Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Galeterone and Abiraterone as Inhibitors of Dehydroepiandrosterone Sulfonation Catalyzed by Human Hepatic Cytosol, SULT2A1, SULT2B1b, and SULT1E1

Galeterone and abiraterone acetate are antiandrogens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1) and compared their effects to those of other antiandrogens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 μM) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols. Enzyme kinetic analysis showed that galeterone and abiraterone acetate inhibited human liver cytosolic DHEA sulfonation with apparent Ki values at submicromolar concentrations, whereas cyproterone acetate, spironolactone, and danazol inhibited it with apparent Ki values at low micromolar concentrations. The temporal pattern of abiraterone formation and abiraterone acetate depletion suggested that the metabolite abiraterone, not the parent drug abiraterone acetate, was responsible for the inhibition of DHEA sulfonation in incubations containing human liver cytosol and abiraterone acetate. Consistent with this proposal, similar apparent Ki values were obtained, regardless of whether abiraterone or abiraterone acetate was added to the enzymatic incubation. Abiraterone was more effective than abiraterone acetate in inhibiting DHEA sulfonation when catalyzed by human recombinant SULT2A1 or SULT2B1b. In conclusion, galeterone and abiraterone are novel inhibitors of DHEA sulfonation, as determined in enzymatic incubations containing human tissue cytosol (liver or intestinal) or human recombinant SULT enzyme (SULT2A1, SULT2B1b, or SULT1E1). Our findings on galeterone and abiraterone may have implications in drug-drug interactions and biosynthesis of steroid hormones.
Value Relativism and Perspective Taking are Two Distinct Facets of Wisdom-Related Knowledge

Objectives There has been mixed evidence for age differences in wisdom-related knowledge across the adult life span. This study investigated two potential moderators of the link between age and wisdom-related knowledge: the wisdom criteria and the wisdom tasks. Method To test these moderators, 40 younger and 40 older participants completed four wisdom tasks differing in context-richness. Independent trained raters coded the resulting think-aloud protocols in terms of value relativism, as defined in the Berlin wisdom paradigm, and perspective taking, as defined by Grossmann. Results The type of task did not show any main or interaction effects on the present two wisdom criteria. However, age differences in the two wisdom criteria were multidirectional: whereas perspective taking did not differ by age group, value relativism was lower in older than younger adults. In addition, value relativism, but not perspective taking, was related to measures of fluid and crystallized intelligence, whereas perspective taking, but not value relativism, was related to a measure of life investment. Discussion This study provides evidence for the idea that value relativism and perspective taking are two distinct facets of wisdom-related knowledge. Implications for future age-comparative research interested in wisdom are discussed.
A Mathematical Framework to Evaluate Flexible Outdoor User Association in Urban Two-Tier Cellular Networks

In this paper, we present a mathematical framework to evaluate the performance of a typical outdoor user in an urban two-tier mobile network under a biased user association. The urban environment is abstracted by a Boolean scheme of blockages, which affects the deployment of outdoor base stations (BSs) and indoor small cell BSs, and the signal propagation characteristics of the wireless channels. A building is served by an indoor small cell BS with a certain probability, which we denote as occupation probability. Employing tools from stochastic geometry, we derive mathematical expressions for the coverage probability and the average spectral efficiency of a typical outdoor user. Numerical evaluations are carried out with the third generation partnership project compliant outdoor BS scenarios. Our results show that the increasing blockage density has a negative impact on the spectral efficiency in sparse outdoor BSs scenarios, but it has a positive impact on the performance of the network in dense outdoor BSs scenarios. We build our analysis on several assumptions, which are verified by extensive Monte Carlo simulations.
Journal of Enterprise Information Management The Role of IT in Automotive Supplier Supply Chains

