Validation of precision-cut liver slices to study drug-induced cholestasis:A transcriptomics approach

Hepatotoxicity is one of the major reasons for withdrawal of drugs from the market. Therefore, there is a need to screen new drugs for hepatotoxicity in humans at an earlier stage. The aim of this study was to validate human precision-cut liver slices (PCLS) as an ex vivo model to predict drug-induced cholestasis and identify the possible mechanisms of cholestasis-induced toxicity using gene expression profiles. Five hepatotoxicants, which are known to induce cholestasis (alpha-naphthyl isothiocyanate, chlorpromazine, cyclosporine, ethinyl estradiol and methyl testosterone) were used at concentrations inducing low (<30 %) and medium (30-50 %) toxicity, based on ATP content. Human PCLS were incubated with the drugs in the presence of a non-toxic concentration (60 µM) of a bile acid mixture (portal vein concentration and composition) as model for bile acid-induced cholestasis. Regulated genes include bile acid transporters and cholesterol transporters. Pathway analysis revealed that hepatic cholestasis was among the top ten regulated pathways, and signaling pathways such as farnesoid X receptor- and liver X receptor-mediated responses, which are known to play a role in cholestasis, were significantly affected by all cholestatic compounds. Other significantly affected pathways include unfolded protein response and protein ubiquitination implicating the role of endoplasmic reticulum stress. This study shows that human PCLS incubated in the presence of a physiological bile acid mixture correctly reflect the pathways affected in drug-induced cholestasis in the human liver. In the future, this human PCLS model can be used to identify cholestatic adverse drug reactions of new chemical entities

A transcriptomic approach for evaluating the relative potency and mechanism of action of azoles in the rat Whole Embryo Culture.

We evaluated the effect of six azoles on embryonic development in the rat whole embryo culture (WEC). Using the total morphological scoring system (TMS), we calculated the ID10concentration (effective dose for 10% decrease in TMS). For evaluating gene specific responses, we combined previously and newly collected transcriptomics data of rat WEC exposed to a total of twelve azoles at their ID10for 4h. Results revealed shared expressions responses in genes involved in the retinoic acid (RA) and sterol biosynthesis pathways, which are respectively representatives of developmental toxicity and targeted fungicidal action of the azoles. Azoles with more pronounced effects on the regulation of RA-associated genes were generally characterized as more potent embryotoxicants. Overall, compounds with strong sterol biosynthesis related responses and low RA related responses were considered as more favourable candidates, as they specifically regulated genes related to a desired target response. Among the identified sterol associated genes, we detected that methylsterol monooxygenase 1 (Msmo1) was more sensitively induced compared to Cyp51, a classical biomarker of this pathway. Therefore, we suggest that Msmo1 could be a better biomarker for screening the fungicidal value of azoles. In summary, we conclude that the embryonic regulation of RA and sterol metabolic pathways could be indicators for ranking azoles as embryotoxicants and determining their drug efficacy

Ultracompact, low-loss directional couplers on InP based on self-imaging by multimode interference

We report extremely compact (494-µm-long 3 dB splitters, including input/output bends), polarization-insensitive, zero-gap directional couplers on InP with a highly multimode interference region that are based on the self-imaging effect. We measured cross-state extinctions better than 28 dB and on-chip insertion losses of 0.5 dB/coupler plus 1 dB/cm guide propagation loss at 1523 nm wavelength

Ultracompact monolithic integration of balanced, polarization diversity photodetectors for coherent lightwave receivers

The authors have monolithically integrated an optical front-end on InP for balanced, polarization-diversity coherent lightwave reception which is only 1.3-mm long. Low on-chip insertion loss (<4.5 dB) and balanced photoresponse (1.05:1 or better) are achieved at 1.5-μm wavelength using straightforward, regrowth-free fabrication. Low-capacitance photodetectors (≤0.15 pF) are employed for high bandwidth operation

Meta-Analysis of Pulmonary Transcriptomes from Differently Primed Mice Identifies Molecular Signatures to Differentiate Immune Responses following Bordetella pertussis

Respiratory infection with Bordetella pertussis leads to severe effects in the lungs. The resulting immunity and also immunization with pertussis vaccines protect against disease, but the induced type of immunity and longevity of the response are distinct. In this study the effects of priming, by either vaccination or infection, on a subsequent pathogen encounter were studied. To that end, three postchallenge transcriptome datasets of previously primed mice were combined and compared to the responses in unprimed control mice. In total, 205 genes showed different transcription activity. A coexpression network analysis assembled these genes into 27 clusters, combined into six groups with overlapping biological function. Local pulmonary immunity was only present in mice with infection-induced immunity. Complement-mediated responses were more prominent in mice immunized with an outer membrane vesicle pertussis vaccine than in mice that received a whole-cell pertussis vaccine. Additionally, 46 genes encoding for secreted proteins may serve as markers in blood for the degree of protection (Cxcl9, Gp2, and Pla2g2d), intensity of infection (Retnla, Saa3, Il6, and Il1b), or adaptive recall responses (Ighg, C1qb). The molecular signatures elucidated in this study contribute to better understanding of functional interactions in challenge-induced responses in relation to pertussis immunity

