Robotic multiwell planar patch-clamp for native and primary mammalian cells

Robotic multiwell planar patch-clamp has become common in drug development and safety programs because it enables efficient and systematic testing of compounds against ion channels during voltage-clamp. It has not, however, been adopted significantly in other important areas of ion channel research, where conventional patch-clamp remains the favored method. Here, we show the wider potential of the multiwell approach with the ability for efficient intracellular solution exchange, describing protocols and success rates for recording from a range of native and primary mammalian cells derived from blood vessels, arthritic joints and the immune and central nervous systems. The protocol involves preparing a suspension of single cells to be dispensed robotically into 4-8 microfluidic chambers each containing a glass chip with a small aperture. Under automated control, giga-seals and whole-cell access are achieved followed by preprogrammed routines of voltage paradigms and fast extracellular or intracellular solution exchange. Recording from 48 chambers usually takes 1-6 h depending on the experimental design and yields 16-33 cell recordings.

New insights into probiotic mechanisms: a harvest from functional and metagenomic studies

There has been continued and expanding recognition of probiotic approaches for treating gastrointestinal and systemic disease, as well as increased acceptance of probiotic therapies by both the public and the medical community. A parallel development has been the increasing recognition of the diverse roles that the normal gut microbiota plays in the normal biology of the host. This advance has in turn has been fed by implementation of novel investigative technologies and conceptual paradigms focused on understanding the fundamental role of the microbiota and indeed all commensal bacteria, on known and previously unsuspected aspects of host physiology in health and disease. This review discusses current advances in the study of the host-microbiota interaction, especially as it relates to potential mechanisms of probiotics. It is hoped these new approaches will allow more rational selection and validation of probiotic usage in a variety of clinical conditions.

Radical Conservatism

In 1938, Yugoslav sculptor Oscar Nemon arrived in Britain, having fled the Nazi invasion of Brussels, where he was living with Magritte. He was part of the European avant-garde that came to the UK as a refugee. Shortly thereafter, Nemon proposed a bold architectural plan to construct a temple of universal ethics in London and was in correspondence over this with central figures in Britain. After the war, he became know for his portrayal of figures like Churchil, culminating in a bust of Margaret Thatcher that is currently at the Tory HQ. Shown at Castlefield Gallery in 2013-2014, Radical Conservatism was an exhibition that explored the space between these two moments and asked whether these two terms are really antithetical. In the British context in particular, where the European avant-garde never really took hold, a kind of reactionary modernism has always defined a culture wary of revolution. But today more than ever, with the left increasingly holding on to the past of the welfare state as an ideal, and the right quietly revolutionising our world through neoliberal reforms, the paradigms of radicalism and conservatism need to be redefined. Can conservatism be seen as a radical position in itself? If art is defined by a movement towards the new - could 'holding on to the past' stubbornly be seen as a critical position, now that neo-liberalism has forced a far more radical shift in politics than the left has managed in a long time? Curated by Pil and Galia Kollectiv, featuring work by Chris Evans, IRWIN, Pil and Galia Kollectiv, Joseph Lewis, Patrick Moran, Oscar Nemon and Public Movement and a symposium with contributions from Professor Alun Rowlands and Robert Garnett.

Increases in prefrontal cortex activity when regulating negative emotion predicts symptom severity trajectory over six months in depression

Context: Emotion regulation is critically disrupted in depression and use of paradigms tapping these processes may uncover essential changes in neurobiology during treatment. In addition, as neuroimaging outcome studies of depression commonly utilize solely baseline and endpoint data – which is more prone to week-to week noise in symptomatology – we sought to use all data points over the course of a six month trial. Objective: To examine changes in neurobiology resulting from successful treatment. Design: Double-blind trial examining changes in the neural circuits involved in emotion regulation resulting from one of two antidepressant treatments over a six month trial. Participants were scanned pretreatment, at 2 months and 6 months posttreatment. Setting: University functional magnetic resonance imaging facility. Participants: 21 patients with Major Depressive Disorder and without other Axis I or Axis II diagnoses and 14 healthy controls. Interventions: Venlafaxine XR (doses up to 300mg) or Fluoxetine (doses up to 80mg). Main Outcome Measure: Neural activity, as measured using functional magnetic resonance imaging during performance of an emotion regulation paradigm as well as regular assessments of symptom severity by the Hamilton Rating Scale for Depression. To utilize all data points, slope trajectories were calculated for rate of change in depression severity as well as rate of change of neural engagement. Results: Those depressed individuals showing the steepest decrease in depression severity over the six months were those individuals showing the most rapid increases in BA10 and right DLPFC activity when regulating negative affect over the same time frame. This relationship was more robust than when using solely the baseline and endpoint data. Conclusions: Changes in PFC engagement when regulating negative affect correlate with changes in depression severity over six months. These results are buttressed by calculating these statistics which are more reliable and robust to week-to-week variation than difference scores.

