A new, more efficient waterwheel design for very-low-head hydropower schemes

Very-low-head hydropower constitutes a large untapped renewable energy source, estimated at 1 GW in the UK alone. A new type of low-impact waterwheel has been developed and tested at Abertay University in Scotland to improve the economic viability of such schemes. For example, on a 2·5 m high weir in the UK with 5 m3/s mean flow, one waterwheel could produce an annual investment return of 7·5% for over 100 years. This paper describes the evolution of the design and reports on scale-model tests. These show that the new design harnesses significant potential and kinetic energy to generate power and handles over four times as much water per metre width compared to traditional designs

Response to ionising radiation of glioblastoma stem-like cells

Introduction: Glioblastoma (GBM) is characterised by local recurrence following surgery, radiotherapy and chemotherapy. GBM has a poor prognosis and novel approaches are required. Recently, a hierarchical organisation of tumour cells in GBM has been proposed. This hypothesis suggests only a subset of cancer cells, termed ‘cancer stem-like cells’ (CSCs) drive tumour growth and possess properties of self renewal and unlimited proliferative capacity. CSCs have been described as radioresistant, implicating CSCs as a determinant of tumour recurrence following therapy. Therefore improved patient outcomes could potentially be achieved by targeting GBM CSCs. Nevertheless, reports of GBM CSC radioresistance have been conflicting, with some authors demonstrating CSC radiosensitivity. Furthermore, investigations of GBM CSC radioresponse have lacked robust radiobiological quantification and this aspect of the CSC phenotype remains controversial. Aims: To investigate the radioresponse of GBM CSCs in comparison to non CSCs, characterise the DNA damage response (DDR) in GBM CSCs to radiation and investigate effects of inhibition of DNA damage response (DDR) in GBM CSCs. Methods: Primary GBM cells were cultured in CSC enriching conditions and differentiating (‘tumour bulk’) conditions. The radioresponse of CSC and tumour bulk cultures derived from single parental tumours were thus compared by clonogenic survival assay. DDR was analysed in CSC and tumour bulk cells via Western blotting for DDR phosphoproteins and flow cytometric quantification of mitotic cells. DNA double strand break (DSB) repair was quantified by analysis of gamma H2AX foci. CSCs and tumour bulk response to irradiation in combination with inhibition of key DDR elements (ataxia telangiectasia mutated, (ATM); ataxia telangiectasia and Rad3 related, (ATR); and poly (ADP-ribose) polymerase, (PARP) by small molecule inhibitor agents was characterised. Results: CSC cultures were tumourigenic or recapitulated pathological features of parental tumours in orthotopic mouse models, whereas differentiated tumour bulk cultures did not. CSC cultures exhibited upregulation of putative CSC markers relative to tumour bulk. CSC cultures were radioresistant, demonstrated upregulated DDR and more efficient activation of the G2/M checkpoint compared to tumour bulk. CSC cultures repaired DNA DSBs more efficiently at 24 hours following irradiation. Inhibition of ATM in CSCs led to abrogation of the G2/M checkpoint response, reduced efficiency of DNA DSB repair and potent radiosensitisation. Inhibition of PARP in CSCs produced an increase in unresolved DNA DSBs in GBM CSCs at 24 hours post irradiation in G2 phase cells and modest levels of radiosensitisation. Inhibition of ATR in CSCs abrogated the G2/M checkpoint in CSCs efficiently and was associated with modest radiosensitisation. Dual ATR and PARP inhibition provided highly potent radiosensitisation of GBM CSCs. Conclusions: GBM CSCs were shown to be radioresistant relative to tumour bulk cells due to upregulated DDR, in support of the hypothesis that CSCs contribute to local recurrence, implying a need for CSC targeted therapies. The inhibition of G2/M checkpoint activation and DNA DSB repair via ATM inhibition or combined ATR/PARP inhibition potently radiosensitised GBM CSCs suggesting targeting both checkpoint and DNA DSB repair is important for optimal radiosensitisation of GBM CSCs. This study has demonstrated that DDR is a potential therapeutic target for radiosensitisation of GBM CSCs

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells

Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem-like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133- non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double strand breaks (DSB) which co-localized with 'replication factories' and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro. These data identify RS as a cancer stem cell-specific target with significant clinical potential

Language as an instrument of thought

I show that there are good arguments and evidence to boot that support the language as an instrument of thought hypothesis. The underlying mechanisms of language, comprising of expressions structured hierarchically and recursively, provide a perspective (in the form of a conceptual structure) on the world, for it is only via language that certain perspectives are avail- able to us and to our thought processes. These mechanisms provide us with a uniquely human way of thinking and talking about the world that is different to the sort of thinking we share with other animals. If the primary function of language were communication then one would expect that the underlying mechanisms of language will be structured in a way that favours successful communication. I show that not only is this not the case, but that the underlying mechanisms of language are in fact structured in a way to maximise computational efficiency, even if it means causing communicative problems. Moreover, I discuss evidence from comparative, neuropatho- logical, developmental, and neuroscientific evidence that supports the claim that language is an instrument of thought

Verbal Reports and "Real' Reasons" : Confabulation and Conflation

This document is the Accepted Manuscript version of a published work that appeared in final form in Ethical Theory and Moral Practice after peer review and technical editing by the publisher. Constantine Sandis, ‘Verbal Reports and “Real” Reasons: Confabulation and Conflation’, Ethical Theory and Moral Practice, Vol. 18(2): 267-280, first published online 18 March 2015. The final publication is available at Springer via http://dx.doi.org/10.1007/s10677-015-9576-6 © Springer Science+Business Media Dordrecht 2015This paper examines the relation between the various forces which underlie human action and verbal reports about our reasons for acting as we did. I maintain that much of the psychological literature on confabulations rests on a dangerous conflation of the reasons for which people act with a variety of distinct motivational factors. In particular, I argue that subjects frequently give correct answers to questions about the considerations they acted upon while remaining largely unaware of why they take themselves to have such reasons to act. Pari passu, experimental psychologists are wrong to maintain that they have shown our everyday reason talk to be systematically confused. This is significant because our everyday reason-ascriptions affect characterizations of action (in terms of intention, knowledge, foresight, etc.) that are morally and legally relevant. I conclude, more positively, that far from rendering empirical research on confabulations invalid, my account helps to reveal its true insights into human nature.Peer reviewe

A systematic genome-wide analysis of zebrafish protein-coding gene function

Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches1, 2, 3 and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes3, 4, this number falls considerably short of the more than 22,000 mouse protein-coding genes5. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning6, insertional mutagenesis7, 8, 9, antisense morpholino oligonucleotides10, targeted re-sequencing11, 12, 13, and zinc finger and TAL endonucleases14, 15, 16, 17 have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes18. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence18, 19, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis

Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide chemotherapy in pre-clinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side-effects of temozolomide. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib, and assess the safety and tolerability of its combination with temozolomide. Methods: Pre-clinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose temozolomide in a 3+3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumour core and tumour margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results: Olaparib was a substrate for multi-drug resistance protein-1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients, median 496nM) and 21/21 tumor margin specimens (9 patients, median 512.3nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150mg (3 days/week) with TMZ 75mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression-free at 6 months. Olaparib radiosensitized six glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusions: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better pre-clinical models