

Using self-construal (Independent self vs. Interdependent self) as the individual level variable standing for culture, this research investigates the effects of culture and parent brands' culture specific associations on brand extension evaluation at the individual level. Experiment 1 finds that brand extensions extended by brands with high culture specific associations lead to more favorable attitudes for individuals with the target self-construal relative to a nontarget self-construal, while brand extensions extended by brands with low culture specific associations lead to more attitudinal similarities across self-construals. We further explores the extent to which differences in perceived diagnosticity as compared with differences in the accessibility of parent brands' associations better account for the attitudinal differences. Experiment 2 explores the two alternative (accessibility vs. diagnosticity) explanations for these effects of parent brands' attitude transfer process. The evidence is more supportive of the differential accessibility explanation. That is, high culture specific associations of the parent brands may be valued for individuals with the nontarget self-construal but are relatively inaccessible in their memory. The results of the two experiments help to reconcile conflicting findings in the brand extension literature, shed insight on why and how cultural differences might influence brand extension evaluation at the individual level.
Two Essays on the Relationship Between Actors’ Field Position, Meaning Construction and Action During Transformational Field Change: The Case of Market-Based Reforms in English Legal Services

Author(s): Jha, Harsh Kumar | Advisor(s): Beckman, Christine M. ; Okhuysen, Gerardo | Abstract: The relationship between actors’ field position, meaning construction and action during change is one of the central questions in literature. In my dissertation I examine these relationships in the context of recent market based reforms in English legal services, which led to the enactment of Legal Services Act (LSA) 2007 in England a Wales. I bring together Bourdieu’s and Fligstein a McAdam’s sociological theories of fields in a novel way to conceptualize actors’ field position and categorize four types of legal professional actors – barristers, small law firms, corporate law firms and in-house lawyers – in four distinct field positions, based on their centrality within the legal services field (central or peripheral) and membership of the overlapping client field (public or corporate clients). In essay 1, I analyze actors’ sensemaking of change (through content analysis of legal trade media coverage) and organizational action (based on patterns of formal responses to various regulatory commissions – individual organizations versus associations). My analysis suggests that actors’ field position both (1) independently influences sensemaking and actions; and (2) mediates the influence of sensemaking on actions. In essay 2, I undertake frame analysis of responses submitted by professional actors to various regulatory commissions to examine how frames and framing strategies adopted by actors evolve over time. My analysis suggests that the shifts in frames and framing strategies adopted by actors during contested change are influenced by actors’ field position (which influences actors’ choice of meta-frames) and perceived threats to interests (which influences the diversity of frames adopted and shifts in framing strategies). Overall, this dissertation contributes to our understanding of actors’ cognition and discursive strategies; specifically, how these processes may be related to actors’ contextual embeddedness (field position). Essay 1 examines various mechanisms through which actors’ field position, sensemaking and action may be related, and in doing so advances our current understanding of the relationships between actors’ context, cognition, and actions. Essay 2 extends our understanding of framing processes by drawing attention to the fact that use of frames and framing strategies by actors is only partially agentic; and actors’ frames and framing strategies are influenced by their respective field positions and perceived threats to their interests. This dissertation also makes an overall contribution to the literature on organizational fields, by suggesting that analysis of fields may require a richer specification of actors’ position; instead of unidimensional categorizations, such as incumbent or challenger.
Indoor Propagation Channel Simulations at 60 GHz Using Point Cloud Data

Deterministic field prediction has been widely used to provide channel data for coverage analysis. Among these prediction tools, point cloud-based methods have been developed for millimeter-wave frequencies in order to characterize the environment with higher precision, but they have not taken into account all the necessary propagation mechanisms. In this paper, we present the implementation for predicting both specular reflections and diffraction as well as the total channel, including the aforementioned mechanisms along with scattering and shadowing. Both line-of-sight (LOS) and non-LOS channels are predicted and validated against measurements in a cafeteria. The result shows excellent agreement between prediction and measurement in terms of power delay profiles, power angular spectra, path loss, mean delay, delay spread, and azimuth spread.
The Est1 Subunit of Yeast Telomerase Binds the Tlc1 Telomerase RNA

