Host space, not energy or symbiont size, constrains feather mite abundance across passerine bird species.

Comprehending symbiont abundance among host species is a major ecological endeavour, and the metabolic theory of ecology has been proposed to understand what constrains symbiont populations. We parameterized metabolic theory equations to investigate how bird species' body size and the body size of their feather mites relate to mite abundance according to four potential energy (uropygial gland size) and space constraints (wing area, total length of barbs and number of feather barbs). Predictions were compared with the empirical scaling of feather mite abundance across 106 passerine bird species (26,604 individual birds sampled), using phylogenetic modelling and quantile regression.

Genetic toxicology in silico protocol.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol.

In vitro screening of cell bioenergetics to assess mitochondrial dysfunction in drug development.

Drug-induced mitochondrial toxicity is considered as a common cellular mechanism that can induce a variety of organ toxicities. In the present manuscript, 17 in vitro mitochondrial toxic drugs, reported to induce Drug-Induced Liver Injury (DILI) and 6 non-mitochondrial toxic drugs (3 with DILI and 3 without DILI concern), were tested in HepG2 cells using a bioenergetics system. The 17 mitochondrial toxic drugs represent a wide variety of mitochondrial dysfunctions as well as DILI and include 4 pairs of drugs which are structurally related but associated with different DILI concerns in human.

Current trends in in silico, in vitro toxicology, and safety biomarkers in early drug development.

The development of new medicines is a long and expensive process. Despite growing efforts in R&D over the last decades, attrition rate due to safety issues (especially cardiac and hepatic toxicity) remains a major challenge for the pharmaceutical industry. This may lead to market withdrawal or late stage halting of a drug development program.

Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans.

Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority.

Alpha synuclein dimers and oligomers are increased in overexpressing conditions in vitro and in vivo.

Parkinson's disease is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the formation of intracellular fibrillar inclusions (Lewy bodies and Lewy neuritis), which are mainly composed of aggregated α-synuclein (ASYN). This latter is a 14 kDa protein that localizes to synaptic vesicles in nerve terminals and promotes soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex assembly. We explored the monomeric and oligomeric state of ASYN in vitro in HEK293s and SH-SY5Y cell lines.

Repeatability of feather mite prevalence and intensity in passerine birds.

Understanding why host species differ so much in symbiont loads and how this depends on ecological host and symbiont traits is a major issue in the ecology of symbiosis. A first step in this inquiry is to know whether observed differences among host species are species-specific traits or more related with host-symbiont environmental conditions. Here we analysed the repeatability (R) of the intensity and the prevalence of feather mites to partition within- and among-host species variance components.

Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans.

Drug induced liver injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies.

Evaluation of impedance-based label-free technology as a tool for pharmacology and toxicology investigations.

The use of label-free technologies based on electrical impedance is becoming more and more popular in drug discovery. Indeed, such a methodology allows the continuous monitoring of diverse cellular processes, including proliferation, migration, cytotoxicity and receptor-mediated signaling. The objective of the present study was to further assess the usefulness of the real-time cell analyzer (RTCA) and, in particular, the xCELLigence platform, in the context of early drug development for pharmacology and toxicology investigations.

The automated micronucleus assay for early assessment of genotoxicity in drug discovery.

Recent publications on the automated in vitro micronucleus assay show predictive values higher than 85% for the classification of in vitro aneugens, clastogens and non-genotoxic compounds. In the present work, the CHO-k1 micronucleus assay in combination with cellular imaging was further evaluated. Firstly, the effect of a range of S9 concentrations on micronucleus formation and cytotoxicity was investigated.

Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins.

In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e.

Transcriptomic effects of di-(2-ethylhexyl)-phthalate in Syrian hamster embryo cells: an important role of early cytoskeleton disturbances in carcinogenesis?

Background: Di-(2-ethylhexyl)-phthalate (DEHP) is a commonly used plasticizer in polyvinylchloride (PVC) formulations and a potentially non-genotoxic carcinogen. The aim of this study was to identify genes whose level of expression is altered by DEHP by using a global wide-genome approach in Syrian hamster embryo (SHE) cells, a model similar to human cells regarding their responses to this type of carcinogen. With mRNA Differential Display (DD), we analysed the transcriptional regulation of SHE cells exposed to 0, 12.

Comparison of a genomic and a multiplex cell imaging approach for the detection of phospholipidosis.

Phospholipidosis (PLD) is a topic of concern in drug development because it may be associated with toxicological consequences. The aim of the study was to determine the best method to screen proprietary compounds with regard to their potential to induce PLD. Two in vitro approaches, a genomic method previously evaluated in our laboratory and a fluorescent cell based approach to detect PLD were compared using HepG2 cells.

