REST: transcriptional and epigenetic regulator

Acquisition and maintenance of cell fate and potential are dependent on the complex interplay of extracellular signaling, gene regulatory networks and epigenetic states. During embryonic development, embryonic stem cells become progressively more restricted along specific lineages, ultimately giving rise to the diversity of cell types in the adult mammalian organism. Recent years have seen major advances in our understanding of the mechanisms that regulate the underlying transcriptional programmes during development. In particular, there has been a significant increase in our knowledge of how epigenetic marks on chromatin can regulate transcription by generating more or less permissive chromatin conformations. This article focuses on how a single transcription factor, repressor element-1 silencing transcription factor, can function as both a transcriptional and epigenetic regulator, controlling diverse aspects of development. We will discuss how the elucidation of repressor element-1 silencing transcription factor function in both normal and disease conditions has provided valuable insights into how the epigenome and transcriptional regulators might cooperatively orchestrate correct development.

A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets

Proneural genes such as Ascl1 are known to promote cell cycle exit and neuronal differentiation when expressed in neural progenitor cells. The mechanisms by which proneural genes activate neurogenesis--and, in particular, the genes that they regulate--however, are mostly unknown. We performed a genome-wide characterization of the transcriptional targets of Ascl1 in the embryonic brain and in neural stem cell cultures by location analysis and expression profiling of embryos overexpressing or mutant for Ascl1. The wide range of molecular and cellular functions represented among these targets suggests that Ascl1 directly controls the specification of neural progenitors as well as the later steps of neuronal differentiation and neurite outgrowth. Surprisingly, Ascl1 also regulates the expression of a large number of genes involved in cell cycle progression, including canonical cell cycle regulators and oncogenic transcription factors. Mutational analysis in the embryonic brain and manipulation of Ascl1 activity in neural stem cell cultures revealed that Ascl1 is indeed required for normal proliferation of neural progenitors. This study identified a novel and unexpected activity of the proneural gene Ascl1, and revealed a direct molecular link between the phase of expansion of neural progenitors and the subsequent phases of cell cycle exit and neuronal differentiation.

Characterization and antimicrobial efficacy against E. coli of a helium/air plasma at atmospheric pressure created in a plastic package

A plasma source, sustained by the application of a floating high voltage (±15 kV) to parallel-plate electrodes at 50 Hz, has been achieved in a helium/air mixture at atmospheric pressure (P = 105 Pa) contained in a zip-locked plastic package placed in the electrode gap. Some of the physical and antimicrobial properties of this apparatus were established with a view to ascertain its performance as a prototype for the disinfection of fresh produce. The current–voltage (I–V) and charge–voltage (Q–V) characteristics of the system were measured as a function of gap distance d, in the range (3 × 103 ≤ Pd ≤ 1.0 × 104 Pa m). The electrical measurements showed this plasma source to exhibit the characteristic behaviour of a dielectric barrier discharge in the filamentary mode and its properties could be accurately interpreted by the two-capacitance in series model. The power consumed by the discharge and the reduced field strength were found to decrease quadratically from 12.0 W to 4.5 W and linearly from 140 Td to 50 Td, respectively, in the range studied. Emission spectra of the discharge were recorded on a relative intensity scale and the dominant spectral features could be assigned to strong vibrational bands in the 2+ and 1− systems of N2 and ${\rm N}_2^+$ , respectively, with other weak signatures from the NO and OH radicals and the N+, He and O atomic species. Absolute spectral intensities were also recorded and interpreted by comparison with the non-equilibrium synthetic spectra generated by the computer code SPECAIR. At an inter-electrode gap of 0.04 m, this comparison yielded typical values for the electron, vibrational and translational (gas) temperatures of (4980 ± 100) K, (2700 ± 200) K and (300 ± 100) K, respectively and an electron density of 1.0 × 1017 m−3. A Boltzmann plot also provided a value of (3200 ± 200 K) for the vibrational temperature. The antimicrobial efficacy was assessed by studying the resistance of both Escherichia coli K12 its isogenic mutants in soxR, soxS, oxyR, rpoS and dnaK selected to identify possible cellular responses and targets related with 5 min exposure to the active gas in proximity of, but not directly in, the path of the discharge filaments. Both the parent strain and mutants populations were significantly reduced by more than 1.5 log cycles in these conditions, showing the potential of the system. Post-treatment storage studies showed that some transcription regulators and specific genes related to oxidative stress play an important role in the E. coli repair mechanism and that plasma exposure affects specific cell regulator systems.