ABSTRACT Est1 is a component of yeast telomerase, and est1mutants have senescence and telomere loss phenotypes. The exact function of Est1 is not known, and it is not homologous to components of other telomerases. We previously showed that Est1 protein coimmunoprecipitates with Tlc1 (the telomerase RNA) as well as with telomerase activity. Est1 has homology to Ebs1, an uncharacterized yeast open reading frame product, including homology to a putative RNA recognition motif (RRM) of Ebs1. Deletion of EBS1 results in short telomeres. We created point mutations in a putative RRM of Est1. One mutant was unable to complement either the senescence or the telomere loss phenotype of est1 mutants. Furthermore, the mutant protein no longer coprecipitated with the Tlc1 telomerase RNA. Mutants defective in the binding of Tlc1 RNA were nevertheless capable of binding single-stranded TG-rich DNA. Our data suggest that an important role of Est1 in the telomerase complex is to bind to the Tlc1 telomerase RNA via an RRM. Since Est1 can also bind telomeric DNA, Est1 may tether telomerase to the telomere.
Interdisciplinary treatment of ruptured cerebral aneurysms in elderly patients.

OBJECT The aim of the study was to assess postprocedural neurological deterioration and outcome in patients older than 70 years of age in whom treatment was managed in an interdisciplinary context. METHODS This prospective longitudinal study included all patients 70 years of age or older treated for ruptured cerebral aneurysm over 10 years (June 1997-June 2007). The population was composed of 64 patients. The neurovascular interdisciplinary team jointly discussed the early obliteration procedure for each aneurysm. Neurological deterioration during the postprocedural 2 months and outcome at 6 months were assessed during consultation according to the modified Rankin Scale (mRS) as follows: favorable (mRS score < or = 2) and unfavorable (mRS score > 2). RESULTS Aneurysm sac obliteration was performed by microvascular clipping in 34 patients (53.1%) and by endovascular coiling in 30 (46.9%). Postprocedural neurological deterioration occurred in 30 patients (46.9%), related to ischemia in 19 (29.7%), rebleeding in 1 (1.6%), and hydrocephalus in 10 (15.6%). At 6 months, the outcome was favorable in 39 patients (60.9%). By multivariate regression logistic analysis, the independent factors associated with unfavorable outcome were age exceeding 75 years (p = 0.005), poor initial grade (p < 0.0001), and the occurrence of ischemia (p < 0.0001). CONCLUSIONS The baseline characteristics of SAH in the elderly were only slightly different from those in younger patients. In the elderly, the interdisciplinary approach may be considered useful to decrease the ischemic consequences.
Phylogeography and regional endemism of a passively dispersing zooplankter: mitochondrial DNA variation in rotifer resting egg banks

We investigated the phylogeography of the salt water rotifer Brachionus plicatilis, a cyclical parthenogen with passive dispersal mechanisms, using resting eggs recovered from saline lake sediments. Individual resting eggs were obtained from a large selection of lakes which were representative of five endorheic basins and the chain of coastal ponds in the Iberian Peninsula. The novel use of resting eggs allows the integration of seasonal and annual variations as well as the impact of stochastic effects such as drift and local extinction. A 653 bp fragment of the mitochondrial cytochrome oxidase subunit I (COI) gene was sequenced from 98 eggs. Our results revealed a deep phylogeographical structure in this species, with a division into two main lineages with distinct geographical distributions, which probably diverged at the beginning of the Pleistocene period. Most of the mitochondrial DNA haplotypes were restricted to single lakes. Nested clade analysis supported Early Pleistocene fragmentation of populations, low gene flow and some long–distance colonization. These conclusions contrast strongly with previous ideas on rotifer biogeography and this pattern is consistent with a recolonization of the Iberian Peninsula from two glacial refugia. The results provide new insights into the processes responsible for the genetic diversification of passive dispersers, a life–history trait typical of zooplanktonic biotas.
Pricing dynamics in the market for catastrophe bonds