Linguistic interfaces and language acquisition in childhood: introduction to the special issue

Much contemporary L1 acquisition theory and empirical research are guided by the hypothesis that acquisition delays in children are often related to the integration of information across grammatical and other cognitive modules, such as syntax and discourse-pragmatics (see e.g., Grinstead, 2010). This special issue brings together cutting edge research from all relevant paradigms addressing interface issues in child language acquisition and provides a platform for the study of the interaction between different levels of linguistic knowledge. In this introduction, we present the reader with the tools needed to best understand the contributions of the individual studies and what they bring to bear on larger theoretical questions as a collective.

Evaluating the interdependencies between managing business change, IT sourcing and IT governance

Organisations need the right business and IT capabilities in order to achieve future business success. It follows that the sourcing of these capabilities is an important decision. Yet, there is a lack of consensus on the approach to decid-ing where and how to source the core operational capabilities. Furthermore, de-veloping its dynamic capability enables an organisation to effectively manage change its operational capabilities. Recent research has proposed that analysing business capabilities is a key pre-requisite to defining its Information Technology (IT) solutions. This research builds on these findings by considering the interde-pendencies between the dynamic business change capability and the sourcing of IT capabilities. Further it examines the decision-making oversight of these areas as implemented through IT governance. There is a good understanding of the direct impact of IT sourcing decision on operational capabilities However, there is a lack of research on the indirect impact to the capability of managing business change. Through a review of prior research and initial pilot field research, a capability framework and three main propositions are proposed, each examining a two-way interdependency. This paper describes the development of the integrated capa-bility framework and the rationale for the propositions. These respectively cover managing business change, IT sourcing and IT governance. Firstly, the sourcing of IT affects both the operational capabilities and the capability to manage business change. Similarly a business change may result in new or revised operational ca-pabilities, which can influence the IT sourcing decision resulting in a two-way rela-tionship. Secondly, this IT sourcing is directed under IT governance, which pro-vides a decision-making framework for the organisation. At the same time, the IT sourcing can have an impact on the IT governance capability, for example by out-sourcing key capabilities; hence this is potentially again a two-way relationship. Finally, there is a postulated two-way relationship between IT governance and managing business change in that IT governance provides an oversight of manag-ing business change through portfolio management while IT governance is a key element of the business change capability. Given the nature and novelty of this framework, a philosophical paradigm of constructivism is preferred. To illustrate and explore the theoretical perspectives provided, this paper reports on the find-ings of a case study incorporating eight high-level interviews with senior execu-tives in a German bank with 2300 employees. The collected data also include or-ganisational charts, annual reports, project and activity portfolio and benchmark reports for the IT budget. Recommendations are made for practitioners. An understanding of the interdependencies can support professionals in improving business success through effectively managing business change. Additionally, they can be assisted to evaluate the impact of IT sourcing decisions on the organisa-tion’s operational and dynamic capabilities, using an appropriate IT governance framework.

Parameterising ecological validity and integrating individual differences within second-person neuroscience

This commentary situates the second person account within a broader framework of ecological validity for experimental paradigms in social cognitive neuroscience. It then considers how individual differences at psychological and genetic levels can be integrated within the proposed framework.

Direct involvement, partnership and setting: a study in bounded diversity

This paper brings a comparative aspect to the analysis of direct involvement as the foundation for partnership. It considers how various forms of direct involvement can represent components of a broader partnership paradigm of people management, or a limited shallow partnership concession to facilitate the diffusion of top-down human resource management policies. Through the use of survey evidence, we explore the settings in which involvement is more likely to be encountered. Contrary to predictions in much of the literature as to their universal applicability, we found that they tended to be concentrated in specific locales, organisational types and sectors, as part and parcel of wider cooperative production paradigms; in practical terms, if involvement is a prerequisite for meaningful partnership, then the latter is more likely to be encountered in more coordinated varieties of capitalism. This does not suggest, however, that ‘shallow’ or instrumentalist partnerships do not occur, or that in infertile ground genuine partnerships are not possible. On one hand, national variations encountered were broadly on the lines of the literature on comparative capitalism. On the other hand, there was much diversity within national settings; we identify the contexts in which such engagement is more or less likely and consider the implications.

Increased resting state functional connectivity in the default mode network in recovered anorexia nervosa.