The regulation of seasonal flowering in the Rosaceae

Molecular mechanisms regulating the flowering process have been extensively studied in model annual plants; in perennials, however, understanding of the molecular mechanisms controlling flowering has just started to emerge. Here we review the current state of flowering research in perennial plants of the rose family (Rosaceae), which is one of the most economically important families of horticultural plants. Strawberry (Fragaria spp.), raspberry (Rubus spp.), rose (Rosa spp.), and apple (Malus spp.) are used to illustrate how photoperiod and temperature control seasonal flowering in rosaceous crops. We highlight recent molecular studies which have revealed homologues of TERMINAL FLOWER1 (TFL1) to be major regulators of both the juvenile to adult, and the vegetative to reproductive transitions in various rosaceous species. Additionally, recent advances in understanding of the regulation of TFL1 are discussed.

Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.

The Corporate Gini Index (CGI) determinants and advantages: lessons from a multinational retail company case study

This article identifies and compares the determinants of CEO compensation to median employee earnings with those of the Corporate Gini Index (CGI). Using a multinational retail company, the article posits that the CGI is an advantageous corporate alternative pay inequality measure that concerns CEO pay multiples to median employee earnings, which regulators should consider using and disclosing in proxy statements. Although CGI and the official measure of multiples of CEO pay to median employee earnings share some of the challenges, the advantages of CGI as an alternative measure are greater. Our findings suggest that the CGI is a much better measure of corporate income inequality bringing clear benefits at both micro and macro levels of intervention.

Paying for long-term performance: restructuring bankers’ pay for risk regulation

The purpose of this paper is to propose hybrid capital securities as a new approach to compensation for senior bank executives and risk-takers instead of cash or equity-based compensation currently adopted by the industry. The global financial turmoil indicated that misaligned pay-for-performance compensation arrangements encouraged management short-termism and rewarded excessive risk-taking behaviour in Anglo-Saxon system. Rather than regulating specific instruments and processes, we believe that it is much more efficient to overhaul the compensation scheme to align it with risk management and governance. This empirical paper investigates the European hybrid market by employing data from the Merrill Lynch Global Index System from 2000 to 2010. Our paper contributes to both literature and practices by designing a structured scheme to tie the executive’s interests to long-term performance of the bank, the goal of regulators and the economy at large which consequently reduce the probability of future bank failures.

Managing governance, risk and compliance for post-crisis regulatory change: a model of IS capabilities for financial organizations

The 2008-2009 financial crisis and related organizational and economic failures have meant that financial organizations are faced with a ‘tsunami’ of new regulatory obligations. This environment provides new managerial challenges as organizations are forced to engage in complex and costly remediation projects with short deadlines. Drawing from a longitudinal study conducted with nine financial institutions over twelve years, this paper identifies nine IS capabilities which underpin activities for managing regulatory themed governance, risk and compliance efforts. The research shows that many firms are now focused on meeting the Regulators’ deadlines at the expense of developing a strategic, enterprise-wide connected approach to compliance. Consequently, executives are in danger of implementing siloed compliance solutions within business functions. By evaluating the maturity of their IS capabilities which underpin regulatory adherence, managers have an opportunity to develop robust operational architectures and so are better positioned to face the challenges derived from shifting regulatory landscapes.

RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro

Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate. © 2015 Wiley Periodicals, Inc.