Purpose—This research explores the impact of IT on supply chain performance in the automotive industry. Prior studies that analyzed the impact of IT on supply chain performance report results representing the situation of the “average industry. ” This research focuses on the automotive industry because of its major importance in many national economies and due to the fact that automotive supply chains do not represent the supply chain of the average industry. Design/methodology/approach—A research model is proposed to examine the relationships between IT capabilities, supply chain capabilities, and supplier performance. The model divides IT capabilities into functional and data capabilities, and supply chain capabilities into internal process excellence and information sharing. Data has been collected from 343 automotive first-tier suppliers. Structural equation modeling with partial least squares is used to analyze the data. Findings—The results suggest that functional capabilities have the greatest impact on internal process excellence, which in turn enhances supplier performance. However, frequent and adequate information sharing also contributes significantly to supplier performance. Data capabilities enable supply chain capabilities through their positive impact on functional capabilities. Practical implications—The findings will help managers to understand the effect of IT implementation on company performance and to decide whether to invest in the expansion of IT capacities. Originality/value—This research reports the impact of IT on supply chain performance in one of the most important industries in many industrialized countries, and it provides a new perspective on evaluating the contribution of IT on firm performance.
Developing Social Media-Based Suicide Prevention Messages in Partnership With Young People: Exploratory Study

Background Social media is increasingly being used by young people for health-related issues, including communicating about suicide. Due to the concerns about causing distress or inducing suicidal thoughts or behaviors, to date young people neither have been engaged in the development of social media–based suicide prevention interventions nor have interventions focused on educating young people about safe ways to communicate about suicide online. Given the potential that social media holds to deliver messages to vast numbers of people across space and time and the fact that young people often prefer to seek help from their friends and peers, safely educating and engaging young people to develop suicide prevention messages that can be delivered via social media is an obvious next step. Objectives The objectives of this study were to (1) provide education to a small number of secondary school students about safe ways to communicate about suicide via social media; (2) engage the same young people in the development of a suite of social media–based suicide prevention multimedia messages; (3) assess the impact of this on participants; and (4) assess the acceptability and safety of the messages developed. Methods This study involved two phases. In phase 1, 20 participants recruited from two schools took part in an 8- to 10-week program during which they were provided with psychoeducation about mental health and suicide, including how to talk safely about suicide online, and they were then supported to design and develop their own media messages. These participants completed an evaluation questionnaire at the conclusion of the program. In phase 2, a larger group of participants (n=69), recruited via an opt-in process, viewed the media messages and completed a short questionnaire about each one. Results Participants in phase 1 enjoyed the program and reported that they learned new skills, such as how to talk safely about suicide online, and felt more able to provide emotional support to others (16/20, 80%). No participants reported that the program made them feel suicidal. Participants in phase 2 generally rated the media messages as safe and acceptable, although some messages were rated more highly than others. Conclusions This study suggests that young people can be safely engaged in developing suicide prevention messages, which can be disseminated via social media. Engaging young people in this process may improve the traction that such campaigns will have with other young people. The study also suggests that educating young people regarding how to talk safely about suicide online has multiple benefits and is not associated with distress. Overall, these findings pave the way for new approaches to prevent suicide among young people.
Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides

Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-β1–16 peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 Å and 5°. Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-β1–16 peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 Å over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand.
Which Aspects of Social Support Are Associated With Which Cognitive Abilities for Which People?

Objectives To assess the relations between 11 aspects of social support and five cognitive abilities (vocabulary, reasoning, spatial visualization, memory, and speed of processing) and to determine whether these relations between social support and cognition are moderated by age or sex. Method A sample of 2,613 individuals between the ages of 18 and 99 years completed a battery of cognitive tests and a questionnaire assessing aspects of social support. A measure of general intelligence was computed using principal components analysis. Multiple regressions were used to evaluate whether each aspect of support and/or its interactions with age or sex predicted each cognitive ability and g. Results Several aspects of social support were significantly related to all five cognitive abilities and to g. When g was included as a predictor, there were few relations with specific cognitive abilities. Age and sex did not moderate any of the relations. Discussion These results suggest that contact with family and friends, emotional and informational support, anticipated support, and negative interactions are related to cognition, whereas satisfaction with and tangible support were not. In addition, these aspects of support were primarily related to g, with the exception of family contact. Social support- cognition relations are comparable across the life span and the sexes.
Hepatitis B Virus Reactivation in Patients Receiving Interferon-Free Direct-Acting Antiviral Agents for Chronic Hepatitis C Virus Infection