Functional brain imaging studies have shown abnormal neural activity in individuals recovered from anorexia nervosa (AN) during both cognitive and emotional task paradigms. It has been suggested that this abnormal activity which persists into recovery might underpin the neurobiology of the disorder and constitute a neural biomarker for AN. However, no study to date has assessed functional changes in neural networks in the absence of task-induced activity in those recovered from AN. Therefore, the aim of this study was to investigate whole brain resting state functional connectivity in nonmedicated women recovered from anorexia nervosa. Functional magnetic resonance imaging scans were obtained from 16 nonmedicated participants recovered from anorexia nervosa and 15 healthy control participants. Independent component analysis revealed functionally relevant resting state networks. Dual regression analysis revealed increased temporal correlation (coherence) in the default mode network (DMN) which is thought to be involved in self-referential processing. Specifically, compared to healthy control participants the recovered anorexia nervosa participants showed increased temporal coherence between the DMN and the precuneus and the dorsolateral prefrontal cortex/inferior frontal gyrus. The findings support the view that dysfunction in resting state functional connectivity in regions involved in self-referential processing and cognitive control might be a vulnerability marker for the development of anorexia nervosa.

NK1 receptor antagonism and the neural processing of emotional information in healthy volunteers

The neuropeptide substance P and its receptor NK1 have been implicated in emotion, anxiety and stress in preclinical studies. However, the role of NK1 receptors in human brain function is less clear and there have been inconsistent reports of the value of NK1 receptor antagonists in the treatment of clinical depression. The present study therefore aimed to investigate effects of NK1 antagonism on the neural processing of emotional information in healthy volunteers. Twenty-four participants were randomized to receive a single dose of aprepitant (125 mg) or placebo. Approximately 4 h later, neural responses during facial expression processing and an emotional counting Stroop word task were assessed using fMRI. Mood and subjective experience were also measured using self-report scales. As expected a single dose of aprepitant did not affect mood and subjective state in the healthy volunteers. However, NK1 antagonism increased responses specifically during the presentation of happy facial expressions in both the rostral anterior cingulate and the right amygdala. In the emotional counting Stroop task the aprepitant group had increased activation in both the medial orbitofrontal cortex and the precuneus cortex to positive vs. neutral words. These results suggest consistent effects of NK1 antagonism on neural responses to positive affective information in two different paradigms. Such findings confirm animal studies which support a role for NK1 receptors in emotion. Such an approach may be useful in understanding the effects of novel drug treatments prior to full-scale clinical trials.

Introducing matrix management within a children's services setting - personal reflections

This article reflects on the introduction of ‘matrix management’ arrangements for an Educational Psychology Service (EPS) within a Children’s Service Directorate of a Local Authority (LA). It seeks to demonstrate critical self-awareness, consider relevant literature with a view to bringing insights to processes and outcomes, and offers recommendations regarding the use of matrix management. The report arises from an East Midland’s LA initiative: ALICSE − Advanced Leadership in an Integrated Children’s Service Environment. Through a literature review and personal reflection, the authors consider the following: possible tensions within the development of matrix management arrangements; whether matrix management is a prerequisite within complex organizational systems; and whether competing professional cultures may contribute barriers to creating complementary and collegiate working. The authors briefly consider some research paradigms, notably ethnographic approaches, soft systems methodology, activity theory and appreciative inquiry. These provide an analytic framework for the project and inform this iterative process of collaborative inquiry. Whilst these models help illuminate otherwise hidden processes, none have been implemented following full research methodologies, reflecting the messy reality of local authority working within dynamic organizational structures and shrinking budgets. Nevertheless, this article offers an honest reflection of organizational change within a children’s services environment.

Effects of action observation on corticospinal excitability: muscle specificity, direction, and timing of the mirror response

Many human behaviours and pathologies have been attributed to the putative mirror neuron system, a neural system that is active during both the observation and execution of actions. While there are now a very large number of papers on the mirror neuron system, variations in the methods and analyses employed by researchers mean that the basic characteristics of the mirror response are not clear. This review focuses on three important aspects of the mirror response, as measured by modulations in corticospinal excitability: (1) muscle specificity, (2) direction, and (3) timing of modulation. We focus mainly on electromyographic (EMG) data gathered following single-pulse transcranial magnetic stimulation (TMS), because this method provides precise information regarding these three aspects of the response. Data from paired-pulse TMS paradigms and peripheral nerve stimulation (PNS) are also considered when we discuss the possible mechanisms underlying the mirror response. In this systematic review of the literature, we examine the findings of 85 TMS and PNS studies of the human mirror response, and consider the limitations and advantages of the different methodological approaches these have adopted in relation to discrepancies between their findings. We conclude by proposing a testable model of how action observation modulates corticospinal excitability in humans. Specifically, we propose that action observation elicits an early, non-specific facilitation of corticospinal excitability (at around 90 ms from action onset), followed by a later modulation of activity specific to the muscles involved in the observed action (from around 200 ms). Testing this model will greatly advance our understanding of the mirror mechanism and provide a more stable grounding on which to base inferences about its role in human behaviour.