We study the time variation of the market price of catastrophe (CAT) bonds for the period 1999–2016. While we find an overall decreasing trend in the price of expected loss risk, large catastrophes increase this price by 34% on average. Our empirical tests show that the latter effect is temporary and unlikely to be the byproduct of behavioural changes in investors’ perceptions about catastrophic risk, as previously argued. Instead, we find evidence that changes in the price of expected loss risk may be explained by changes in investor effective risk aversion, initiated by catastrophic events triggering CAT bond losses that could bring investors closer to their habit consumption levels and lead to a hard reinsurance market environment. Contagion effects from reinsurance markets are more relevant after main catastrophes given the levels of liquidity in the markets. Furthermore, contagion effects from financial markets are minor and only relevant during the subprime financial crisis, as documented in previous studies.
Effect of Knowledge Management Activities and Dynamic Capabilities on Employee Performance in the Banking Sector: Empirical Evidence From Pakistan

Abstract The banking sector is facing constant change and fierce competition. In this scenario, banks need to align themselves with the ever-changing environment by enhancing employee knowledge base to create capabilities. The basic objective of the current study is to examine the effect of knowledge management activities and dynamic capabilities on employee performance in the banking sector of Pakistan. This research employed a quantitative method to analyse the data. The sample was taken from employees who are working in public and private banks in Pakistan. A self-administered questionnaire was distributed among employees of public and private banks adopting stratified random sampling technique. Ordinary Least Square (OLS) method is used to testify the hypothesis and factor analysis to examine the validity and reduction of the items. This research finds that both knowledge management activities and dynamic capabilities have significant effect on employee performance in the banking sector of Pakistan.
Evaluation of Four DNA Extraction Methods for the Detection of Tritrichomonas Foetus in Feline Stool Specimens by Polymerase Chain Reaction

Feces are increasingly valued as practical samples for molecular diagnosis of infectious disease. However, extraction of polymerase chain reaction (PCR) quality DNA from fecal samples can be challenging because of coextraction of PCR inhibitors. Because the type and quantity of PCR inhibitors is influenced by diet, endogenous flora, and concurrent disease, it is unlikely that extraction method performance with human feces can be directly extrapolated to that of domestic cats. In the present study, 4 commercially available DNA extraction methods were examined for their influence on the sensitivity of PCR for the detection of Tritrichomonas foetus in feline stool. DNA was extracted from serially diluted feline-origin T. foetus trophozoites in the absence or presence of feline feces. The ZR Fecal DNA kit was identified as affording the greatest analytical sensitivity and reproducibility and was able to detect ≥10 T. foetus organisms per 100 mg feces in 100% of PCR reactions. Further, the identified extraction method could be completed in the shortest time of all kits tested.
An exploratory randomized controlled study of a healthy living intervention in early intervention services for psychosis: the INTERvention to encourage ACTivity, improve diet, and reduce weight gain (INTERACT) study.

BACKGROUND People with psychosis often experience weight gain, which places them at risk of cardiovascular disease, diabetes, and early death. OBJECTIVE To determine the uptake, adherence, and clinical effectiveness of a healthy living intervention designed to reduce weight gain. METHOD An exploratory randomized controlled trial, comparing the intervention with treatment as usual (TAU) in 2 early intervention services for psychosis in England. DSM-IV classification was the diagnostic criteria used to assign the psychiatric diagnoses. The primary outcome was change in body mass index (BMI) from baseline to 12-month follow-up. The study was conducted between February 2009 and October 2012. RESULTS 105 service users, with a BMI of ≥ 25 (≥ 24 in South Asians), were randomized to intervention (n = 54) or TAU (n = 51) after stratification by recent commencement of antipsychotic medication. Ninety-three service users (89%) were followed up at 12 months. Between-group difference in change in BMI was not significant (effect size = 0.11). The effect of the intervention was larger (effect size = 0.54, not significant) in 15 intervention (28%) and 10 TAU (20%) participants who were taking olanzapine or clozapine at randomization. CONCLUSIONS The healthy living intervention did not show a significant difference in BMI reduction compared to the TAU group. TRIAL REGISTRATION www.isrctn. org identifier: ISRCTN22581937.
Profiling sedentary behavior in breast cancer survivors: Links with depression symptoms during the early survivorship period

Depression symptoms are prevalent among breast cancer survivors (BCS). Reducing sedentary behavior (SED) may be a non‐pharmaceutical strategy for alleviating depression symptoms. However, little is known about SED among BCS. The present study aimed to: (i) describe SED behaviors among BCS and identify unique SED groups based on different SED dimensions; (ii) identify personal and cancer‐specific factors that discriminate SED clusters; and (iii) examine the association between SED clusters and depression symptoms.
Killing by Bactericidal Antibiotics Does Not Depend on Reactive Oxygen Species

Antibiotic Mechanisms Revisited Several recent studies have suggested that bactericidal antibiotics kill cells by a common mechanism involving reactive oxygen species (ROS). Two groups tested this hypothesis using diverse experiments, with both finding that quinolone, lactam, and aminoglycoside antibiotics had similar efficacy for killing in the presence or absence of oxygen (or nitrate). Liu et al. (p. 1210) saw no increase in hydrogen peroxide production in antibiotic-exposed cells and found no association between antibiotic exposure and the expected symptoms of oxidative damage, such as the breakdown of iron-sulfur clusters in enzymes or of hydroxyl radical injuries to DNA. Similarly, Keren et al. (p. 1213) found no correlation between the production of ROS, inferred from hydroxyphenyl fluorescein dye measurements, and bacterial survival, nor was there any significant protective effect engendered by thiourea. The results do not support a common mode of action for bactericidal antibiotics mediated by ROS. Tests of the oxidative damage mechanism for antibiotic killing do not support the generality of the hypothesis. Bactericidal antibiotics kill by modulating their respective targets. This traditional view has been challenged by studies that propose an alternative, unified mechanism of killing, whereby toxic reactive oxygen species (ROS) are produced in the presence of antibiotics. We found no correlation between an individual cell's probability of survival in the presence of antibiotic and its level of ROS. An ROS quencher, thiourea, protected cells from antibiotics present at low concentrations, but the effect was observed under anaerobic conditions as well. There was essentially no difference in survival of bacteria treated with various antibiotics under aerobic or anaerobic conditions. This suggests that ROS do not play a role in killing of bacterial pathogens by antibiotics.
Genomic haplotype within the Peroxisome Proliferator‐Activated Receptor Delta (PPARD) gene is associated with elite athletic status

Peroxisome proliferator‐activated receptor delta (PPARδ; encoded by the PPARD gene) plays a role in energy metabolism and mitochondrial function. We have investigated the distribution of PPARD rs2267668, rs2016520 and rs1053049 polymorphisms, individually and in haplotype, in a cohort of 660 elite athletes which was subdivided into four different groups based on the different metabolic demands of their respective sports and 704 healthy controls. PPARD rs2016529 and rs1053049 were individually associated with overall elite athletic performance (P = 0.00002; and P = 0.0002) and also with athletes grouped as strength endurance (P = 0.00008; and P = 0.0003). Furthermore, PPARD A/C/C haplotype (rs2267668/rs2016520/rs1053049) was significantly underrepresented in all athletes and each subgroup of athletes when compared with controls (P < 0.000001), suggesting that harboring this specific haplotype is unfavorable for becoming an elite athlete. These results help to identify which genetic profiles may contribute to elite athletic performance, specifically the role of variants within the PPARD gene, and may be useful in talent identification or optimizing the response to training.
Accelerating Basic Science in an Intergovernmental Framework: Learning from CERN's Science Diplomacy

CERN offers a highly relevant case to probe some of the assumptions of current debates on science diplomacy. Building on the existing literature and a number of expert interviews, this article discusses the origin of CERN, its governance structure, and the particular constellation of interests that form part of CERN's science diplomacy. We understand science diplomacy as a practice and explore this at the intersection between goals and values, everyday conduct, and the governance structure guiding interactions. Reaching beyond CERN as a specific case, we address the tension at the heart of science diplomacy debates between promoting peaceful relations and furthering strategic and national interests. We argue that it is precisely within this tension that science diplomacy unfolds. Further, the particular governance structure that CERN employs emerges as a blueprint for supporting a level playing field between scientists and diplomats and promoting scientific goals beyond narrow political considerations. Lastly, we make suggestions for capacity building and training in science diplomacy that focus on bringing the ‘world of science’ and the ‘world of diplomacy’, a distinction which emerged prominently from the literature and the interviews, together in useful ways.