Expert consensus document: the International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic.

An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics. It is now 13 years since the definition of probiotics and 12 years after guidelines were published for regulators, scientists and industry by the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO). The FAO/WHO definition of a probiotic—“live microorganisms which when administered in adequate amounts confer a health benefit on the host”—was reinforced as relevant and sufficiently accommodating for current and anticipated applications. However, inconsistencies between the FAO/WHO Expert Consultation Report and the FAO/WHO Guidelines were clarified to take into account advances in science and applications. A more precise use of the term 'probiotic' will be useful to guide clinicians and consumers in differentiating the diverse products on the market. This document represents the conclusions of the ISAPP consensus meeting on the appropriate use and scope of the term probiotic.

Adding a treatment arm to an ongoing clinical trial: a review of methodology and practice

Incorporating an emerging therapy as a new randomisation arm in a clinical trial that is open to recruitment would be desirable to researchers, regulators and patients to ensure that the trial remains current, new treatments are evaluated as quickly as possible, and the time and cost for determining optimal therapies is minimised. It may take many years to run a clinical trial from concept to reporting within a rapidly changing drug development environment; hence, in order for trials to be most useful to inform policy and practice, it is advantageous for them to be able to adapt to emerging therapeutic developments. This paper reports a comprehensive literature review on methodologies for, and practical examples of, amending an ongoing clinical trial by adding a new treatment arm. Relevant methodological literature describing statistical considerations required when making this specific type of amendment is identified, and the key statistical concepts when planning the addition of a new treatment arm are extracted, assessed and summarised. For completeness, this includes an assessment of statistical recommendations within general adaptive design guidance documents. Examples of confirmatory ongoing trials designed within the frequentist framework that have added an arm in practice are reported; and the details of the amendment are reviewed. An assessment is made as to how well the relevant statistical considerations were addressed in practice, and the related implications. The literature review confirmed that there is currently no clear methodological guidance on this topic, but that guidance would be advantageous to help this efficient design amendment to be used more frequently and appropriately in practice. Eight confirmatory trials were identified to have added a treatment arm, suggesting that trials can benefit from this amendment and that it can be practically feasible; however, the trials were not always able to address the key statistical considerations, often leading to uninterpretable or invalid outcomes. If the statistical concepts identified within this review are considered and addressed during the design of a trial amendment, it is possible to effectively assess a new treatment arm within an ongoing trial without compromising the original trial outcomes.

Intensified impact of tropical Atlantic SST on the western North Pacific summer climate under a weakened Atlantic thermohaline circulation

The tropical North Atlantic (TNA) sea surface temperature (SST) has been identified as one of regulators on the boreal summer climate over the western North Pacific (WNP), in addition to SSTs in the tropical Pacific and Indian Oceans. The major physical process proposed is that the TNA warming induces a pair of cyclonic circulation anomaly over the eastern Pacific and negative precipitation anomalies over the eastern to central tropical Pacific, which in turn lead to an anticyclonic circulation anomaly over the western to central North Pacific. This study further demonstrates that the modulation of the TNA warming to the WNP summer climate anomaly tends to be intensified under background of the weakened Atlantic thermohaline circulation (THC) by using a water-hosing experiment. The results suggest that the weakened THC induces a decrease in thermocline depth over the TNA region, resulting in the enhanced sensitivity of SST variability to wind anomalies and thus intensification of the interannual variation of TNA SST. Under the weakened THC, the atmospheric responses to the TNA warming are westward shifted, enhancing the anticyclonic circulation and negative precipitation anomaly over the WNP. This study supports the recent finding that the negative phase of the Atlantic multidecadal oscillation after the late 1960s has been favourable for the strengthening of the connection between TNA SST variability and WNP summer climate and has important implications for seasonal prediction and future projection of the WNP summer climate.

Evolutionary rewiring of bacterial regulatory networks

Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks – homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. In our recent study [Taylor, et al. Science (2015), 347(6225)] we find that mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but that such mutations come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs.