Mismatch Negativity (MMN) reveals inefficient auditory ventral stream function in chronic auditory comprehension impairments

Background: Auditory discrimination is significantly impaired in Wernicke’s aphasia (WA) and thought to be causatively related to the language comprehension impairment which characterises the condition. This study used mismatch negativity (MMN) to investigate the neural responses corresponding to successful and impaired auditory discrimination in WA. Methods: Behavioural auditory discrimination thresholds of CVC syllables and pure tones were measured in WA (n=7) and control (n=7) participants. Threshold results were used to develop multiple-deviant mismatch negativity (MMN) oddball paradigms containing deviants which were either perceptibly or non-perceptibly different from the standard stimuli. MMN analysis investigated differences associated with group, condition and perceptibility as well as the relationship between MMN responses and comprehension (within which behavioural auditory discrimination profiles were examined). Results: MMN waveforms were observable to both perceptible and non-perceptible auditory changes. Perceptibility was only distinguished by MMN amplitude in the PT condition. The WA group could be distinguished from controls by an increase in MMN response latency to CVC stimuli change. Correlation analyses displayed relationship between behavioural CVC discrimination and MMN amplitude in the control group, where greater amplitude corresponded to better discrimination. The WA group displayed the inverse effect; both discrimination accuracy and auditory comprehension scores were reduced with increased MMN amplitude. In the WA group, a further correlation was observed between the lateralisation of MMN response and CVC discrimination accuracy; the greater the bilateral involvement the better the discrimination accuracy. Conclusions: The results from this study provide further evidence for the nature of auditory comprehension impairment in WA and indicate that the auditory discrimination deficit is grounded in a reduced ability to engage in efficient hierarchical processing and the construction of invariant auditory objects. Correlation results suggest that people with chronic WA may rely on an inefficient, noisy right hemisphere auditory stream when attempting to process speech stimuli.

Investigating early years teachers’ understanding and response to children’s preconceptions

This paper focuses on young children’s scientific preconceptions and discusses teachers’ identification of these preconceptions when teaching science in the early years, on which research is still limited. This paper is based on the theoretical framework of constructivism and it defines preconceptions as children’s erroneous concepts prior to formal education. A two phase case study approach was employed, facilitating in-depth investigation though the use of questionnaires, interviews and observations. The results indicate that the teachers did not dedicate time to identify children’s preconceptions when planning and teaching science, even when acknowledging preconceptions’ possible existence. This indicates a possible lack of appreciation of the importance of children’s preconceptions of the consequences when ignoring them. The results also indicate the need for further training and professional development in relation to the teaching of early-years science, especially since only a very small percentage of early years teachers tend to study science during their years compulsory education. A number of suggestions are also provided for practice and policy that can be useful for other subjects as well.

Rerum cognoscere causas: part I - How do the ideas of system dynamics relate to traditional social theories and the voluntarism/determinism debate?

This is the first half of a two-part paper which deals with the social theoretic assumptions underlying system dynamics. The motivation is that clarification in this area can help mainstream social scientists to understand how our field relates to their literature, methods and concerns. Part I has two main sections. The aim of the first is to answer the question: How do the ideas of system dynamics relate to traditional social theories? The theoretic assumptions of the field are seldom explicit but rather are implicit in its practice. The range of system dynamics practice is therefore considered and related to a framework - widely used in both operational research (OR) and systems science - that organises the assumptions behind traditional social theoretic paradigms. Distinct and surprisingly varied groupings of practice are identified, making it difficult to place system dynamics in any one paradigm with any certainty. The difficulties of establishing a social theoretic home for system dynamics are exemplified in the second main section. This is done by considering the question: Is system dynamics deterministic? An analysis shows that attempts to relate system dynamics to strict notions of voluntarism or determinism quickly indicate that the field does not fit with either pole of this dichotomous, and strictly paradigmatic, view. Part I therefore concludes that definitively placing system dynamics with respect to traditional social theories is highly problematic. The scene is therefore set for Part II of the paper, which proposes an innovative and potentially fruitful resolution to this problem.