Abstract Background Little is known about the risk of hepatitis B virus (HBV) reactivation in patients receiving interferon (IFN)-free direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV). Methods Patients who were seropositive for HBV core antibody and who received IFN-free DAAs for HCV were enrolled. Hepatitis B virus reactivation was defined as reappearance of serum HBV deoxyribonucleic acid (DNA) ≥100 IU/mL in patients with baseline undetectable viral load, or ≥2 log10 IU/mL increase of HBV DNA in patients with baseline detectable viral load. Hepatitis B virus-related alanine aminotransferase (ALT) flare was defined as ALT ≥5 times upper limit of normal or ≥2 times of the baseline level. Hepatitis B virus-related hepatic decompensation was defined as presence of jaundice, coagulopathy, hepatic encephalopathy, or ascites. Results Compared with no HBV reactivation in 81 HBV surface antigen (HBsAg)-negative patients, 2 of 12 HBsAg-positive patients had HBV reactivation (0% [confidence interval {95% CI}, 0%–4.5%] vs 16.7% [95% CI, 4.7%–44.8%], P = .015). No patients had ALT flare or hepatic decompensation. Baseline HBsAg level at a cutoff value of 500 IU/mL was associated with HBV reactivation in HBsAg-positive patients. There was no HBsAg seroreversion in HBsAg-negative patients. Conclusions Hepatitis B virus reactivation is limited to HBsAg-positive patients receiving IFN-free DAAs for HCV. Higher baseline HBsAg levels are associated with HBV reactivation. The risk of ALT flares or hepatic decompensation is low in these patients.
Isorhynchophylline, a Potent Plant Alkaloid, Induces Apoptotic and Anti-Metastatic Effects in Human Hepatocellular Carcinoma Cells through the Modulation of Diverse Cell Signaling Cascades

Isorhynchophylline (Rhy) is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of Rhy against various human carcinoma cell lines. We found that Rhy exhibited substantial cytotoxic effect against human hepatocellular carcinoma HepG2 cells when compared with other human carcinoma cell lines including those of lung, pancreas, prostate, head and neck, breast, multiple myeloma, brain and renal cell carcinoma. Rhy induced apoptosis as characterized by accumulation of cells in sub G1 phase; positive Annexin V binding; activation of caspase-8, -9, and -3; and cleavage of PARP (poly-ADP ribose polymerase). This effect of Rhy correlated with the down-regulation of various proteins that mediated cell proliferation, cell survival, metastasis, and angiogenesis. Moreover, cell proliferation, migration, and constitutive CXCR4 (C-X-C chemokine receptor type 4), MMP-9 (Matrix metallopeptidase-9), and MMP-2 expression were inhibited upon Rhy treatment. We further investigated the effect of Rhy on the oncogenic cell signaling cascades through phospho-kinase array profiling assay. Rhy was found to abrogate phospho-p38, ERK, JNK, CREB, c-Jun, Akt, and STAT3 signals, but interestingly enhanced phospho-p53 signal. Overall, our results indicate, for the first time, that Rhy could exert anticancer and anti-metastatic effects through regulation of multiple signaling cascades in hepatocellular carcinoma cells.
The role of life histories and trophic interactions in population recovery

Factors affecting population recovery from depletion are at the focus of wildlife management. Particularly, it has been debated how life‐history characteristics might affect population recovery ability and productivity. Many exploited fish stocks have shown temporal changes towards earlier maturation and reduced adult body size, potentially owing to evolutionary responses to fishing. Whereas such life‐history changes have been widely documented, their potential role on stock's ability to recover from exploitation often remains ignored by traditional fisheries management. We used a marine ecosystem model parameterized for Southeastern Australian ecosystem to explore how changes towards “faster” life histories might affect population per capita growth rate r. We show that for most species changes towards earlier maturation during fishing have a negative effect (3–40% decrease) on r during the recovery phase. Faster juvenile growth and earlier maturation were beneficial early in life, but smaller adult body sizes reduced the lifetime reproductive output and increased adult natural mortality. However, both at intra‐ and inter‐specific level natural mortality and trophic position of the species were as important in determining r as species longevity and age of maturation, suggesting that r cannot be predicted from life‐history traits alone. Our study highlights that factors affecting population recovery ability and productivity should be explored in a multi‐species context, where both age‐specific fecundity and survival schedules are addressed simultaneously. It also suggests that contemporary life‐history changes in harvested species are unlikely to increase their resilience and recovery ability.
The Neurocognitive Profile of Attention-Deficit/Hyperactivity Disorder: A Review of Meta-Analyses

Objective Numerous meta-analyses have summarized studies comparing the neurocognitive performance of individuals with attention-deficit/hyperactivity disorder (ADHD) to that of healthy controls. Method The present study is a systematic review and quantitative summary of those meta-analyses that aimed to determine the extent to which individuals with ADHD differ cognitively from typically developing controls. Results Of 253 standardized mean differences (SMDs) drawn from 34 meta-analyses, 244 (96%) were positive, indicating better neurocognitive performance in the control group than the ADHD group. The mean effect size was . 45 (SD = .27). Unweighted means of SMDs for neurocognitive domains ranged from . 35 (set shifting) to . 54 (working memory). When weighted by the number of studies aggregated, they ranged from . 35 (set shifting) to . 66 (reaction time variability). Neurocognitive domains with mean effects over . 50 included working memory (.54), reaction time variability (.53), response inhibition (.52), intelligence/achievement (.51), and planning/organization (.51). When weighted by number of aggregated studies, the domains with mean effects over . 50 were reaction time variability (.66), intelligence/achievement (.60), vigilance (.56), working memory (.54), and response inhibition (.52). Age moderated the relationship between ADHD diagnosis and neurocognitive functioning, with greater between-groups differences among children and adults than among adolescents. Funding also moderated this relationship: meta-analyses that received drug funding found larger effect sizes than those without drug funding. Conclusions The evidence suggests that ADHD is associated with substantial deficits across a variety of neurocognitive domains. This is the most in-depth review of the neurocognitive functioning of people with ADHD to date.
Preliminary Evidence for Disrupted Nucleus Accumbens Reactivity and Connectivity to Reward in Binge Drinkers

Aims Dysfunctional brain reward circuitry, particularly in the nucleus accumbens (NAcc), has been proposed as a risk factor for alcohol use disorder (AUD). This risk factor may be evident in binge drinkers (BD), who are at high risk for developing AUD. We examined whole-brain and NAcc reactivity to reward in BD compared to non-binge drinkers (NBD), hypothesizing that groups would differ in their neural reactivity and connectivity. Methods Healthy BD (N = 27) and NBD (N = 23)-none meeting AUD criteria-completed a reward-guessing game, the 'Doors' task, during functional magnetic resonance imaging. We conducted an exploratory whole-brain search for group differences, but given our a priori hypotheses, we also extracted activation from the NAcc to examine reactivity during reward (Win > Loss) and functional connectivity (FC) to the prefrontal cortex. Results Compared to NBD, BD exhibited greater activation in both the right and left NAcc during reward relative to loss. Additionally, NBD drinkers exhibited positive FC between the NAcc and dorsal anterior cingulate (dACC) whereas the BD showed negative FC between these regions. Furthermore, less NAcc-dACC FC was related to more past month alcohol use. Conclusions Our results provide preliminary evidence that BD exhibit greater NAcc activation during reward receipt relative to loss. This is consistent with the broader AUD literature and suggests aberrant neural reactivity may precede disorder onset. In addition, BD exhibited less NAcc-dACC FC, perhaps reflecting deficient regulation of activation to rewards compared to losses. This profile of reward brain circuitry could represent neural correlates of vulnerability for AUD. Short summary Healthy binge drinkers, at risk for alcohol use disorder, exhibited greater nucleus accumbens activation during reward relative to loss. In addition, binge drinkers exhibited reduced connectivity between the nucleus accumbens and dorsal anterior cingulate, which was associated with more past month alcohol use.
Premature Ovarian Insufficiency in Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort

Context Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited. Objective To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes. Design Cross-sectional. Setting The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center. Patients Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis. Main Outcome Measure POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED). Results The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI. Conclusion High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.