The neurogenic potential of astrocytes is regulated by inflammatory signals

Although the adult brain contains neural stem cells (NSCs) that generate new neurons throughout life, these astrocyte-like populations are restricted to two discrete niches. Despite their terminally differentiated phenotype, adult parenchymal astrocytes can re-acquire NSC-like characteristics following injury, and as such, these 'reactive' astrocytes offer an alternative source of cells for central nervous system (CNS) repair following injury or disease. At present, the mechanisms that regulate the potential of different types of astrocytes are poorly understood. We used in vitro and ex vivo astrocytes to identify candidate pathways important for regulation of astrocyte potential. Using in vitro neural progenitor cell (NPC)-derived astrocytes, we found that exposure of more lineage-restricted astrocytes to either tumor necrosis factor alpha (TNF-α) (via nuclear factor-κB (NFκB)) or the bone morphogenetic protein (BMP) inhibitor, noggin, led to re-acquisition of NPC properties accompanied by transcriptomic and epigenetic changes consistent with a more neurogenic, NPC-like state. Comparative analyses of microarray data from in vitro-derived and ex vivo postnatal parenchymal astrocytes identified several common pathways and upstream regulators associated with inflammation (including transforming growth factor (TGF)-β1 and peroxisome proliferator-activated receptor gamma (PPARγ)) and cell cycle control (including TP53) as candidate regulators of astrocyte phenotype and potential. We propose that inflammatory signalling may control the normal, progressive restriction in potential of differentiating astrocytes as well as under reactive conditions and represent future targets for therapies to harness the latent neurogenic capacity of parenchymal astrocytes.

Training on the use of a bespoke continuing professional development framework improves the quality of CPD records

BACKGROUND: Using continuing professional development (CPD) as part of the revalidation of pharmacy professionals has been proposed in the UK but not implemented. We developed a CPD Outcomes Framework (‘the framework’) for scoring CPD records, where the score range was -100 to +150 based on demonstrable relevance and impact of the CPD on practice. OBJECTIVE: This exploratory study aimed to test the outcome of training people to use the framework, through distance-learning material (active intervention), by comparing CPD scores before and after training. SETTING: Pharmacy professionals were recruited in the UK in Reading, Banbury, Southampton, Kingston-upon-Thames and Guildford in 2009. METHOD: We conducted a randomised, double-blinded, parallel-group, before and after study. The control group simply received information on new CPD requirements through the post; the active intervention group also received the framework and associated training. Altogether 48 participants (25 control, 23 active) completed the study. All participants submitted CPD records to the research team before and after receiving the posted resources. The records (n=226) were scored blindly by the researchers using the framework. A subgroup of CPD records (n=96) submitted first (before-stage) and rewritten (after-stage) were analysed separately. MAIN OUTCOME MEASURE: Scores for CPD records received before and after distributing group-dependent material through the post. RESULTS: Using a linear-regression model both analyses found an increase in CPD scores in favour of the active intervention group. For the complete set of records, the effect was a mean difference of 9.9 (95% CI = 0.4 to 19.3), p-value = 0.04. For the subgroup of rewritten records, the effect was a mean difference of 17.3 (95% CI = 5.6 to 28.9), p-value = 0.0048. CONCLUSION: The intervention improved participants’ CPD behaviour. Training pharmacy professionals to use the framework resulted in better CPD activities and CPD records, potentially helpful for revalidation of pharmacy professionals. IMPACT: • Using a bespoke Continuing Professional Development outcomes framework improves the value of pharmacy professionals’ CPD activities and CPD records, with the potential to improve patient care. • The CPD outcomes framework could be helpful to pharmacy professionals internationally who want to improve the quality of their CPD activities and CPD records. • Regulators and officials across Europe and beyond can assess the suitability of the CPD outcomes framework for use in pharmacy CPD and revalidation in their own setting.