Development of an In Silico Profiler for Respiratory Sensitisation

In this article, we outline work that led the QSAR and Molecular Modelling Group at Liverpool John Moores University to be jointly awarded the 2013 Lush Science Prize. Our research focuses around the development of in silico profilers for category formation within the Adverse Outcome Pathway paradigm. The development of a well-defined chemical category allows toxicity to be predicted via read-across. This is the central approach used by the OECD QSAR Toolbox. The specific work for which we were awarded the Lush Prize was for the development of such an in silico profiler for respiratory sensitisation. The profiler was developed by an analysis of the mechanistic chemistry associated with covalent bond formation in the lung. The data analysed were collated from clinical reports of occupational asthma in humans. The impact of the development of in silico profilers on the Three Rs is also discussed

The Effect of Focal Damage to the Right Medial Posterior Cerebellum on Word and Sentence Comprehension and Production

Functional imaging studies of neurologically intact adults have demonstrated that the right posterior cerebellum is activated during verb generation, semantic processing, sentence processing, and verbal fluency. Studies of patients with cerebellar damage converge to show that the cerebellum supports sentence processing and verbal fluency. However, to date there are no patient studies that investigated the specific importance of the right posterior cerebellum in language processing, because: (i) case studies presented patients with lesions affecting the anterior cerebellum (with or without damage to the posterior cerebellum), and (ii) group studies combined patients with lesions to different cerebellar regions, without specifically reporting the effects of right posterior cerebellar damage. Here we investigated whether damage to the right posterior cerebellum is critical for sentence processing and verbal fluency in four patients with focal stroke damage to different parts of the right posterior cerebellum (all involving Crus II, and lobules VII and VIII). We examined detailed lesion location by going beyond common anatomical definitions of cerebellar anatomy (i.e., according to lobules or vascular territory), and employed a recently proposed functional parcellation of the cerebellum. All four patients experienced language difficulties that persisted for at least a month after stroke but three performed in the normal range within a year. In contrast, one patient with more damage to lobule IX than the other patients had profound long-lasting impairments in the comprehension and repetition of sentences, and the production of spoken sentences during picture description. Spoken and written word comprehension and visual recognition memory were also impaired, however, verbal fluency was within the normal range, together with object naming, visual perception and verbal shortterm memory. This is the first study to show that focal damage to the right posterior cerebellum leads to language difficulties after stroke; and that processing impairments persisted in the case with most damage to lobule IX. We discuss these results in relation to current theories of cerebellar contribution to language processing. Overall, our study highlights the need for longitudinal studies of language function in patients with focal damage to different cerebellar regions, with functional imaging to understand the mechanisms that support recovery

Discourse or dialogue? Habermas, the Bakhtin Circle, and the question of concrete utterances

This is the author's accepted manuscript. The final publication is available at Springer via the link below.This article argues that the Bakhtin Circle presents a more realistic theory of concrete dialogue than the theory of discourse elaborated by Habermas. The Bakhtin Circle places speech within the “concrete whole utterance” and by this phrase they mean that the study of everyday language should be analyzed through the mediations of historical social systems such as capitalism. These mediations are also characterized by a determinate set of contradictions—the capital-labor contradiction in capitalism, for example—that are reproduced in unique ways in more concrete forms of life (the state, education, religion, culture, and so on). Utterances always dialectically refract these processes and as such are internal concrete moments, or concrete social forms, of them. Moreover, new and unrepeatable dialogic events arise in these concrete social forms in order to overcome and understand the constant dialectical flux of social life. But this theory of dialogue is different from that expounded by Habermas, who tends to explore speech acts by reproducing a dualism between repeatable and universal “abstract” discursive processes (commonly known as the ideal speech situation) and empirical uses of discourse. These critical points against Habermas are developed by focusing on six main areas: sentences and utterances; the lifeworld and background language; active versus passive understandings of language; validity claims; obligation and relevance in language; and dialectical universalism

