Miracle-dz/UniFAR-FTUs huggingface dataset:
Morphological and Functional Characterization and Assessment of iPSC-Derived Hepatocytes for In Vitro Toxicity Testing.

Drug-induced liver injury (DILI) remains a great challenge and a major concern during late-stage drug development. Induced pluripotent stem cells (iPSC) represent an exciting alternative in vitro model system to explore the role of genetic diversity in DILI, especially when derived from patients who have experienced drug-induced hepatotoxicity. The development and validation of the iPSC-derived hepatocytes as an in vitro cell-based model of DILI is an essential first step in creating more predictive tools for understanding patient-specific hepatotoxic responses to drug treatment. In this study, we performed extensive morphological and functional analyses on iPSC-derived hepatocytes from a commercial source. iPSC-derived hepatocytes exhibit many of the key morphological and functional features of primary hepatocytes, including membrane polarity and production of glycogen, lipids, and key hepatic proteins, such as albumin, asialoglycoprotein receptor and α1-antitrypsin. They maintain functional activity for many drug-metabolizing enzyme pathways and possess active efflux capacity of marker substrates into bile canalicular compartments. Whole genome-wide array analysis of multiple batches of iPSC-derived cells showed that their transcriptional profiles are more similar to those from neonatal and adult hepatocytes than those from fetal liver. Results from experiments using prototype DILI compounds, such as acetaminophen and trovafloxacin, indicate that these cells are able to reproduce key characteristic metabolic and adaptive responses attributed to the drug-induced hepatotoxic effects in vivo. Overall, this novel system represents a promising new tool for understanding the underlying mechanisms of idiosyncratic DILI and for screening new compounds for DILI-related liabilities.
The Antiprion Compound 6-Aminophenanthridine Inhibits the Protein Folding Activity of the Ribosome by Direct Competition*

Background: 6-Aminophenanthridine (6AP) is an inhibitor of the protein folding activity of the ribosome (PFAR). Results: The protein substrates and 6AP bind at common sites on rRNA; mutations at those sites abolish binding and inhibit PFAR. Conclusion: 6AP competitively obstructs the protein-binding sites and thereby inhibits PFAR. Significance: We have clarified the mechanism by which 6AP inhibits PFAR. Domain V of the 23S/25S/28S rRNA of the large ribosomal subunit constitutes the active center for the protein folding activity of the ribosome (PFAR). Using in vitro transcribed domain V rRNAs from Escherichia coli and Saccharomyces cerevisiae as the folding modulators and human carbonic anhydrase as a model protein, we demonstrate that PFAR is conserved from prokaryotes to eukaryotes. It was shown previously that 6-aminophenanthridine (6AP), an antiprion compound, inhibits PFAR. Here, using UV cross-linking followed by primer extension, we show that the protein substrates and 6AP interact with a common set of nucleotides on domain V of 23S rRNA. Mutations at the interaction sites decreased PFAR and resulted in loss or change of the binding pattern for both the protein substrates and 6AP. Moreover, kinetic analysis of human carbonic anhydrase refolding showed that 6AP decreased the yield of the refolded protein but did not affect the rate of refolding. Thus, we conclude that 6AP competitively occludes the protein substrates from binding to rRNA and thereby inhibits PFAR. Finally, we propose a scheme clarifying the mechanism by which 6AP inhibits PFAR.
A phase I trial assessing the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of single‐dose Auron Misheil therapy in healthy male subjects

Background and objective: Auron Misheil therapy (AMT) is a combination of widely used pharmaceuticals and herbal components that has been used since the 1980s as a supportive therapy, mainly in end‐stage cancer patients on a compassionate basis. This phase I study was conducted to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of AMT in a controlled trial environment.
The Catalytic Subunit of Protein Phosphatase 2A (PP2Ac) Promotes DNA Hypomethylation by Suppressing the Phosphorylated Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (ERK) Kinase (MEK)/Phosphorylated ERK/DNMT1 Protein Pathway in T-cells from Controls and Systemic Lupus Erythe