‘What are you going to do, confiscate their passports?’ Professional perspectives on cross-border reproductive travel

Objective: This article reports findings from a UK-based study which explored the phenomenon of overseas travel for fertility treatment. The first phase of this project aimed to explore how infertility clinicians and others professionally involved in fertility treatment understand the nature and consequences of cross-border reproductive travel. Background: There are indications that, for a variety of reasons, people from the UK are increasingly travelling across national borders to access assisted reproductive technologies. While research with patients is growing, little is known about how ‘fertility tourism’ is perceived by health professionals and others with a close association with infertility patients. Methods: Using an interpretivist approach, this exploratory research included focussed discussions with 20 people professionally knowledgeable about patients who had either been abroad or were considering having treatment outside the UK. Semi-structured interviews were recorded, transcribed verbatim and subjected to a thematic analysis. Results: Three conceptual categories are developed from the data: ‘the autonomous patient’; ‘cross-border travel as risk’, and ‘professional responsibilities in harm minimisation’. Professionals construct nuanced, complex and sometimes contradictory narratives of the ‘fertility traveller’, as vulnerable and knowledgeable; as engaged in risky behaviour and in its active minimisation. Conclusions: There is little support for the suggestion that states should seek to prevent cross-border treatment. Rather, an argument is made for less direct strategies to safeguard patient interests. Further research is required to assess the impact of professional views and actions on patient choices and patient experiences of treatment, before, during and after travelling abroad

Universal Rights and Wrongs

This paper argues for the important role of customers as a source of competitive advantage and firm growth, an issue which has been largely neglected in the resource-based view of the firm. It conceptualizes Penrose’s (1959) notion of an ‘inside track’ and illustrates how in-depth knowledge about established customers combines with joint problem-solving activities and the rapid assimilation of new and previously unexploited skills and resources. It is suggested that the inside track represents a distinct and perhaps underestimated way of generating rents and securing long-term growth. This also implies that the sources of sustainable competitive advantage in important respects can be sought in idiosyncratic interfirm relationships rather than within the firm itself

Peripheral Nerve Regeneration and Functional Nerve Recovery After Reconstruction with a Thin-Walled Biodegradable Poly(DL-lactide-ε-caprolactone) Nerve Guide

The aim of this study was to evaluate functional nerve recovery after reconstruction of a 1 em gap in the sciatic nerve of the rat, with a thin-walled biodegradable poly(DLLA-ε-CL) nerve guide. To evaluate both motor and sensory nerve recovery, walking track analysis and electrostimulation tests were carried out after implantation periods ranging from 3 to 26 weeks post-operatively. The first signs of functional nerve recovery could already be observed after 5 weeks. From the histological analysis, it could be concluded that most of the thin-walled nerve guides had collapsed. Despite collapsing, functional nerve recovery was relatively good after 26 weeks (motor nerve recovery 54% and sensory nerve recovery 100%), probably due to guidance of the regenerating nerve fibers along the outside of the poly(DLLA-ε-CL) nerve guide. This thin-walled nerve guide should, therefore, be used in combination with mechanical support

Manager migration, learning-by-hiring, and cultural distance in international soccer

Research Summary: We investigate the international transfer of managerial know-how by analyzing manager migration patterns in the setting of international soccer. We characterize a country's managerial know-how by estimating a stochastic frontier model, which relates the country's soccer performance to socioeconomic and climatic conditions. We find evidence of learning-by-hiring in that hiring a migrant manager hailing from a high know-how country is beneficial to the destination country's performance. Larger cultural distance between the migrant manager and destination country reduces the effectiveness of learning-by-hiring, but this effect is moderated by the migrant manager's prior international experience. The transfer of managerial know-how contributes to the overall convergence of low-performing versus high-performing soccer countries. Managerial Summary: In this study, we ask whether firms in developing countries, which often suffer from having low-quality manage

Gene Expression Profiling in a Mouse Model Identifies Fetal Liver- and Placenta-Derived Potential Biomarkers for Down Syndrome Screening

BACKGROUND: As a first step to identify novel potential biomarkers for prenatal Down Syndrome screening, we analyzed gene expression in embryos of wild type mice and the Down Syndrome model Ts1Cje. Since current Down Syndrome screening markers are derived from placenta and fetal liver, these tissues were chosen as target. METHODOLOGY/PRINCIPAL FINDINGS: Placenta and fetal liver at 15.5 days gestation were analyzed by microarray profiling. We confirmed increased expression of genes located at the trisomic chromosomal region. Overall, between the two genotypes more differentially expressed genes were found in fetal liver than in placenta. Furthermore, the fetal liver data are in line with the hematological aberrations found in humans with Down Syndrome as well as Ts1Cje mice. Together, we found 25 targets that are predicted (by Gene Ontology, UniProt, or the Human Plasma Proteome project) to be detectable in human serum. CONCLUSIONS/SIGNIFICANCE: Fetal liver might harbor more promising targets for Down Syndrome screening studies. We expect these new targets will help focus further experimental studies on identifying and validating human maternal serum biomarkers for Down Syndrome screening