Multiplexing cell viability assays.

Today, obtaining mechanistic insights into biological, toxicological, and pathological processes is of upmost importance. Researchers aim to obtain as many as possible data from one cell sample to understand the biological processes under study. Multiplexing, which is the ability to gather more than one set of data from the same sample, fulfills completely this objective.

Selection of cytotoxicity markers for the screening of new chemical entities in a pharmaceutical context: a preliminary study using a multiplexing approach.

The present study was undertaken to validate a battery of cytotoxicity assays performed in a multiplex format to screen pharmaceutical compounds at an early stage of drug development. Two experiments were performed on HepG2 cells and the parameters were measured in 96-well plates. Biological and technical triplicates were performed to evaluate the reproducibility of the assay.

Feather mites and birds: an interaction mediated by uropygial gland size?

Feather mites (Arachnida: Acari: Astigmata) feed mainly on secretions of the uropygial gland of birds. Here, we use analyses corrected for phylogeny and body size to show that there is a positive correlation between the size of this gland and mite abundance in passerine birds at an interspecific level during the breeding season, suggesting that the gland mediates interactions between mites and birds. As predicted on the basis of hypothesized waterproofing and antibiotic functions of uropygial gland secretions, riparian/marsh bird species had larger glands and higher mite loads than birds living in less mesic terrestrial environments.

Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.

Phospholipidosis (PLD) is characterized by an intracellular accumulation of phospholipids in lysosomes and the concurrent development of concentric lamellar bodies. Recently, H. Sawada et al.

The random amplified polymorphic DNA (RAPD) assay and related techniques applied to genotoxicity and carcinogenesis studies: a critical review.

More than 9000 papers using the random amplified polymorphic DNA (RAPD) or related techniques (e.g. the arbitrarily primed polymerase chain reaction (AP-PCR)) have been published from 1990 to 2005.

Genotoxic, cytotoxic, developmental and survival effects of tritiated water in the early life stages of the marine mollusc, Mytilus edulis.

Using an integrated approach linking different levels of biological organisation, the genotoxic, cytotoxic, developmental and survival impact of tritiated water (HTO) were investigated in the embryo-larvae of marine mollusc Mytilus edulis. One-hour-old embryos were exposed to a range of concentrations (0.37-370 kBq ml(-1)) of HTO, which delivered a dose between 0.

The random amplified polymorphic DNA (RAPD) assay to determine DNA alterations, repair and transgenerational effects in B(a)P exposed Daphnia magna.

The random amplified polymorphic DNA (RAPD) is a useful assay for the detection of genotoxin-induced DNA damage and mutations. In this study, we have further evaluated the potential of this assay to measure benzo(a)pyrene [B(a)P]-induced DNA changes, and repair (in kinetic experiments) as well as transgenerational effects in the water fleas, Daphnia magna. The organisms, which reproduce parthenogenetically, were exposed to 50 microg L(-1) B(a)P for 3 or 6 days and were allowed to recover in clean medium for 12 or 9 days, respectively.

Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes.

In the field of gene expression analysis, DNA microarray technology is having a major impact on many different areas including toxicology. For instance, a number of studies have shown that transcription profiling can generate the information needed to assign a compound to a mode-of-action class. In this study, we investigated whether compounds inducing similar toxicological endpoints produce similar changes in gene expression.

4-n-Nonylphenol and 17-beta estradiol may induce common DNA effects in developing barnacle larvae.

There is a growing concern over the potential effects of environmental endocrine disrupters on both human and wildlife populations. However, to date, minimal research has been conducted to determine the effect of estrogens and xenoestrogens at the DNA level. In this study, we used the random amplified polymorphic DNA (RAPD) assay to evaluate the effects on the genomic DNA of barnacle larvae that had been exposed to 17beta-estradiol (E2) and low concentrations of 4-n-nonylphenol (NP).

Evaluation of the random amplified polymorphic DNA (RAPD) assay for the detection of DNA damage and mutations.

The random amplified polymorphic DNA (RAPD) assay and related techniques like the arbitrarily primed polymerase chain reaction (AP-PCR) have been shown to detect genotoxin-induced DNA damage and mutations. The changes occurring in RAPD profiles following genotoxic treatments include variation in band intensity as well as gain or loss of bands. However, the interpretation of the molecular events responsible for differences in the RAPD patterns is not an easy task since different DNA alterations can induce similar type of changes.