Background: PP2A is a serine/threonine phosphatase with a central role in the pathogenesis of SLE. Results: Suppression of PP2A mediates increased DNA methylation through the MEK/ERK/DNMT1 pathway in normal and SLE T-cells. Conclusion: PP2A overexpression accounts for DNA hypomethylation in SLE T-cells. Significance: Here, we propose a link between increased PP2A expression and reduced DNA methylation in SLE. DNA hypomethylation is a characteristic feature of systemic lupus erythematosus (SLE) immune cells. Numerous reports have implicated the involvement of the MEK/ERK pathway in the reduction of DNA methyltransferase (DNMT) expression, hence inducing the transcription of methylation-sensitive genes in SLE patients. However, the molecular mechanisms involved remain unclear. Here, we investigated whether the catalytic subunit of protein phosphatase 2A (PP2Ac), which is overexpressed in SLE T-cells, contributes to reduced DNA methylation. We show that both chemical suppression and siRNA silencing of PP2Ac in T-cells resulted in sustained phosphorylation of MEK and ERK following stimulation with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, PP2Ac suppression resulted in increased DNMT enzyme activity, DNA hypermethylation, and decreased expression of methylation-sensitive genes. Similarly, in SLE T-cells, suppression of PP2Ac resulted in increased MEK/ERK phosphorylation, enhanced DNMT1 expression and suppressed expression of the methylation-sensitive CD70 gene. Our results demonstrate that PP2A regulates DNA methylation by influencing the phosphorylation of MEK/ERK. We propose that enhanced PP2Ac in SLE T-cells may dephosphorylate and activate the signaling pathway upstream of DNMT1, thus disturbing the tight control of methylation-sensitive genes, which are involved in SLE pathogenesis.
Vitamin D Receptor Inhibits Nuclear Factor κB Activation by Interacting with IκB Kinase β Protein*

Background: 1,25(OH)2D3 inhibits NF-κB activation by an undefined mechanism. Results: Vitamin D receptor protein binds to IKKβ protein, blocking TNFα-induced IKK complex formation and NF-κB activity. Conclusion: The vitamin D receptor suppresses NF-κB activation by directly interacting with IKKβ. Significance: This is a novel mechanism whereby 1,25(OH)2D3-VDR inhibits NF-κB. 1,25-Dihydroxyvitamin D (1,25(OH)2D3) is known to suppress NF-κB activity, but the underlying mechanism remains poorly understood. Here we show that the vitamin D receptor (VDR) physically interacts with IκB kinase β (IKKβ) to block NF-κB activation. 1,25(OH)2D3 rapidly attenuates TNFα-induced p65 nuclear translocation and NF-κB activity in a VDR-dependent manner. VDR overexpression inhibits IKKβ-induced NF-κB activity. GST pull-down assays and coimmunoprecipitation experiments demonstrated that VDR physically interacts with IKKβ and that this interaction is enhanced by 1,25(OH)2D3. Protein mapping reveals that VDR-IKKβ interaction occurs between the C-terminal portions of the VDR and IKKβ proteins. Reconstitution of VDR−/− cells with the VDR C terminus restores the ability to block TNFα-induced NF-κB activation and IL-6 up-regulation. VDR-IKKβ interaction disrupts the formation of the IKK complex and, thus, abrogates IKKβ phosphorylation at Ser-177 and abolishes IKK activity to phosphorylate IκBα. Consequently, stabilization of IκBα arrests p65/p50 nuclear translocation. Together, these data define a novel mechanism whereby 1,25(OH)2D3-VDR inhibits NF-κB activation.
Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model.

Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships.
Evaluation of health services use following the initiation of risperidone long‐acting therapy among schizophrenia patients in the veterans health administration

What is known and Objective: The introduction of long‐acting injection antipsychotic agents has been associated with better treatment persistence and better subsequent patient outcomes. However, limited empirical data are available on patient outcomes resulting from the initiation of long‐acting injectable antipsychotic agents. In this study, we assessed patterns of health‐care utilization following the initiation of risperidone long‐acting therapy (RLAT), the first and only second generation long‐acting injectable antipsychotic agent, in schizophrenia patients within the Veterans Health Administration.
PENGARUH POSISI KERJA TERHADAP KEJADIAN LOW BACK PAIN PADA PEKERJA DI KAMPUNG SEPATU, KELURAHAN MIJI, KECAMATAN PRAJURIT KULON, KOTA MOJOKERTO

Low Back Pain is the main symptom on the report it to health practitioners associated with decreased work productivity. Low Back Pain associated with frequent lifting, carrying, pushing and pulling of heavy goods, frequent or long to bend the body, bending, sitting or standing for long or other body posture is not natural. standing in the long term, the body can only tolerate stood with one position only for 20 minutes. If more than these limits, the elasticity of the tissue will decrease gradually and finally the pressure increased and muscle discomfort arises on the back. The ergonomics work positions be a deciding factor of occurrence of Low Back Pain. This research aims to know the influence of the working position of the genesis of Low Back Pain, and compare the influence of two working positions (standing and seated) against the occurrence of Low Back Pain. Based on data results showed that job position does have an impact on incidence of Low Back Pain. Evidenced by the results of the statistical test of Chi Square Test Crosstab values X2 count or value of the Pearson Chi-Square Test is 8,480 and the Degree of Freedom (df) is worth 3. And the value of Asymp. Sig (2-sided) is 0,037. The second comparison results analysis of the position of sitting and standing work, then both positions work standing or sitting equally had a significant influence on the incidence of Low Back Pain. However, when compared in more detail, seated position has the more influence than the standing position , it can be proved by the results of Chi Square Test Crosstab, the value of X2 count on higher seating position work i.e. 14,267 compared with 13,467 standing work position. Keywords: working position, low back pain, ergonomy
Capecitabine for the treatment for advanced gastric cancer: efficacy, safety and ethnicity

What is known and Objective: Capecitabine‐ and 5‐fluorouracil (5‐FU)‐based regimens are widely used for the treatment for advanced gastric cancer (AGC). We aimed to compare the efficacy of the two regimens for both Caucasian and Asian subjects, through a meta‐analysis of the available trial evidence.
Mechanisms of Mitochondrial Damage in Keratinocytes by Pemphigus Vulgaris Antibodies*

Background: Previous studies suggested that mitochondrial antibodies contribute to pemphigus vulgaris (PV). Results: PV sera elicited mitochondrial damage, and mitochondria-protecting drugs exhibited protective effect in cell culture and mouse skin. Conclusion: PV antibodies altered O2 respiration, disrupted electron transfer chain, and increased reactive oxygen species. Significance: Results provide the mechanism of therapeutic action and justify the use of mitochondria-protecting drugs in PV. The development of nonhormonal treatment of pemphigus vulgaris (PV) has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte (KC) detachment and death in pemphigus. In this study, we sought to identify changes in the vital mitochondrial functions in KCs treated with the sera from PV patients and healthy donors. PV sera significantly increased proton leakage from KCs, suggesting that PV IgGs increase production of reactive oxygen species. Indeed, measurement of intracellular reactive oxygen species production showed a drastic increase of cell staining in response to treatment by PV sera, which was confirmed by FACS analysis. Exposure of KCs to PV sera also caused dramatic changes in the mitochondrial membrane potential detected with the JC-1 dye. These changes can trigger the mitochondria-mediated intrinsic apoptosis. Although sera from different PV patients elicited unique patterns of mitochondrial damage, the mitochondria-protecting drugs nicotinamide (also called niacinamide), minocycline, and cyclosporine A exhibited a uniform protective effect. Their therapeutic activity was validated in the passive transfer model of PV in neonatal BALB/c mice. The highest efficacy of mitochondrial protection of the combination of these drugs found in mitochondrial assay was consistent with the ability of the same drug combination to abolish acantholysis in mouse skin. These findings provide a theoretical background for clinical reports of the efficacy of mitochondria-protecting drugs in PV patients. Pharmacological protection of mitochondria and/or compensation of an altered mitochondrial function may therefore become a novel approach to development of personalized nonhormonal therapies of patients with this potentially lethal autoimmune blistering disease.
Gender and falls : perceptions of older people and their key family members