Right cerebral motor areas that support accurate speech production following damage to cerebellar speech areas

Specific regions of the cerebellum are activated when neurologically intact adults speak, and cerebellar damage can impair speech production early after stroke, but how the brain supports accurate speech production years after cerebellar damage remains unknown. We investigated this in patients with cerebellar lesions affecting regions that are normally recruited during speech production. Functional MRI activation in these patients, measured during various single word production tasks, was compared to that of neurologically intact controls, and patient controls with lesions that spared the cerebellar speech production regions. Our analyses revealed that, during a range of speech production tasks, patients with damage to cerebellar speech production regions had greater activation in the right dorsal premotor cortex (r-PMd) and right supplementary motor area (r-SMA) compared to neurologically intact controls. The loci of increased activation in cerebral motor speech areas motivate future studies to delineate the functional contributions of different parts of the speech production network, and test whether non-invasive stimulation to r-PMd and r-SMA facilitates speech recovery after cerebellar stroke

Glue ear, hearing loss and IQ:an association moderated by the child's home environment

BACKGROUND: Glue ear or otitis media with effusion (OME) is common in children and may be associated with hearing loss (HL). For most children it has no long lasting effects on cognitive development but it is unclear whether there are subgroups at higher risk of sequelae. OBJECTIVES: To examine the association between a score comprising the number of times a child had OME and HL (OME/HL score) in the first four/five years of life and IQ at age 4 and 8. To examine whether any association between OME/HL and IQ is moderated by socioeconomic, child or family factors. METHODS: Prospective, longitudinal cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). 1155 children tested using tympanometry on up to nine occasions and hearing for speech (word recognition) on up to three occasions between age 8 months and 5 years. An OME/HL score was created and associations with IQ at ages 4 and 8 were examined. Potential moderators included a measure of the child's cognitive stimulation at home (HOME score). RESULTS: For the whole sample at age 4 the group with the highest 10% OME/HL scores had performance IQ 5 points lower [95% CI -9, -1] and verbal IQ 6 points lower [95% CI -10, -3] than the unaffected group. By age 8 the evidence for group differences was weak. There were significant interactions between OME/HL and the HOME score: those with high OME/HL scores and low 18 month HOME scores had lower IQ at age 4 and 8 than those with high OME/HL scores and high HOME scores. Adjusted mean differences ranged from 5 to 8 IQ points at age 4 and 8. CONCLUSIONS: The cognitive development of children from homes with lower levels of cognitive stimulation is susceptible to the effects of glue ear and hearing loss

Sulforaphane Protects the Liver against CdSe Quantum Dot-Induced Cytotoxicity.

The potential cytotoxicity of cadmium selenide (CdSe) quantum dots (QDs) presents a barrier to their use in biomedical imaging or as diagnostic and therapeutic agents. Sulforaphane (SFN) is a chemoprotective compound derived from cruciferous vegetables which can up-regulate antioxidant enzymes and induce apoptosis and autophagy. This study reports the effects of SFN on CdSe QD-induced cytotoxicity in immortalised human hepatocytes and in the livers of mice. CdSe QDs induced dose-dependent cell death in hepatocytes with an IC50 = 20.4 μM. Pre-treatment with SFN (5 μM) increased cell viability in response to CdSe QDs (20 μM) from 49.5 to 89.3%. SFN induced a pro-oxidant effect characterized by depletion of intracellular reduced glutathione during short term exposure (3-6 h), followed by up-regulation of antioxidant enzymes and glutathione levels at 24 h. SFN also caused Nrf2 translocation into the nucleus, up-regulation of antioxidant enzymes and autophagy. siRNA knockdown of Nrf2 suggests that the Nrf2 pathway plays a role in the protection against CdSe QD-induced cell death. Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death. Moreover, the role of autophagy in SFN protection against CdSe QD-induced cell death was confirmed using mouse embryonic fibroblasts lacking ATG5. CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment. In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy