Methods for the modulation and analysis of NF-κB-dependent adult neurogenesis

The hippocampus plays a pivotal role in the formation and consolidation of episodic memories, and in spatial orientation. Historically, the adult hippocampus has been viewed as a very static anatomical region of the mammalian brain. However, recent findings have demonstrated that the dentate gyrus of the hippocampus is an area of tremendous plasticity in adults, involving not only modifications of existing neuronal circuits, but also adult neurogenesis. This plasticity is regulated by complex transcriptional networks, in which the transcription factor NF-κB plays a prominent role. To study and manipulate adult neurogenesis, a transgenic mouse model for forebrain-specific neuronal inhibition of NF-κB activity can be used. In this study, methods are described for the analysis of NF-κB-dependent neurogenesis, including its structural aspects, neuronal apoptosis and progenitor proliferation, and cognitive significance, which was specifically assessed via a dentate gyrus (DG)-dependent behavioral test, the spatial pattern separation-Barnes maze (SPS-BM). The SPS-BM protocol could be simply adapted for use with other transgenic animal models designed to assess the influence of particular genes on adult hippocampal neurogenesis. Furthermore, SPS-BM could be used in other experimental settings aimed at investigating and manipulating DG-dependent learning, for example, using pharmacological agents.

Pharmacological actions of nobiletin in the modulation of platelet function

Background and Purpose The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin in the modulation of platelet function. Experimental Approach The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. The fibrinogen binding, α-granule secretion and calcium mobilisation assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice. Key Results Nobiletin was shown to supress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilisation and thrombus formation. Nobiletin was shown to extend bleeding time in mice and reduce the phosphorylation of Akt and PLCγ2 within the collagen receptor (GPVI) - stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of VASP, a protein whose activity is associated with inhibitory cyclic nucleotide signalling. Conclusions and Implications This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore nobiletin may represent a potential antithrombotic agent of dietary origins.

Further considerations of cosmic ray modulation of infra-red radiation in the atmosphere

Understanding effects of ionisation in the lower atmosphere is a new interdisciplinary area, crossing the traditionally distinct scientific boundaries between astro-particle and atmospheric physics and also requiring understanding of both heliospheric and magnetospheric influences on cosmic rays. Following the paper of Erlykin et al. (2014) we develop further the interpretation of our observed changes in long-wave (LW) radiation, Aplin and Lockwood (2013) by taking account of both cosmic ray ionisation yields and atmospheric radiative transfer. To demonstrate this, we show that the thermal structure of the whole atmosphere needs to be considered along with the vertical profile of ionisation. Allowing for, in particular, ionisation by all components of a cosmic ray shower and not just by the muons, reveals that the effect we have detected is certainly not inconsistent with laboratory observations of the LW absorption cross section. The analysis presented here, although very different from that of Erlykin et al., does come to the same conclusion that the events detected by AL were not caused by individual cosmic ray primaries – not because it is impossible on energetic grounds, but because events of the required energy are too infrequent for the 12 h_1 rate at which they were seen by the AL experiment. The present paper numerically models the effect of three different scenario changes to the primary GCR spectrum which all reproduce the required magnitude of the effect observed by AL. However, they cannot solely explain the observed delay in the peak effect which, if confirmed, would appear to open up a whole new and interesting area in the study of water oligomers and their effects on LW radiation. We argue that a technical artefact in the AL experiment is highly unlikely and that our initial observations merit both a wide-ranging follow-up experiment and more rigorous, self-consistent, three-dimensional radiative transfer modelling

Disambiguating with Bourdieu: unravelling policy from practice in the teaching of children with English as an additional language

This article explores the use of Bourdieusian analysis for examining how policy and practice interact in the teaching of English and therefore in the development of children’s language and literacy; in particular how Bourdieusian analysis uncovers the ways in which teachers’ practice has been influenced unconsciously by centralised shaping of the curriculum for English in England while the pupil demographic in schools has become more linguistically diverse. Data were collected from interviews with both newly qualified and very experienced primary school (pupil ages 5 – 11) teachers, whose pedagogical norms for the teaching of English were challenged by the arrival of non-English speakers in their classrooms. The discussion highlights how the use of Bourdieusian constructs of field, habitus and capital can disambiguate teachers’ practical classroom decisions from the influences of policy expectations.

Good practice for pupils learning English as an additional language; lessons from effective literacy teachers in inner city primary schools.

This article presents observations and discussion of the successful teaching of English to pupils, in English primary schools, for whom English is an additional language (EAL). It draws on research in Year 2 (6/7year old) classes in three inner-city primary schools carried out in 2003 and 2005. Three recognised, effective teachers of literacy were selected for case study; all worked in successful schools where results for literacy, measured by national tests, were in line with or better than national averages. Following analyses of lesson observations and interviews with the teachers, their Headteachers and the EAL co-ordinators in the schools, a number of common elements in their practice emerged. Discussion centres on how these pedagogical features supported effective learning environments for the early literacy development of bilingual children, and on the implications for the practice of teaching English to all pupils.

Teaching English as an additional language: a MESHGuide

This guide has been co-authored by Naomi Flynn, an Associate Professor at The University of Reading, working with Chris Pim and Sarah Coles who are specialist advisory teachers with Hampshire’s Ethnic Minority and Traveller Achievement Service (EMTAS). It was constructed with the support of teachers in primary and secondary schools in Hampshire, selected for their existing expertise in teaching EAL learners, who used the guidance for action research during the spring and summer of 2015. The guide is written principally to support teachers and learning support assistants working with EAL learners in any educational setting and who are at any stage of fluency in the learning of English. It will also support senior leaders in their strategic response to the EAL learners in their schools. As with all MESH guides it seeks to share knowledge with professionals in order to support the growth of evidence informed practice that works in promoting the best in pupil outcomes

Modulation of potassium channels inhibits bunyavirus infection

Bunyaviruses are considered to be emerging pathogens facilitated by the segmented nature of their genome that allows reassortment between different species to generate novel viruses with altered pathogenicity. Bunyaviruses are transmitted via a diverse range of arthropod vectors, as well as rodents, and have established a global disease range with massive importance in healthcare, animal welfare and economics. There are no vaccines or anti-viral therapies available to treat human bunyavirus infections and so development of new anti-viral strategies is urgently required. Bunyamwera virus (BUNV; genus Orthobunyavirus) is the model bunyavirus, sharing aspects of its molecular and cellular biology with all Bunyaviridae family members. Here, we show for the first time that BUNV activates and requires cellular potassium (K+) channels to infect cells. Time of addition assays using K+ channel modulating agents demonstrated that K+ channel function is critical to events shortly after virus entry but prior to viral RNA synthesis/replication. A similar K+ channel dependence was identified for other bunyaviruses namely Schmallenberg virus (Orthobunyavirus) as well as the more distantly related Hazara virus (Nairovirus). Using a rational pharmacological screening regimen, twin-pore domain K+ channels (K2P) were identified as the K+ channel family mediating BUNV K+ channel dependence. As several K2P channel modulators are currently in clinical use, our work suggests they may represent a new and safe drug class for the treatment of potentially lethal bunyavirus disease.

Regulation of gene and protein expression in cardiac myocyte hypertrophy and apoptosis

Considerable efforts have been expended in elucidating the inter-cellular and intra-cellular signaling pathways which elicit cardiac myocyte hypertrophy or apoptosis, and in identifying the changes which are associated with the end-stage of the response. The challenge now is to link the two. Although some of the signaling effects will be the acute modulation of existing protein function, long-term effects which bring about and maintain the hypertrophic state or which culminate in cell death are mediated at the level of gene and protein expression. With the advances in micro-array technology and genome sequencing, it is now possible to obtain a picture of the global gene expression profile in myocytes or in whole heart which dictates the proteins which could be made. This is not the final picture since additional regulation at the level of translation modulates the relative proportions of each protein that can be made from the transcriptome. Even here, further regulation of protein stability and turnover means that ultimately it is still necessary to examine the proteome to determine what may cause the functional changes in a cell. Thus, in order to gain a full picture of events which regulate the response and gain some insight into possible points of intervention for therapy, it is necessary to examine gene expression, mRNA translation and protein expression in concert.

Modulation of equatorial Pacific westerly/easterly wind events by the Madden-Julian oscillation and convectively-coupled Rossby waves

Synoptic wind events in the equatorial Pacific strongly influence the El Niño/Southern Oscillation (ENSO) evolution. This paper characterizes the spatio-temporal distribution of Easterly (EWEs) and Westerly Wind Events (WWEs) and quantifies their relationship with intraseasonal and interannual large-scale climate variability. We unambiguously demonstrate that the Madden–Julian Oscillation (MJO) and Convectively-coupled Rossby Waves (CRW) modulate both WWEs and EWEs occurrence probability. 86 % of WWEs occur within convective MJO and/or CRW phases and 83 % of EWEs occur within the suppressed phase of MJO and/or CRW. 41 % of WWEs and 26 % of EWEs are in particular associated with the combined occurrence of a CRW/MJO, far more than what would be expected from a random distribution (3 %). Wind events embedded within MJO phases also have a stronger impact on the ocean, due to a tendency to have a larger amplitude, zonal extent and longer duration. These findings are robust irrespective of the wind events and MJO/CRW detection methods. While WWEs and EWEs behave rather symmetrically with respect to MJO/CRW activity, the impact of ENSO on wind events is asymmetrical. The WWEs occurrence probability indeed increases when the warm pool is displaced eastward during El Niño events, an increase that can partly be related to interannual modulation of the MJO/CRW activity in the western Pacific. On the other hand, the EWEs modulation by ENSO is less robust, and strongly depends on the wind event detection method. The consequences of these results for ENSO predictability are discussed.

The role of local atmospheric forcing on the modulation of the ocean mixed layer depth in reanalysis and a coupled single column ocean model

The role of the local atmospheric forcing on the ocean mixed layer depth (MLD) over the global oceans is studied using ocean reanalysis data products and a single-column ocean model coupled to an atmospheric general circulation model. The focus of this study is on how the annual mean and the seasonal cycle of the MLD relate to various forcing characteristics in different parts of the world's ocean, and how anomalous variations in the monthly mean MLD relate to anomalous atmospheric forcings. By analysing both ocean reanalysis data and the single-column ocean model, regions with different dominant forcings and different mean and variability characteristics of the MLD can be identified. Many of the global oceans' MLD characteristics appear to be directly linked to different atmospheric forcing characteristics at different locations. Here, heating and wind-stress are identified as the main drivers; in some, mostly coastal, regions the atmospheric salinity forcing also contributes. The annual mean MLD is more closely related to the annual mean wind-stress and the MLD seasonality is more closely to the seasonality in heating. The single-column ocean model, however, also points out that the MLD characteristics over most global ocean regions, and in particular the tropics and subtropics, cannot be maintained by local atmospheric forcings only, but are also a result of ocean dynamics that are not simulated in a single-column ocean model. Thus, lateral ocean dynamics are essentially in correctly simulating observed MLD.

Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and are typically associated with deficient in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1R antagonists. Of further interest are various findings that CB1R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky2J’ model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.

Corticomuscular coherence modulation with the pattern of finger force coordination

We assess the corticomuscular coherence (CMC) of the contralateral primary motor cortex and the hand muscles during a finger force-tracking task and explore whether the pattern of finger coordination has an impact on the CMC level. Six healthy subjects (three men and three women) were recruited to conduct the force-tracking tasks comprising two finger patterns, i.e., natural combination of index and middle fingers and unnatural combination of index and middle fingers (i.e., simultaneously producing equal force strength in index and middle finger). During the conducting of the tasks with right index and middle finger, MEG and sEMG signals were recorded from left primary motor cortex (M1) and right flexor digitorum superficialis (FDS), respectively; the contralateral CMC was calculated to assess the neuromuscular interaction. Finger force-tracking tasks of Common-IM only induce beta-band CMC, whereas Uncommon-IM tasks produce CMC in both beta and low-gamma band. Compared to the force-tracking tasks of Common-IM, the Uncommon-IM task is associated with the most intensive contralateral CMC. Our study demonstrated that the pattern of finger coordination had significant impact on the CMC between the contralateral M1 and hand muscles, and more corticomuscular interaction was necessary for unnaturally coordinated finger activities to regulate the fixed neural drive of hand muscles.

Peptide based hydrogels for cancer drug release: modulation of stiffness, drug release and proteolytic stability of hydrogels by incorporating D-amino acid residue(s)

Synthetic tripeptide based noncytotoxic hydrogelators have been discovered for releasing an anticancer drug at physiological pH and temparature. Interestingly, gel stiffness, drug release capacity and proteolytic stability of these hydrogels have been successfully modulated by incorporating D-amino acid residues, indicating their potential use for drug delivery in the future.

Spectral modulation detection in normal hearing children

This Capstone Project attempts to determine the ability of normal hearing children to resolve spectral information, and the relationship between spectral resolution ability and speech recognition ability in noise. This study also examines how these abilities develop with age.