This thesis explores the ways in which gender impacts upon the construction of the meaning and risk of falling among older people who have had recurrent falls, and their key family members. Older people aged 65 and over, who have had two or more falls in the past 12 months were studied. In depth interviews were conducted with 40 older people, consisting of twenty older men and twenty older women, and 35 key family members. The family members consisted of mainly sons (n=ll) and daughters (n=17); the remainder comprised wives (n=4), a brother (n=l), and nieces (n=2). All interviews were tape-recorded, fully transcribed and analysed using NUD*IST. The social meaning of falls constructed by older people who have had falls revolves around three inter-related components: the language of falls, gendered stigma associated with private and public falls, and gendered disruption. Risk perception of falls by older people is linked to gendered notions of how 'at risk' they were, their awareness of risk, and the responsibilities attached to risk taking. Older men were more likely than older women to see themselves as rational individuals who would not deliberately put themselves at risk. The subsequent actions taken by older people to prevent future falls were gendered; older men were not only more pro-active in that they initiated more actions but were more often encouraged by family members to make decisions. Older men drew upon their gender identity and social position within the family, to exert control over what should or ought to be done, in order to minimise their risk of falling. In contrast, older women's exertion of control was less evident. The gender of the older person and their key family member influenced their respective actions. The power imbalance between men and women resulted in the younger male within the older female/younger male dyads undertaking 'protective' actions and 'coercive' actions. Within the older male/younger female dyads, the power imbalance resulted in daughters undertaking 'engaging' and 'negotiating' actions. Similarly 'negotiating' as well as some 'engaging' actions were taken by the younger female member within the younger female/older female dyads, but these were explained as reflecting feminine sensitivity among women. The presence of 'mutual respect' within father/son and brotherlbrother dyads resulted in minimal actions being taken by both members of the dyad, due to the potential conflict arising from each trying to retain power and control. This study indicates that gender impacts upon the meaning of falls and the risk of falling with more older men perceiving falls to be discrediting. This, in tum, impacts upon the subsequent actions taken by older people and their key family members. However, older men who had had falls continue to retain their power resulting in more empowering types of actions taken by their key family members.
Editor's Highlight: Glutathione S‐Transferase Activity Moderates Methylmercury Toxicity During Development in Drosophila

&NA; Glutathione (GSH) pathways play a central role in methylmercury (MeHg) metabolism and elimination, largely due to formation of a more readily transported MeHg‐GSH conjugate. Glutathione S‐transferases (GSTs) have therefore been proposed to facilitate MeHg elimination by catalyzing MeHg‐GSH conjugation. A role for human GSTP1 in MeHg disposition is suggested by the association of two common polymorphisms in the coding region (Ile105Val and Ala114Val) with Hg levels in either blood or hair. In this study, we investigated a functional role for GSTs in modulating MeHg toxicity during development. Using the Drosophila model to execute targeted manipulations of both endogenous GSTs and introduced human GSTP1 variants we correlate gene and protein expression levels with GST activity and also with MeHg body burden and developmental outcomes. RNAi knockdown of endogenous GSTD1, GSTE1, or GSTS1, individually, increased susceptibility to MeHg during pupal development resulting in a reduced rate of adult eclosion. Exogenous expression of human GSTP1 in developing flies resulted in increased MeHg tolerance relative to control flies as seen with elevated eclosion rates when reared on MeHg containing food. Furthermore, the GSTP1105 and GSTP1114 variants showed a reduced enzyme activity relative to wild‐type GSTP1 (GSTP1wt). Finally, we observed a trend whereby Hg body burden was inversely related to the levels of GST activity. However, in some instances GSTP1 expression resulted in increased eclosion rates without reducing Hg body burden suggesting that GSTs interact with MeHg via both toxicokinetic and toxicodynamic mechanisms. These findings indicate that GSTs moderate MeHg toxicity during development in our experimental model.
Comparing and combining real and virtual experimentation: an effort to enhance students' conceptual understanding of electric circuits

The purpose of this study was to investigate value of combining Real Experimentation (RE) with Virtual Experimentation (VE) with respect to changes in students' conceptual understanding of electric circuits. To achieve this, a pre-post comparison study design was used that involved 88 undergraduate students. The participants were randomly assigned to an experimental (45 students) and a control group (43 students). Each group attended a one semester course in physics for preservice elementary school teachers. Both groups used the same inquiry-based curriculum materials. Participants in the control group used RE to conduct the study's experiments, whereas, participants in the experimental group used RE in the first part of the curriculum and VE in another part. Conceptual tests were administered to assess students' understanding of electric circuits before, during and after the teaching intervention. Results indicated that the combination of RE and VE enhanced students' conceptual understanding more than the use of RE alone. A further analysis showed that differences between groups on that part of the curriculum in which the experimental group used VE and the control group RE, in favour of VE.
Incidentie van gastro-enteritis inhuisartsenpeilstations in Nederland, 1992-1993

In the Netherlands gastroenteritis belongs to the ten diseases with the highest incidence rates. A sentinel study on the incidence of gastrointestinal complaints and the occurrence of the investigated pathogens (Campylobacter, Salmonella and Shigella) was carried out in about 40 general practices in 1992 and 1993. The sentinel stations were as representative as possible of the Dutch population. The study was undertaken by the National Institute of Public Health and Environmental Protection (RIVM) and the Netherlands Institute of Primary Health Care (NIVEL) in cooperation with the general practitioners who participated in the Dutch Sentinel Practice Network and 24 laboratories. Age and sex of patients who met the case definition were reported to the NIVEL. These patients were asked by their GP to provide a stool sample and to complete a questionnaire. The number of patients that were either reported to the NIVEL or have been given a questionnaire by their GP was estimated at about 2370. A completed questionnaire was received from 58.9% (1400/2370) of these patients. Eighty percent (1400/1744) of the cases completed the questionnaire they received. Results of microbiological analysis were obtained for 89.1% (1248/1400) of patients who completed the questionnaire. The crude incidence rate of acute gastrointestinal complaints was 55.3 per 10,000 person years, after correction for non response it was 89.9 per 10,000 person years. The incidence was lower in 1993 than in 1992. Between men and women no differences have been found. The highest incidences have been found in the agegroups under five. The incidence rate for Campylobacter was 6.9 per 10,000 person years (182 samples positive), for Salmonella 2.2 (55 samples positive) and for Shigella 0.4 per 10,000 person years (10 samples positive). After correction for non response these incidences were 11.7 and 3.5 and 0.6 per 10,000 person years. The Salmonella incidence rate was higher in 1993 than in 1992 and higher in men than in women. The highest incidence rates for Campylobacter and Salmonella were found in the agegroups under five. The (late) summer months as expected, showed the highest incidence rates. Incidence rates for gastroenteritis as well as for microorganisms were lower than incidences found in other sentinels. To follow trends in incidence rates and microorganisms it is necessary to undertake sentinels repeatedly with the same methodology and population. However results cannot be generalised to the general population and consequently it remains necessary to carry out a population cohort study every 5 to 10 years.